Background The host-response to bacterial infection is highly heterogeneous; there is therefore a need for stratified treatment strategies instead of the traditional ‘one-size-fits-all’ approach. A precision medicine approach can improve patient outcomes by identifying endotypes in whom an intervention is likely to be beneficial, harmful or ineffective. Aim/objective To embed, within the Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection trial, a mechanistic sub-study to determine endotypes of endothelial dysfunction using mid-regional proadrenomedullin and based on host immune response biomarkers tumour necrosis factor-related apoptosis-inducing ligand, interferon gamma-induced protein 10 and C-reactive protein in whom a procalcitonin-guided antibiotic algorithm might be (a) particularly beneficial, (b) ineffective, or (c) harmful. To determine, within the Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection trial, if there were specific sub-groups of patients (based on host response and organ dysfunction) in whom the addition of procalcitonin testing to current best practice based on the National Institute for Health and Care Excellence antimicrobial stewardship guidelines could safely allow a reduction in duration of antibiotic therapy in hospitalised children with suspected or confirmed bacterial infection compared to current best practice alone. Design Mechanism of action study embedded into the Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection randomised controlled trial. Setting Paediatric wards or paediatric intensive care units within children’s hospitals (n = 4) in the United Kingdom. Participants Children recruited into the Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection trial aged between 72 hours and 18 years old admitted to hospital, and being treated with intravenous antibiotics for suspected or confirmed bacterial infection. Recruitment to the sub-study occurred between December 2020 and October 2022. Intervention Procalcitonin-guided algorithm versus usual standard care alone. Main outcome measures Time from starting to stopping intravenous antibiotic therapy was the primary (time-to-event) end point. Baseline mid-regional proadrenomedullin and host immune response biomarkers (tumour necrosis factor-related apoptosis-inducing ligand, interferon gamma-induced protein 10 and C-reactive protein) defined subgroups for the primary comparison, and serial measurements for additional analyses. Results The primary analysis data set included 305 patients (n = 235 in procalcitonin arm; n = 70 in usual care arm). Median age was 3.7 years, 42.3% (129/305) were female, 94.1% (287/305) were White, and 48.7% (147/302) had at least one comorbidity. Unadjusted p-values suggested potential interaction effects between Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection procalcitonin arm and C-reactive protein on antibiotic duration (intravenous, total, broad-spectrum), indicating a tendency for antibiotic durations to be shorter in the procalcitonin arm than in the usual care arm when baseline C-reactive protein is high, and vice versa when baseline C-reactive protein is low. However, after adjustment for multiple testing none of these effects remained statistically significant at the 5% level. For the other biomarkers at baseline (tumour necrosis factor-related apoptosis-inducing ligand, interferon gamma-induced protein 10 and mid-regional proadrenomedullin) and outcomes (time to discharge from hospital), there was no interaction. Limitations The study recruited from only four National Health Service sites in England; laboratory analyses were not reproducible and C-reactive protein values did not correlate well with National Health Service laboratory values. Conclusions This research does not support stratification by baseline mid-regional proadrenomedullin and host immune response biomarkers (tumour necrosis factor-related apoptosis-inducing ligand and interferon gamma-induced protein 10) to identify patients who will benefit from a procalcitonin-guided antibiotic algorithm, although stratification by baseline C-reactive protein may identify patients who will benefit from a procalcitonin-guided antibiotic algorithm. Future work Further studies of embedding host immune response stratification within randomised controlled trials in larger numbers of patients are needed. Study registration This study is registered as Current Controlled Trials ISRCTN14945050 (Registered 17 December 2020). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (NIHR award ref: NIHR129960) and is published in full in Efficacy and Mechanism Evaluation; Vol. 13, No. 4. See the NIHR Funding and Awards website for further award information. Plain language summary The Department of Health recommends that antibiotics should be given for as short a course as is safe, to prevent antimicrobial resistance. Most hospitals in the National Health Service use a blood test called C-reactive protein to monitor the body’s response to infection, but this test is not specific for bacterial infection and shows a delayed response to infection. An alternative test is a procalcitonin test which is specific for bacterial infection and responds more quickly than C-reactive protein but is not routinely used in the National Health Service. The Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection trial looked at procalcitonin testing to see if it could guide how long to give intravenous antibiotics (into a vein) used to treat infection for and help identify how children and young people (aged from 72 hours to 18 years) respond to antibiotics. In the PRECISE study, four other blood markers were looked at, which measure the body’s response to infection and organ dysfunction, to see if they could provide additional information to help identify groups of children who may benefit, be harmed or have no difference, when procalcitonin testing to guide antibiotic use is used. To do this, additional samples of a small amount of blood (0.5–1 ml) were collected from the children and young people recruited into the Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection trial. The samples were sent to a laboratory at the University of Liverpool for analysis. The PRECISE study found that using these additional blood markers did not help to decide which children might benefit from the procalcitonin test to guide antibiotic stopping. Scientific summary Background The host-response to bacterial infection is highly heterogeneous; there is therefore a need for stratified treatment strategies instead of the traditional ‘one-size-fits-all’ approach. A precision medicine approach can improve patient outcomes by identifying endotypes in whom the intervention is likely to be beneficial, harmful or ineffective. Within the NIHR Health Technology Assessment-funded Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection (BATCH) trial, an embedded mechanistic sub-study was included to determine endotypes of endothelial dysfunction [mid-regional proadrenomedullin (MR-proADM)] and host immune response biomarkers tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein 10 (IP-10) and C-reactive protein (CRP) in whom a procalcitonin (PCT)-guided antibiotic algorithm might be (a) particularly beneficial, (b) ineffective or (c) harmful. Research question In children hospitalised with suspected or confirmed bacterial infection, do endothelial dysfunction and a likely viral host immune response profile (as indicated by biomarkers) diminish the effectiveness of a PCT-guided antibiotic algorithm in reducing intravenous (IV) antibiotic duration, compared to usual care? Hypothesis In children (aged from 72 hours to 18 years) treated with IV antibiotics for suspected or confirmed bacterial infection, (a) persistent endothelial dysfunction will be associated with increased duration of IV antibiotics and a PCT-guided antibiotic algorithm may be harmful, and (b) a likely viral or other host immune response will be associated with reduced duration of IV antibiotics and a PCT-guided antibiotic algorithm may be ineffective. The aim of the PRECISE study [embedded within the BATCH randomised controlled trial (RCT)] was to determine if there are specific sub-groups of patients for whom a PCT-guided antibiotic algorithm may be beneficial, harmful, or ineffective. Outcomes Primary outcome measures Time from starting to stopping IV antibiotic therapy was the primary (time-to-event) end point, same as in the BATCH trial. Baseline MR-proADM and host–response protein (TRAIL, IP-10 and CRP) concentrations defined subgroups for the primary comparison. Secondary outcome measures Total duration of antibiotics (oral and IV), time from starting broad spectrum to switching to narrow spectrum antibiotics, time from admission to discharge from hospital, suspected adverse drug reactions, hospital acquired infection up to day 28. Methods Design Embedded mechanism of action study (n = 266) within a multi-centre, prospective, individually randomised, open-label two-arm RCT comparing a PCT-guided antibiotic algorithm versus usual care. Recruitment to the host (BATCH) trial commenced in June 2018; recruitment for the PRECISE study commenced in December 2020. Participants Children aged 72 hours up to < 18 years hospitalised with suspected or confirmed bacterial infection recruited into the BATCH trial. Results The primary analysis data set included 305 patients, 235 of which were randomised in the BATCH PCT arm and 70 in the BATCH usual care arm. Their median age was 3.7 years, 42.3% (129/305) were female, 94.1% (287/305) were White and 48.7% (147/302) had at least one comorbidity. For baseline CRP measured in the central research laboratory on the MSD multiplex immunoassay, unadjusted p-values suggested potential interaction effects between BATCH intervention arm and baseline CRP on antibiotic duration (IV, total, broad-spectrum), indicating a tendency for antibiotic durations to be shorter in the PCT arm than in the usual care arm when baseline CRP is high, and vice versa when baseline CRP is low. However, after correction for multiple testing none of these effects remained statistically significant at the 5% level. For the other biomarkers at baseline (TRAIL, IP-10, MR-proADM) and outcomes (time to discharge from hospital), there was no interaction. For baseline CRP values measured as part of routine care using different NHS laboratory analysers at each recruitment site, the interaction was significant only for CRP > 25 mg/l for broad-spectrum antibiotic duration, but again did not remain significant following multiplicity correction. The correlation between NHS laboratory measured CRP values and CRP values analysed centrally in the research laboratory using MSD multiplex immunoassay was weak. This may explain why the previously observed interaction was not replicable and suggests that combining CRP values from several different laboratory analysers might not be robust. Conclusions This research does not support stratification by MR-proADM and host immune response biomarkers at baseline TRAIL and IP-10 to identify patients who will benefit from a PCT-guided antibiotic algorithm, although stratification by baseline CRP may identify patients who will benefit from a PCT-guided antibiotic algorithm. Study registration This study is registered as Current Controlled Trials ISRCTN14945050. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (NIHR award ref: NIHR129960) and is published in full in Efficacy and Mechanism Evaluation; Vol. 13, No. 4. See the NIHR Funding and Awards website for further award information.
Background Immunoglobulin E-mediated (immediate) cow’s milk allergy is one of the most frequent food allergies in infants, with a significant adverse impact on quality of life. There is no satisfactory treatment for cow’s milk allergy, and guidelines recommend milk avoidance, feeding with ‘hypoallergenic’ formulas (extensively hydrolysed formulas), emergency management of accidental reactions and waiting for the allergy to resolve spontaneously. Currently, the only potentially curative regimen is oral immunotherapy, that is, exposing patients to increasing doses of cow’s milk using a strictly controlled dose schedule. However, milk immunotherapy is not used in clinical practice due to risk of reactions. DREAM’s intention was to explore whether oral immunotherapy with a partially hydrolysed cow’s milk formula would be able to provide a safe and effective means of oral immunotherapy for milk-allergic infants. Limitations The trial was affected by a serious breach that led most of the participants to receive partially hydrolysed formula, even if randomised to extensively hydrolysed formula. It also ended prematurely due to unsatisfactory recruitment, and the main outcomes were not reached. Methods DREAM was a two-arm, parallel-group, double-blind randomised controlled trial. Eligible patients were infants aged 6–12 months with convincing medical history of immunoglobulin E-mediated allergy to cow’s milk formula. Inclusion criteria included a titre of cow’s milk-specific immunoglobulin E equal or higher to 2 kU/l, or wheal equal or over 5 mm to skin prick test to milk. Additionally, for the infants to be randomised, they needed to have a positive result to an open oral challenge either to partially hydrolysed formula or to milk. Participants were randomised to extensively hydrolysed formula or partially hydrolysed formula with a 1 : 1 ratio. Following randomisation, participants commenced free-feeding with the blinded product (or strict dose-based oral immunotherapy if they were not tolerant of the blinded product). The main outcome was the result of a double-blind, placebo-controlled food challenge to cow’s milk at the end of 1 year of free-feeding (or of dose-based immunotherapy) to establish if infants had become tolerant. As the trial was discontinued early on account of poor recruitment, no infant progressed to the double-blind, placebo-controlled food challenge. Results Out of 16 randomised participants who underwent an initial partially hydrolysed formula challenge, only 1 (6.25%) reacted to it (95% confidence interval 00.0 to 19.6). Hence, 93.75% of the allergic infants randomised in the trial tolerated partially hydrolysed formula. All fifteen infants that were found to be partially hydrolysed formula-tolerant also received partially hydrolysed formula free-feeding at home, on account of the serious breach. As per the trial’s criteria, these infants (and all randomised participants) were shown to be allergic to cow’s milk via either a positive open challenge to it (for the 15 partially hydrolysed formula-tolerant infants) or a positive open challenge to partially hydrolysed formula (for the single partially hydrolysed formula-reactive infant). Conclusions Partially hydrolysed formula was tolerated by the majority of well-characterised and confirmed cow’s milk-allergic infants in the DREAM trial. Future work Our findings demonstrate that partially hydrolysed formula holds promise as a potential oral immunotherapy medium in free-feeding oral immunotherapy regimens in future research. Further trials designed on the premise of partially hydrolysed formula oral immunotherapy are needed. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme as award number 17/60/44. Plain language summary Cow’s milk allergy is one of the most frequent food allergies in infants. There is no known cure for cow’s milk allergy, and allergic infants need to avoid cow’s milk, feed with ‘hypoallergenic’ formulas (if not solely breastfeeding) and wait for the allergy to go away on its own. The only potentially helpful management is oral immunotherapy, where some infants eat very low regular doses of milk under close doctor follow-up. However, immunotherapy is risky, and many reactions can happen; therefore, it is not normally advised to patients. DREAM was designed to show whether using a particular formula (partially hydrolysed cow’s milk formula) would be safe for immunotherapy. Milk-allergic infants aged 6–12 months were recruited and started to be fed on either extensively hydrolysed formula (safe formula used normally for allergic infants) or partially hydrolysed formula. These infants could also be breastfed, if their mother wanted to. The mother’s diet was not changed. After a year of feeding, also including several visits at the hospital, infants would be given cow’s milk at the hospital to see if they have managed to tolerate cow’s milk after having these formulas for a whole year. Unfortunately, the trial was stopped early due to not managing to recruit as many infants as needed, and therefore no infant reached the end of the trial. Out of 16 infants which did enter the trial, 15 (close to 94% of all infants) were able to have partially hydrolysed formula with no major problems. These infants were shown through the trial’s tests to be very allergic to cow’s milk; therefore, being able to have partially hydrolysed formula with little problem is very important. The trial managed to show that partially hydrolysed formula is promising for future immunotherapy management, because many milk-allergic infants were able to feed on it. More research is needed to show if this formula can be used in the future to help infants grow out of their allergy.
Background Small bowel Crohn’s disease is increasingly treated with biological therapies. Although many patients do not achieve response or remission, this is unpredictable. Motility magnetic resonance imaging reliably measures Crohn’s disease inflammation, but its predictive ability for longer-term response to biologic therapies is unknown. Objectives Primary: to determine if motility magnetic resonance imaging at weeks 12–30 is superior to C-reactive protein for the prediction of response or remission at 1 year in patients commencing biologics for small bowel Crohn’s disease. Secondary: to determine if motility magnetic resonance imaging changes can predict patient quality of life at 1 year; to determine if diffusion-weighted magnetic resonance imaging is predictive of response or remission; to compare the predictive ability of motility magnetic resonance imaging with that of faecal calprotectin; to investigate the effect of body composition on response or remission; to determine the relationship between plasma gut peptide and cytokine levels, patient symptoms and bowel dysmotility. Design and methods Prospective multicentre cohort study. Setting and participants Thirteen National Health Service hospitals with established inflammatory bowel disease and magnetic resonance imaging practices. Participants with active non-stricturing small bowel Crohn’s disease requiring biological therapy. Interventions Motility magnetic resonance imaging (test under evaluation) and C-reactive protein (comparator). Faecal calprotectin as secondary comparator. Diffusion-weighted magnetic resonance imaging and plasma gut peptide/cytokine level measurement in a subset. Main outcome measures Comparative accuracy of motility magnetic resonance imaging, C-reactive protein and faecal calprotectin to predict response or remission at 1 year, defined using a combination of clinical factors and structural magnetic resonance enterography scores, and measures of quality of life at 1 year, using EuroQol-5 Dimensions, five-level version and disease-specific patient-reported outcome measures. Motility magnetic resonance imaging interobserver variability. Post hoc confirmatory analysis of motility magnetic resonance imaging correlation with magnetic resonance enterography-defined disease activity. Results Two hundred and nineteen participants were screened, of whom 199 were treated. Ninety-three participants were excluded prior to their first visit, with a further 20 lost to follow-up subsequently. Eighty-six participants completed all assessments. Stable or improved motility magnetic resonance imaging post induction was more sensitive than normalisation of C-reactive protein for 1-year response or remission (motility magnetic resonance imaging: 71.0%, 95% confidence interval 52.0 to 85.8; C-reactive protein: 45.2%, 95% confidence interval 27.3% to 64.0%; p = 0.008) but less specific (motility magnetic resonance imaging: 30.9%, 95% confidence interval 19.1 to 44.8; C-reactive protein: 67.3%, 95% confidence interval 53.3% to 79.3%; p < 0.001). There was no significant difference in area under the receiver operating characteristic curve (motility magnetic resonance imaging: 0.48; C-reactive protein: 0.53, p = 0.65). Similar results were obtained for faecal calprotectin. None of motility magnetic resonance imaging, C-reactive protein or faecal calprotectin predicted patient quality of life at 1 year. Diffusion-weighted magnetic resonance imaging was also not predictive of response or remission. Interobserver variability of motility magnetic resonance imaging quantified by intraclass correlation coefficients was 0.75–0.83. We confirmed prior work that motility magnetic resonance imaging is negatively correlated with small bowel Crohn’s disease activity (correlation coefficient [rho]= −0.34). Baseline magnetic resonance imaging-measured body composition was not associated with 1-year response or remission. Patient symptoms, gut peptide and cytokine levels and overall small bowel dysmotility were not consistently correlated. Limitations Loss to follow-up was high, mainly due to the coronavirus disease discovered in 2019 (COVID-19) pandemic. Response assessment using ileocolonoscopy was not possible. Conclusions Although improved motility magnetic resonance imaging is more sensitive than C-reactive protein and faecal calprotectin to predict response or remission at 1 year, it is less specific. None of these factors predict patient quality of life. Motility magnetic resonance imaging measurements are reliable between readers, and it remains a marker of disease activity at a given time point. Future work Impact of motility magnetic resonance imaging on therapeutic management decisions and clinician confidence in Crohn’s disease. Utility of motility magnetic resonance imaging in phenotyping stricturing Crohn’s disease. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme as award number 14/201/16. Plain language summary Crohn’s disease is a condition that causes inflammation of the bowels, and this inflammation can eventually lead to irreversible bowel damage. Powerful treatments that suppress inflammation called biologic drugs are now available, but it is not possible to give these to all patients because of side effects, costs and patient inconvenience. Also, they do not always work, but we cannot predict this reliably. In this study, we tested if a novel scanning technique using magnetic resonance imaging that measures bowel motion (called motility magnetic resonance imaging) can help predict which patients are likely to benefit in the longer term from these biologic drugs. The study recruited 86 patients from 13 National Health Service centres, all of whom had motility magnetic resonance imaging before and after starting their biologic treatment. After 1 year, we checked to see if the biologics had worked for each patient. We tested how good motility magnetic resonance imaging was at predicting whether or not the biologics were going to work, and compared this with other simple blood and faeces tests. We also tested some other magnetic resonance imaging techniques called diffusion-weighted imaging and body composition measurements. We found that none of the tests (motility magnetic resonance imaging, blood tests or faeces tests) were better than chance at predicting if biologics were going to work or not. Diffusion-weighted imaging and body composition measurements were not useful either. We did confirm some previous work that motility magnetic resonance imaging is good at telling us if the bowel is inflamed or not, and we also found that many different doctors (not just experts) can measure it reliably. The study means that motility magnetic resonance imaging and diffusion-weighted imaging are not useful ways to predict which patients are likely to benefit from biologic drugs. It can still be used to measure if the bowel is inflamed or not.
Background It is estimated that around 5% of people with asthma have severe asthma. Severe asthma typically presents with poor symptom control, impaired lung function and asthma exacerbations, despite regular inhaled steroids and additional controller medications. In the BEyond Allergic Th2-Severe Asthma clinical trials programme, we worked with severe asthma specialist centres in the United Kingdom to identify patients who experienced frequent asthma attacks (two or more per year), who were potentially eligible for stratified asthma treatments. Objectives There are currently two recognised subtypes of severe asthma which can be characterised by their level of eosinophils (a type of white blood cells). In the BEyond Allergic Th2-Severe Asthma clinical trial programme, we aimed to test whether a simple, once-daily oral antibiotic (doxycycline) can reduce asthma attacks in individuals with lower levels of eosinophils in peripheral blood (T2-Low arm: < 300 cells/µl). We also aimed to test whether a simple twice-daily oral drug (dexpramipexole) can reduce asthma attacks in individuals with high levels of eosinophils in peripheral blood (T2-High arm : ≥ 300 cells/µl). The trial was established using a master protocol and platform trial design with study protocols for the T2-High and T2-Low cohorts. Study outcomes The trial platform was successfully set up during the COVID-19 pandemic and opened across 13 sites in the United Kingdom for recruitment between August 2021 and September 2022, following a 12-month trial pause due to the pandemic. Several changes to the trial protocol were made to make the protocol easier to deliver due to pandemic restrictions. Due to capacity issues at National Health Service trusts in the United Kingdom following the pandemic, the trial was delayed in opening sites by approximately 4 months. Shortly after all sites were opened, a decision was made with the Trial Steering Committee and funders to close the dexpramipexole (T2-High) arm of the trial (October 2022), as the drug had moved on to definitive and confirmatory phase III trials. Recruitment into the doxycycline trial progressed slowly, largely in part due to challenges in finding people with asthma who had the required number of asthma attacks to be eligible, as attack rates in the United Kingdom fell during the pandemic. Furthermore, the trial was recruiting exclusively from severe asthma centres in the United Kingdom and did not have the funding required to change the recruitment model to include screening within primary care also. As a result of these factors, a decision was made by the sponsor of the trial to close the trial (April 2023), in line with National Institute for Health and Care Research post pandemic reset policy. Limitations and future work While no scientific conclusions can be drawn from this trial, following the pandemic a formal review of commercial clinical trials was commissioned by the government (Lord O’Shaughnessy review), with several recommendations to enhance clinical trial delivery in the United Kingdom. Many of the recommendations are applicable to non-commercial asthma trials. Furthermore, pivotal phase III trials of dexpramipexole are currently well underway. We would advocate the development of a Respiratory Clinical Trials Accelerator Platform for airways disease trials in the United Kingdom to support academic trials. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme as award number 16/71/05. Plain language summary What did we want to improve? It is estimated that around 5% of people with asthma have severe asthma. This typically presents as a high number of symptoms and poor lung function, despite regular medications, and repeated asthma attacks frequently, requiring time off work and hospital admission. What did we do? We aimed to test whether a simple, once-daily oral antibiotic (doxycycline) can reduce asthma attacks in individuals with low levels of eosinophils. We also tested whether a simple, twice-daily oral drug (dexpramipexole) can reduce asthma attacks in individuals with high levels of eosinophils. Overall, we aimed to identify the right patients based upon a blood test, looking at a specific immune cell type (blood eosinophils), to give the right drugs with severe asthma. What did we find? Due to the COVID-19 pandemic, we had to pause the trial setup, and once we restarted the trial, there were major challenges in recruiting people with asthma to the trial. The recruitment challenges were mainly due to the impact of the pandemic on being able to find people with asthma that had the required number of documented asthma attacks in the year before entering the trial. One of the treatments, dexpramipexole, moved on to definitive global trials early in the trial course, which meant that we did not need to test it further. For these reasons, the trials group, in consultation with the sponsor and funder, decided to close the trial early. All patients enrolled into the trial were notified of trial closure and the reasons for this. What does this mean? Due to the small number of patients included and incomplete follow-up, no definitive conclusions could be made from this trial. However, dexpramipexole is currently being evaluated in definitive global clinical trials.
Parts of this abstract have been reproduced from Flohr C, Rosala-Hallas A, Jones AP, Beattie P, Baron S, Browne F, et al.; TREAT Trial Investigators. Efficacy and safety of ciclosporin versus methotrexate in the treatment of severe atopic dermatitis in children and young people (TREAT): a multicentre parallel-group assessor-blinded clinical trial. Br J Dermatol 2023;189:674–84. https://doi.org/10.1093/bjd/ljad281. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) licence, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text. Background Atopic dermatitis is a chronic, inflammatory skin disease characterised by intensely itchy skin. Atopic dermatitis has the highest disease burden among cutaneous diseases as measured by disability-adjusted life-years and approximately 20% of United Kingdom children experience atopic dermatitis, of whom 16% have moderate or severe forms. Treatment options for severe childhood atopic dermatitis are limited, and this is compounded by the lack of widely available information regarding short- and long-term side effects and cost-effectiveness of different treatments. Ciclosporin is the most commonly used systemic treatment for severe paediatric atopic dermatitis, but methotrexate is being increasingly used as an alternative first-line systemic treatment. Although these medications are regularly used off-licence in children with severe atopic dermatitis, there had been no firm evidence about the effectiveness, safety, cost-effectiveness, or impact on quality of life from an adequately powered randomised controlled trial using systemic medication in children. Design and methods The TREatment of severe Atopic dermatitis Trial addressed this gap, assessing potential differences in the speed of onset, effectiveness, side-effect profiles and reduction in flares post treatment between ciclosporin and methotrexate, and the cost-effectiveness of the drugs. Treatment impact on quality of life was also examined in addition to whether filaggrin genotype influences treatment response. Furthermore, the trial studied the immunological effects of ciclosporin and methotrexate. TREatment of severe Atopic dermatitis Trial was a multicentre, parallel-group, assessor-blind randomised controlled trial of 15 months duration (9-month treatment phase, 6-month follow-up period). In total, 103 children aged 2–16 years with moderate to severe atopic dermatitis, unresponsive to topical treatment were randomised (1 : 1) to receive methotrexate (0.4 mg/kg/week) or ciclosporin (4 mg/kg/day). Objectives The trial had two primary outcomes: change from baseline to 12 weeks in Objective Severity Scoring of Atopic Dermatitis and time to first significant flare following treatment cessation. Results The TREatment of severe Atopic dermatitis Trial found that ciclosporin had a faster onset of results compared to methotrexate up until approximately 20 weeks on treatment, with a mean difference in change between baseline and 12 weeks of −5.69 (97.5% CI −10.81 to −0.57, p = 0.013). Following this time point, methotrexate became more effective up to the end of treatment and showed better longer-term disease control; however, there was no statistically significant difference between treatment groups in the time to first significant flare after treatment cessation (log-rank test p = 0.15; HR = 1.55; 97.5% CI 0.77 to 3.10, p = 0.16). These results were supported by the immunological readouts measured during the study, suggesting the methotrexate-driven strengthening of the skin barrier. The data also suggest no significant benefit for increased kidney monitoring to detect renal dysfunction. A reduced need for renal monitoring would reduce both financial and carbon costs of care for patients moving forward. Limitations The primary limitations for this project include missing data from patient diaries, a small sample size for a randomised controlled trial comparing two active treatments, and a lack of hepatotoxicity marker collection. Conclusions The results of the TREatment of severe Atopic dermatitis Trial have changed the treatment paradigm for the use of conventional systemic medication, favouring methotrexate, especially because the health economics analysis found that methotrexate is more cost-effective than ciclosporin. The findings of the TREatment of severe Atopic dermatitis Trial have been incorporated into updates of international treatment guidelines for atopic dermatitis. Future work Looking forward, it would be clinically useful to conduct longer-term, real-world studies to determine the optimal duration of methotrexate treatment for atopic dermatitis. It will also be useful to take advantage of atopic dermatitis registers for future research – these provide a wealth of real-world data that can be harnessed for clinical knowledge. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme as award number 13/50/12. Plain language summary Atopic dermatitis, also known as ‘eczema’, is a skin disease that presents with itchiness and inflammation (redness, skin dryness, flaking, and thickening). About one-fifth of United Kingdom children have atopic dermatitis and 16% of those children have moderate or severe disease. There are few treatment options available for children with severe atopic dermatitis, and there is a lack of information about the short- and long-term effectiveness of the available medications. The main option for systemic treatment (drug therapies that work throughout the whole body) is ciclosporin, but a medication called methotrexate is being increasingly used. Even though many clinicians prescribe these medications, there was not much information available about the effectiveness, safety, or overall costs. The TREatment of severe Atopic dermatitis Trial compared the effectiveness, cost, and safety of ciclosporin and methotrexate in children with severe atopic dermatitis. TREatment of severe Atopic dermatitis Trial was a randomised control trial (children are randomly assigned to take either ciclosporin or methotrexate) where patients took one medication for 9 months and we watched their disease for 6 months after the end of treatment. One hundred and three children, between the ages of 2 and 16, were in our trial. The two main goals of TREatment of severe Atopic dermatitis Trial were to assess changes in disease severity and the amount of time it took for disease to come back after stopping medication. We found that ciclosporin worked faster than methotrexate up until around 20 weeks on treatment. After this, methotrexate became more effective up to the end of treatment. There was also reduced disease activity after treatment was stopped in the methotrexate group, compared to ciclosporin. This was supported by the immunological readouts, which suggested a strengthening of the skin barrier. The results have changed the treatment model for use of conventional systemic medication, favouring methotrexate, also because we found that the medication is more cost-effective. The trial is registered ISRCTN15837754 (registered 9 March 2016).
This article consists of a citation of a published article describing research funded by the Efficacy and Mechanism Evaluation programme under project number NIHR134607, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1136/bmjopen-2022-062599 It is unknown if a temporary break in long-term immune-suppressive treatment after vaccination against COVID-19 improves vaccine response. The objective of this study was to evaluate if a 2-week interruption in low-dose weekly methotrexate treatment after SARS-CoV-2 vaccine boosters enhances the immune response compared with continuing treatment in adults with autoimmune inflammatory conditions. An open-label, pragmatic, prospective, parallel group, randomised controlled superiority trial with internal feasibility assessment and nested mechanistic substudy will be conducted in rheumatology and dermatology clinics in approximately 25 UK hospitals. The sample size is 560, randomised 1:1 to intervention and usual care arms. The main outcome measure is anti-spike receptor-binding domain (RBD) antibody level, collected at prebooster (baseline), 4 weeks (primary outcome) and 12 weeks (secondary outcome) post booster vaccination. Other secondary outcome measures are patient global assessments of disease activity, disease flares and their treatment, EuroQol 5- dimention 5-level (EQ-5D-5L), self-reported adherence with advice to interrupt or continue methotrexate, neutralising antibody titre against SARS-CoV-2 (mechanistic substudy) and oral methotrexate biochemical adherence (mechanistic substudy). Analysis of B-cell memory and T-cell responses at baseline and weeks 4 and 12 will be investigated subject to obtaining additional funding. The principal analysis will be performed on the groups as randomised (ie, intention to treat). The difference between the study arms in anti-spike RBD antibody level will be estimated using mixed effects model, allowing for repeated measures clustered within participants. The models will be adjusted for randomisation factors and prior SARS-CoV-2 infection status. This study was approved by the Leeds West Research Ethics Committee and Health Research Authority (REC reference: 21/HRA/3483, IRAS 303827). Participants will be required to give written informed consent before taking part in the trial. Dissemination will be via peer review publications, newsletters and conferences. Results will be communicated to policymakers. ISRCTN11442263. This publication was funded by the Efficacy and Mechanism Evaluation programme as a part of award number NIHR134607. This article reports on one component of the research award Vaccine Response On/Off Methotrexate (VROOM): does temporarily suspending methotrexate treatment for two weeks enhance COVID-19 vaccine response? A randomised controlled trial. For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/NIHR134607] https://doi.org/10.1136/bmjopen-2022-062599
This article consists of a citation of a published article describing research funded by the Efficacy and Mechanism Evaluation programme under project number NIHR134607, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1016/S2213-2600(22)00186-2 Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early. Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the continue methotrexate group and 127 in the suspend methotrexate group. Their mean age was 59·1 years, 155 (61%) were female, 130 (51%) had rheumatoid arthritis, and 86 (34%) had psoriasis with or without arthritis. After 4 weeks, the geometric mean S1-RBD antibody titre was 22 750 U/mL (95% CI 19 314-26 796) in the suspend methotrexate group and 10 798 U/mL (8970-12 997) in the continue methotrexate group, with a geometric mean ratio (GMR) of 2·19 (95% CI 1·57-3·04; p<0·0001; mixed-effects model). The increased antibody response in the suspend methotrexate group was consistent across methotrexate dose, administration route, type of immune-mediated inflammatory disease, age, primary vaccination platform, and history of SARS-CoV-2 infection. There were no intervention-related serious adverse events. A 2-week interruption of methotrexate treatment for people with immune-mediated inflammatory diseases resulted in enhanced boosting of antibody responses after COVID-19 vaccination. This intervention is simple, low-cost, and easy to implement, and could potentially translate to increased vaccine efficacy and duration of protection for susceptible groups. National Institute for Health and Care Research. This publication was funded by the Efficacy and Mechanism Evaluation programme as a part of award number NIHR134607. This article reports on one component of the research award Vaccine Response On/Off Methotrexate (VROOM): does temporarily suspending methotrexate treatment for two weeks enhance COVID-19 vaccine response? A randomised controlled trial. For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/NIHR134607] https://doi.org/10.1016/S2213-2600(22)00186-2
This article consists of a citation of a published article describing research funded by the Efficacy and Mechanism Evaluation programme under project number NIHR134607, and is provided as as part of the complete record of research outputs for this project. The original publication is available at: https://doi.org/10.1016/S2665-9913(23)00298-9 Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early. Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227-29 056) in the suspend methotrexate group and 12 326 U/mL (10 538-14 418) in the continue methotrexate group with a geometric mean ratio (GMR) of 2·08 (95% CI 1·59-2·70; p<0·0001). No intervention-related serious adverse events occurred. 2-week interruption of methotrexate treatment in people with immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 booster vaccination that were sustained at 12 weeks and 26 weeks. There was a temporary increase in inflammatory disease flares, mostly self-managed. The choice to suspend methotrexate should be individualised based on disease status and vulnerability to severe outcomes from COVID-19. National Institute for Health and Care Research. This publication was funded by the Efficacy and Mechanism Evaluation programme as a part of award number NIHR134607. This article reports on one component of the research award Vaccine Response On/Off Methotrexate (VROOM): does temporarily suspending methotrexate treatment for two weeks enhance COVID-19 vaccine response? A randomised controlled trial. For more information about this research please view the award page [https://fundingawards.nihr.ac.uk/award/NIHR134607] https://doi.org/10.1016/S2665-9913(23)00298-9
Non-contrast computed tomography has low sensitivity to brain ischaemia. Higher sensitivity of computed tomography perfusion and computed tomography angiography may identify more thrombolysis-eligible patients, but the role of these imaging modalities in thrombolysis treatment decisions within 4.5 hours is unclear. We hypothesised that multimodal computed tomography (non-contrast computed tomography + computed tomography angiography + computed tomography perfusion) would modify treatment decisions with net increase in thrombolysis rates. Prospective, randomised controlled clinical trial. Hospital acute stroke services. Adults with clinically suspected acute ischaemic stroke eligible for intravenous thrombolytic therapy. 1 : 1 randomisation to non-contrast computed tomography or multimodal imaging (non-contrast computed tomography + computed tomography angiography + computed tomography perfusion). Proportion treated with intravenous thrombolytic therapy (primary outcome). Secondary end points: functional recovery at 3 months, early neurological recovery, times to decision making and treatment delivery, safety (mortality, incidence of symptomatic intracerebral haemorrhage). Over 36 months, 11 United Kingdom sites randomised 271 patients (134 multimodal computed tomography, 137 non-contrast computed tomography). The mean age was 67.6 years and the median National Institutes of Health Stroke Scale score was 6 (interquartile range 3–12). After initial non-contrast computed tomography, 114/134 multimodal computed tomography and 108/137 non-contrast computed tomography patients were found to be thrombolysis-eligible. Significantly fewer multimodal computed tomography patients received thrombolytic therapy (56/114, 49.1%) compared to non-contrast computed tomography alone [73/108, 67.6%, odds ratio 0.46 (95% confidence interval: 0.25 to 0.83), p = 0.0102]. Treatment decision and delivery times, early neurological recovery and day 90 functional outcomes did not differ significantly between groups. Mortality was 6/114 (5.3%) in the multimodal computed tomography group and 11/108 (10.2%) in non-contrast computed tomography alone [odds ratio 0.46 (95% confidence interval: 0.16 to 1.31), p = 0.147]. Symptomatic intracerebral haemorrhage occurred in two patients, both in the non-contrast computed tomography group. There were no significant interactions between stroke subgroups by severity or syndrome. The proportion of patients with confirmed stroke on follow-up imaging at 24 hours did not differ significantly between groups. Recruitment was lower than the planned sample size, but thrombolysis rate was much higher than originally estimated (60% overall vs. 25% estimated). Computed tomography interpretation and treatment decisions were at the discretion of clinicians. Findings reflect United Kingdom practice in a predominantly less severe stroke clinical population. Multimodal computed tomography resulted in significantly fewer patients receiving thrombolysis, principally because multimodal imaging did not identify relevant therapeutic targets (perfusion defects or intracranial vessel occlusion). Treatment decision times and clinical outcomes did not differ significantly between groups. Fewer deaths and no symptomatic intracerebral haemorrhages occurred in the multimodal computed tomography group. Further investigation of potentially lower mortality and symptomatic intracerebral haemorrhage with multimodal imaging is of potential clinical importance. This trial is registered as ClinicalTrials.gov identifier NCT02360670. This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 11/100/78) and is published in full in Efficacy and Mechanism Evaluation; Vol. 12, No. 6. See the NIHR Funding and Awards website for further award information.
Background Merkel cell carcinoma is a rare locally invasive skin cancer of older people. Standard management for primary Merkel cell carcinoma is surgery and/or radiotherapy, with no standard of care or unity of practice, based on retrospective experience without randomised trials. Objectives Feasibility objectives were to determine whether Rational Compare was likely to deliver on its objectives to influence individual treatment decisions and clinical practice, and to determine operational adaptations to reduce variation between patients and in non-randomised components of the management pathway. If the feasibility objectives were met, then the primary objective of the overall trial was to determine if surgery or radiotherapy as first definitive treatment for primary Merkel cell carcinoma results in better loco-regional disease control. Design Rational Merkel cell carcinoma was a multicentre, two-arm, randomised Phase III, adaptive trial with integrated feasibility phase (Rational Compare) plus observational study (Rational Review) designed to produce probabilities that wide local excision or radiotherapy as first treatment for primary Merkel cell carcinoma was at least as good or better than the other in terms of loco-regional control. In the observational protocol (Rational Review), definitive treatment was allocated by regional Specialist Skin Cancer Multidisciplinary Teams to maximise data on this rare cancer. Setting National Health Service hospitals with Specialist Skin Cancer Multidisciplinary Teams. Participants All patients with newly presenting histologically proven Merkel cell carcinoma considered for radical loco-regional control without distant metastases, capable to consent, were eligible for the trial. Randomisation occurred using a bespoke computer randomisation system developed by the Cancer Research UK Clinical Trials Unit employing a stratified minimisation method. Those with primary Merkel cell carcinoma that could be treated with margins of ≥ 1 cm by either surgery or radiotherapy for which the Specialist Skin Cancer Multidisciplinary Team was in equipoise were eligible for Rational Compare. Interventions Wide local excision or radiotherapy as first definitive treatment for primary Merkel cell carcinoma. Main outcome measures Time from randomisation to loco-regional treatment failure. Rates of registration and randomisation. Marginal excision and macroscopic disease at the time of definitive treatment. Results Sixty-four patients were recruited, of whom five were randomised. The trial did not meet its feasibility target for randomisation and closed. The five randomised patients all underwent their allocated treatment (three radiotherapy and two surgery, one with adjuvant radiotherapy following surgery), and none experienced loco-regional failure. Twenty-six loco-regional failure events were reported in 59 observational patients (8 had radiotherapy, 27 had surgery, 18 had surgery with adjuvant radiotherapy, 5 had regional Merkel cell carcinoma without known primary and 1 unknown treatment). About a quarter of patients had macroscopic disease, and a majority likely had microscopic involvement at the primary site at the time of definitive treatment. Conclusions Both wide local excision and radiotherapy are offered as first treatment for primary Merkel cell carcinoma in UK practice, but it remains uncertain whether one should be prioritised. Implications for health care As Merkel cell carcinoma is a rare cancer, the challenge for healthcare systems has been that no specific management strategy currently exists. Merkel cell carcinoma requires a more definitive guideline with optimised referral pathways and interhospital working, which could accelerate and clarify treatments and thus allow better comparison and improvement of outcomes. Limitations Major logistic challenges meant randomisation targets were not met, so the trial closed without answering the primary objective. Future work The design and outcomes of Rational Merkel cell carcinoma will inform design of future studies for rare cancers. Readouts of circulating immune cells and analysis of the immune microenvironment in the Merkel cell carcinoma primary will be explored in relation to the clinical data set and outcomes. Study registration This study is registered as ISRCTN16290169; Clinicaltrials.gov number NCT05253144. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (NIHR award ref: 12/205/36) and is published in full in Efficacy and Mechanism Evaluation; Vol. 12, No. 12. See the NIHR Funding and Awards website for further award information. Plain language summary Merkel cell carcinoma is a skin cancer affecting only 250–300 people in the United Kingdom each year. Its rarity means clinicians advise patients on available treatments based on their experience of past cases rather than on the basis of evidence from past clinical trials. Merkel cell carcinoma starts on the skin (known as the primary), grows quickly and often spreads to nearby lymph nodes in the neck, armpit or groin. It must be treated effectively or it quickly regrows. The primary Merkel cell carcinoma is removed by specialist surgeons who can remove the lesion with a good margin of healthy tissue and who can decide on the possibility of accurate staging. To get a good clearance, large areas of tissue may need to be removed. These patients often need specialist repair after surgery, as well as the consideration of sentinel node staging at the time of surgery, and then possibly radiotherapy. Some patients are instead treated by radiotherapy right away, reducing the need for repair, allowing delivery of radiotherapy sooner. The Rational Merkel cell carcinoma trial was designed to fairly compare surgery or radiotherapy for primary Merkel cell carcinoma so the trial results could help patients and doctors make the best decision for treatment, taking into account other issues for that person, such as which bit of the body the Merkel cell carcinoma was on, their age and fitness, and preferences. People with Merkel cell carcinoma are typically elderly and are referred to travel long distances to specialist centres. Treatment requires co-ordination between specialists. Unfortunately, we found that the trial was not feasible with only five patients entered. We recognised this risk of failure in advance and stopped the trial. The patients all underwent their allocated treatment (three had radiotherapy and two surgery, one with radiotherapy following surgery), and after 2 years, the Merkel cell carcinoma has not come back in these patients. However, it was not possible to say with certainty from these small numbers whether surgery or radiotherapy should be offered as the first treatment. An additional 59 patients, concurrently treated for Merkel cell carcinoma but not entered into the comparison, still contributed data on the patient, tumour, treatment and disease control. This meant the trial still collected useful data along with immune measurements and tumour samples from this rare group of patients for further study. Information on the experience of running this trial and use of a novel trial design may help with design of future research to help people with rare cancers. Scientific summary Background Merkel cell carcinoma (MCC) is a rare locally invasive skin cancer of older people associating with impaired immunity. First treatment of primary MCC is commonly wide local excision (WLE), often necessitating reconstruction and sometimes adjuvant radiotherapy. Some patients instead proceed from biopsy to radiotherapy accelerating start of this modality, but potentially with macroscopic or microscopic disease at the primary site. The evidence base is confounded by being retrospective without trials, often with poor data on margins and disease status at the time of treatment. Design Rational MCC was a programme of work consisting of two strands. The first, Rational Compare, was a multicentre, two-arm, randomised Phase III, adaptive trial comparing WLE versus radiotherapy as first treatment for primary MCC, with integrated feasibility phase. The sample size for Rational Compare was 250 randomised at 5 years using a Bayesian approach to provide evidence on the likelihood of whether each treatment was better/as good as/worse than the other in terms of loco-regional control, thus informing individual treatment decisions. The second, Rational Review, was an observational study whereby definitive treatment was allocated by regional Specialist Skin Cancer Multidisciplinary Teams (SSMDTs). The planned sample size for Rational Review was 150 patients recruited in years 1–3. For both Rational Compare and Review, the primary outcome measure was time to loco-regional failure. A key feasibility outcome measure was that 20 patients must have been randomised by month 24 of accrual. Objectives The primary objective was to determine if WLE or radiotherapy as first definitive treatment for primary MCC results in better loco-regional disease control. Methods Patients newly presenting with histologically proven MCC considered for radical loco-regional control without distant metastases were eligible for the Rational MCC trial. Those with primary MCC that could be treated with margins of ≥ 1 cm by either surgery or radiotherapy for which the SSMDT was in equipoise were eligible for Rational Compare. In Rational Compare, consenting patients were randomised 1 : 1 to either WLE or radiotherapy as first definitive treatment for primary MCC. Additional components of management pathways, such as sentinel lymph node biopsy (SLNB), post-operative adjuvant radiotherapy for the primary and treatment of regional nodes were determined by SSMDT. Consenting non-randomised patients were registered for data, blood and tumour sample collection in Rational Review. Results Sixty-four patients were recruited, of whom five entered Rational Compare and were randomised. Patients on Rational Compare were randomised in a 1 : 1 ratio between Prioritise Radiotherapy and Prioritise Surgery arms using a bespoke computer randomisation system developed by the Cancer Research UK Clinical Trials Unit employing a stratified minimisation method. The remaining patients, N = 59, entered Rational Review. The trial did not meet its feasibility target for randomisation and closed. In Rational Compare, the five randomised patients all underwent their allocated treatment (three radiotherapy and two surgery, one with adjuvant radiotherapy), and none experienced loco-regional failure. In Rational Review, 26 loco-regional failure events were reported in 59 observational patients (8 had radiotherapy, 27 surgery, 18 surgery with adjuvant radiotherapy, 5 had regional MCC without known primary and 1 unknown treatment). About a quarter of patients had macroscopic disease, and a majority had likely microscopic involvement at the primary site at the time of definitive treatment. Discussion Both WLE and radiotherapy are offered as first treatment for primary MCC in UK practice, but it remains uncertain whether one should be prioritised. Blood and tumour samples are available for further research on immunity in MCC. Study registration This study is registered as ISRCTN16290169; Clinicaltrials.gov number NCT05253144. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme (NIHR award ref: 12/205/36) and is published in full in Efficacy and Mechanism Evaluation; Vol. 12, No. 12. See the NIHR Funding and Awards website for further award information.
Background Indwelling urinary catheters are drainage devices inserted into the bladder and are held in place by an inflatable balloon. The use of urinary catheters, while essential to bladder management, places the user at risk of catheter-associated urinary tract infections. Prevention of such infections in long-term catheter users could improve quality of life, and antimicrobial catheters may be more cost-effective compared with current plain catheters. We have developed and extensively characterised an indwelling antimicrobial urinary catheter impregnated with rifampicin, sparfloxacin and triclosan. We aimed to assess the effect of the antimicrobial urinary catheter on the number of catheter-associated urinary tract infections, blockages, unscheduled catheter changes, quality of life and resource use compared to usual care, over a 1-year period. We also aimed to assess the relative long-term safety, acceptability and cost-effectiveness of the novel catheter compared to current practice. Methods Before the clinical trial could be undertaken, the antimicrobial catheters had to be manufactured and validated by an industry partner in a multistage process. Validation included impregnation, accelerated ageing and biocompatibility testing. Progress and challenges Extensive device testing methods were developed and validated, including methods for determining the antimicrobial content of the catheters, detection of residual solvents and for an accelerated ageing process. A randomised clinical trial protocol was developed in parallel, in conjunction with patient advocates. A Trial Steering Committee was convened and a network of urology clinics created. The most significant challenge was that the industry partner was unable to consistently manufacture antimicrobial urinary catheters to the product specification. Much closer oversight of manufacturers processing the catheters is necessary to ensure compliance with protocols. The regulatory requirements for the novel catheters were also more extensive than anticipated and are subject to change. Delays accrued from these challenges, and there was uncertainty around the ability of the industry partner to produce a catheter. Ultimately, the project funder withdrew the funding before the clinical trial commenced. Conclusion Catheter-associated urinary tract infections remain a serious problem, especially to long-term urinary catheter users, and there is currently no effective prophylactic strategy. Protocols for validation of impregnation and sterilisation steps for biocompatibility testing and accelerated ageing studies have been established and can be applied to future manufacture of antimicrobial urinary catheters. A protocol for a randomised trial of such medical device has been developed and can be deployed once a antimicrobial urinary catheter has been correctly manufactured. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme as award number NIHR127982. Plain language summary What was the question? Many people with conditions affecting how the bladder works, such as a spinal cord injury, have to use silicone tubes called catheters to drain urine. Long-term catheter users often experience urinary tract infections, which sometimes can be very serious. Researchers have developed catheters coated with antimicrobial materials, but these had limited success in reducing infections. We had developed a catheter that held antimicrobial chemicals within the silicone, which seep out over time. Whether this new catheter would prevent infections was unknown. What did we plan to do? We employed a medical device company to manufacture a batch of antimicrobial catheters to the standards required by medical regulators. We then wanted to compare the antimicrobial catheter with standard catheters in a clinical trial. We would count the number of infections experienced across a year by users of both types of catheter to see if there was a reduction from use of the antimicrobial catheter. We also aimed to work out the overall costs of care for users of each type. What did we achieve and what were the challenges? We developed several processes and tests to demonstrate that the catheters had been made to the highest standards and contained the right amount of the antimicrobial chemicals. We learnt that the regulations concerning medical devices had become more thorough and we needed help to understand them. We devised a protocol for the clinical trial. However, the company was unable to reliably manufacture catheters to the required standard. What happens next? We hope another company will be able to make the catheters and that we can run the clinical trial in the future. We can highlight to other researchers of new medical devices some challenges they may face. There remains an urgent need for better catheters for long-term catheter users.
Background Chronic lymphocytic leukaemia is the most common leukaemia subtype and associated with profound immunosuppression. Bruton Tyrosine Kinase inhibitors have revolutionised chronic lymphocytic leukaemia management; however, Bruton Tyrosine Kinase inhibitors therapy impairs vaccine-induced immunity. We evaluated if a 3-week pause of Bruton Tyrosine Kinase inhibitors treatment improved spike protein receptor binding domain immunity to severe acute respiratory syndrome coronavirus 2 vaccination while maintaining disease control. Method We performed an open-label, two-arm parallel group, randomised trial in secondary-care haematology clinics in 11 United Kingdom hospitals. Patients aged 18 and over, diagnosed with chronic lymphocytic leukaemia and currently taking Bruton Tyrosine Kinase inhibitors therapy for at least 12 months were eligible. Participants were randomised (1 : 1 stratified by Bruton Tyrosine Kinase inhibitors therapy line) to pause Bruton Tyrosine Kinase inhibitors for 3 weeks or continue their Bruton Tyrosine Kinase inhibitors therapy as usual, starting 6 days before their COVID-19 vaccine booster date. The primary outcome measure was anti-spike-receptor binding domain-specific antibody titre 3 weeks post-vaccination and analysed using linear regression on the log scale. Findings Between 10 October 2022 and 8 June 2023, 99 individuals were randomised to pause (n = 50) or continue (n = 49) their Bruton Tyrosine Kinase inhibitors therapy. At 3 weeks post vaccine, the geometric mean (standard deviation) anti-spike-receptor binding domain antibody titre was 218.8 (122.9) and 153.4 (103.2) U/ml in the continue and pause arms respectively with geometric mean ratio (95% confidence interval) 1.104 (0.565 to 2.158), p = 0.772, mixed-effects model and no difference in seroconversion between the two arms observed. Therapy interruption did not improve antibody neutralisation against Ancestral B.1 virus at 3 or 12 weeks [geometric mean ratio (95% confidence interval) in those that paused compared to those that continued: 1.073 (0.626 to 1.837) and 0.647 (0.378 to 1.109)] respectively. Cellular interferon gamma response to ancestral B.1 or variants of concern at 3 weeks post vaccine did not differ either. No intervention-related serious adverse events were reported, although four participants in the pause arm self-reported lymphadenopathy at 3 weeks, whereas none reported it in the continue arm. No significant differences in other features of disease flare were observed between the two arms. Interpretation This study suggests that pausing Bruton Tyrosine Kinase inhibitors around the time of vaccination is not beneficial for COVID-19 immunity and, therefore, this should not be recommended in clinical practice. It highlights the heterogeneity in response to vaccination among this profoundly immunocompromised group and the need for further research to understand the mechanisms underpinning this. Future work Understanding why the heterogeneity in vaccine responses is now required, along with assessing generalisability of the finding for other patients with chronic lymphocytic leukaemia. Limitations This study was performed when most patients had already received multiple vaccinations. A difference in the primary immune response to the first three doses may have differed. Patients were not blindied and self-reporting measure may have been affected. This study does not completely rule out the possibility of some effect. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme as award number NIHR151892. Plain language summary Vaccination against the COVID-19 virus aims to help the body’s defence system, the white blood cells and produce antibodies against it. These antibodies may then help to protect and fight against further COVID-19 infections. For people with chronic lymphocytic leukaemia who regularly take a type of drug called a Bruton Tyrosine Kinase inhibitor, such as ibrutinib or acalabrutinib, antibody responses can be low or absent to vaccinations. Previous information suggested that pausing Bruton Tyrosine Kinase inhibitor drugs around the time of vaccinations may improve the antibody response. This study considered whether pausing a Bruton Tyrosine Kinase inhibitor drug, for 1 week before and 2 weeks after, a COVID-19 vaccination changed the antibody response. Ninty-nine adults with well-controlled chronic lymphocytic leukaemia who had been taking a Bruton Tyrosine Kinase inhibitor for over a year took part from 11 United Kingdom hospitals. Half were taking acalabrutinib and half ibrutinib. People who took part in the study were similar in age, biological sex and ethnicity to those with chronic lymphocytic leukaemia in the United Kingdom. The Bruton Tyrosine Kinase inhibitor drug was their first chronic lymphocytic leukaemia treatment for two-thirds of participants. Most participants had had five previous COVID-19 vaccinations before taking part. Forty-nine participants paused their Bruton Tyrosine Kinase inhibitor drug; 50 continued their Bruton Tyrosine Kinase inhibitor drug as usual. The group a participant was placed into was decided by a computer programme. No one reported serious side effects as a result of taking part in the study. One participant died during the study from COVID-19 infection. In the pause group, four participants said they had swollen glands (lymph nodes) 3 weeks after vaccination, as did one participant at 12 weeks. COVID-19 antibodies 3 weeks after vaccination were not found to be improved for participants who paused their Bruton Tyrosine Kinase inhibitor drug, rather than continuing their Bruton Tyrosine Kinase inhibitor. These findings suggest people with chronic lymphocytic leukaemia have no reason to pause their Bruton Tyrosine Kinase inhibitor when getting their COVID-19 vaccinations.
Background The 2 × 2 factorial seAFOod trial demonstrated that aspirin and omega-3 polyunsaturated fatty acid eicosapentaenoic acid reduce colorectal polyp number (a biomarker of colorectal cancer risk) during colonoscopy surveillance in the Bowel Cancer Screening Programme. The lack of a risk and/or therapeutic response biomarker limits a precision medicine approach to maximise efficacy of these chemoprevention agents. The seAFOod trial collected a comprehensive biobank of blood, urine and tissue samples. Objective To use the seAFOod Trial biobank and post-trial Bowel Cancer Screening Programme colonoscopy outcomes to (1) identify a biomarker(s) of colorectal polyp risk and therapeutic response, and (2) investigate the mechanism(s) of colorectal cancer prevention, of aspirin and eicosapentaenoic acid. Design Laboratory analysis of biobank samples and retrospective analysis of colonoscopy outcomes linked to clinical trial data. Setting Randomised, double-blind, placebo-controlled trial and the English Bowel Cancer Screening Programme colonoscopy surveillance programme. Participants seAFOod trial participants, who provided informed consent for use of trial samples and post-trial colonoscopy data. Interventions Aspirin 300 mg and/or eicosapentaenoic acid 2000 mg (or respective placebos) daily for 12 months during the seAFOod trial. Main outcome measures (1) Polyp outcomes from Bowel Cancer Screening Programme colonoscopy performed during and after the seAFOod trial; (2) plasma, red blood cell, urine and rectal mucosal polyunsaturated fatty acid and lipid mediator levels; and (3) genetic polymorphisms relevant to the pharmacology and metabolism of aspirin and eicosapentaenoic acid. Results The post-trial polyp detection rate (the number of individuals with ≥ 1 colorectal polyp) after randomisation to placebo was 71.1% compared with 80.1% for individuals, who had received aspirin (odds ratio 1.13, 95% confidence interval 1.02 to 1.24). Several genetic polymorphisms modified the polyp prevention efficacy of aspirin; for example, polyp risk reduction in aspirin users compared with non-aspirin users was restricted to rs4837960 (PTGS1) common homozygotes (incidence rate ratio 0.69, 95% confidence interval 0.53 to 0.90) and eicosapentaenoic acid [the presence of at least one fatty acid desaturase 2 Indel (rs66698963) insertion allele identified eicosapentaenoic acid users with a reduction in colorectal polyp number (incidence rate ratio 0.50, 95% confidence interval 0.28 to 0.90). A high baseline urinary 11-dehydro-thromboxane B2 level predicted increased polyp number (incidence rate ratio 2.26, 95% confidence interval 1.11 to 4.58). A low (quartile 1) on-treatment urinary 11-dehydro-thromboxane B2 level predicted reduced colorectal polyp number compared with placebo (incidence rate ratio 0.34, 95% confidence interval 0.12 to 0.93) for aspirin and eicosapentaenoic acid treatment compared with high on-treatment urinary 11-dehydro-thromboxane B2 values (incidence rate ratio 0.61, 95% confidence interval 0.34 to 1.11). Limitations The seAFOod trial was relatively small with under-representation according to sex and ethnicity. Conclusions STudy Of Prevention by Aspirin anD EPA; kNowledge Of Mechanism of Action has taken a precision medicine approach to colorectal cancer chemoprevention and has generated novel findings that are applicable to the optimal use of aspirin and eicosapentaenoic acid in a targeted manner. Increased polyp number in trial participants that received aspirin suggests higher neoplastic risk after aspirin cessation. Genetic polymorphisms modify the polyp prevention efficacy of aspirin and EPA. The level of urinary 11-dehydro-thromboxane B2 predicts polyp risk prior to treatment and polyp risk reduction during aspirin treatment. Future work Validation of risk and therapeutic response biomarkers for eicosapentaenoic acid (e.g. fatty acid desaturase Indel genotype) and aspirin (e.g. urinary 11-dehydro-thromboxane B2) for colorectal cancer prevention (and other non-communicable diseases) is required in other human cohorts. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme as award number NIHR128210. Plain language summary The seAFOod trial showed that the medicine aspirin and a naturally occurring substance called omega-3 EPA did not reduce the overall risk of fleshy bowel growths called polyps, which predict bowel cancer risk in the future. However, aspirin and EPA treatment reduced the number of polyps in certain situations, depending on the type and location of polyps. The STOP-ADENOMA project used blood, urine and bowel tissue samples from the seAFOod trial, as well as large bowel camera (colonoscopy) results, to identify factors (called biomarkers) that predict which patients benefitted most from using aspirin and/or EPA. The samples were also used to understand how aspirin and EPA work to prevent bowel cancer. The key findings from STOP-ADENOMA were: After the trial finished, there were more bowel polyps in people that had received aspirin during the trial than in those who did not take aspirin. Increased polyp risk after aspirin stops might require extra colonoscopy check-ups. The combination of aspirin and EPA together reduced polyp number more than either agent alone. Genetic differences (called polymorphisms) between individuals controlled how well aspirin and EPA work to prevent polyps. Lower levels of substances in the urine called 11-d-TXB2 and PGE-M confirmed that aspirin and EPA stop a protein called cyclooxygenase from working. The amount of 11-d-TXB2 in the urine predicted individual polyp risk before any treatment started and also whether aspirin would reduce polyp risk while it was used. A substance called resolvin E, which some scientists think explains the anti-cancer activity of EPA, was not found in seAFOod trial blood or bowel samples. The biomarkers that identified individuals who benefitted most from aspirin and EPA in the seAFOod trial need further testing before they are used for a ‘personalised medicine’ approach to prevention of bowel cancer, and other diseases, by aspirin and EPA.
Background Eczema (also known as atopic dermatitis) affects 20% of United Kingdom children, with 16% experiencing moderate-to-severe eczema. Eczema impacts patients’ quality of life, mainly through intense itching and sleep disturbance. Most caregivers are able to control their children’s eczema with topical treatments, including emollients, topical corticosteroids or calcineurin inhibitors. For those who do not respond to these topical treatments, or who require consistent use of high potency topical corticosteroids to maintain control, systemic therapies should be considered. Ciclosporin is the most commonly used systemic treatment for paediatric patients, but methotrexate is a widely used promising alternative. Currently, there is not enough evidence to inform guidance about which treatment (methotrexate or ciclosporin) should be used to treat severe atopic eczema in children and young people. Aim In this study, we sought to compare the cost-effectiveness of two oral drug treatments (methotrexate or ciclosporin) for children and young people who have severe eczema. Methods We collected information on resource use and health-related quality of life using data from the TREAT trial. One hundred and three children and young people aged 2–16 years were randomly allocated to receive either oral methotrexate or ciclosporin for a 36-week treatment period with 24 weeks of further follow-up. An economic evaluation was undertaken, as it is currently uncertain which drug represents the best value for money for the United Kingdom National Health Service. The base case consists of a cost–utility analysis undertaken from a partial National Health Service perspective (limited to medication plus adverse event resource use for which complete data were available from clinical report forms) over 60 weeks; and multiple imputation was used to account for the missing utility data, and the analysis adjusted for baseline cost/utility/Objective Scoring Atopic Dermatitis (as appropriate), gender, age and recruiting centre. Results In the base-case analysis, usage of methotrexate resulted not only in cost savings compared to ciclosporin of −£489.67 (95% confidence interval −£685.78 to −£293.36) per participant but also in a small decrease in quality-adjusted life-years of −0.0057 (95% confidence interval −0.0384 to 0.0270) per participant; the resulting net monetary benefit at a willingness to pay per quality-adjusted life-year threshold of £20,000 (£30,000) was £375.49 (£38.45). The probability of methotrexate being cost-effective was 85.5% (73.1%) for a £20,000 (£30,000) threshold. The results were similar in unadjusted analyses and those analyses taking a wider perspective. However, in the secondary cost-effectiveness analysis, methotrexate was found to dominate ciclosporin as it was both cost saving and resulted in a greater improvement in severity scores. Limitations Both wider National Health Service resource use (collected by patient diary) and utility data had missing data, which was taken account of using multiple imputation assuming data was missing at random. Being a within-trial economic evaluation, the long-term cost-effectiveness beyond 60 weeks cannot be inferred from this data set or analysis. Conclusion and future work This study extends the findings of the TREAT trial by demonstrating that methotrexate and ciclosporin are similar in terms of costs (for visits/monitoring, adverse events and concomitant medications) and quality-adjusted life-years but that methotrexate drug costs are significantly cheaper than ciclosporin drug costs. This supports the conclusion reached in the randomised controlled trial paper that, where first-line novel systemic biologics and small molecules prescribing is generally restricted by health-funding bodies, as is the case in most jurisdictions, methotrexate provides an effective and low-cost, first-line systemic agent and is thus an alternative to ciclosporin. Given its overall cost-effectiveness, methotrexate now needs to be directly compared with novel systemic therapies. Funding This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme as award number 13/50/12, and Research for Patient Benefit (RfPB) programme, as award number PB-PG-1215-20019. Plain language summary Eczema affects 20% of United Kingdom children, 16% of whom will experience moderate-to-severe eczema. The impact on patients’ quality of life, mainly through intense itching and sleep disturbance, and the economic burden is comparable to other chronic conditions in children. This study addresses one of the treatment uncertainties identified by a James Lind Alliance group of patients, carers and health professionals: ‘What is the best and safest way of using drugs that suppress the immune system when treating eczema?’. Public money available to provide health care is limited, so choices must be taken about which treatments to provide. This study sought to help inform these choices by comparing the costs and outcomes of two drug treatments (methotrexate vs. ciclosporin) for children who have severe eczema. We did this by collecting information on medication use and appointments with National Health Service services related to eczema and individuals’ health-related quality-of-life for those children participating in the TREAT trial. One hundred and three children and young people aged 2–16 years were given either methotrexate or ciclosporin randomly for a 36-week treatment period with 24 weeks of further follow-up. It is currently uncertain which drug represents best value for money for the United Kingdom National Health Service. This study shows that methotrexate and ciclosporin are similar in terms of costs (for visits/monitoring, adverse events and medications) and outcomes but that methotrexate drug costs were significantly cheaper than ciclosporin drug costs. Methotrexate was found to offer greater value for money for the National Health Service than ciclosporin over the 60 weeks, and there was low uncertainty around this. This result may help inform management guidelines for childhood eczema. In addition, the findings are particularly valuable for healthcare settings with limited financial and drug safety monitoring resources.
Background A previous study by our group using dendritic cells pulsed ex vivo with the lysate of the HepG2 cell line showed clinical benefit with evidence of antigen-specific T-cell responses in some patients with advanced hepatocellular carcinoma. This trial set out to investigate the activity of this vaccine in combination with chemoembolisation compared to chemoembolisation alone in patients with intermediate stage hepatocellular carcinoma. All patients also received a conditioning regimen comprising low-dose cyclophosphamide. Objectives To determine whether the addition of a dendritic cell vaccine to chemoembolisation and preconditioning cyclophosphamide prolongs progression-free survival and warrants further investigation. Design Multicentre, open-label, randomised Phase II trial. Setting Three tertiary referral units in the United Kingdom: Queen Elizabeth Hospital, Birmingham; Aintree University Hospital/Clatterbridge Cancer Centre, Liverpool and Queen’s Medical Centre, Nottingham. Participants Patients > 18 years with intermediate stage hepatocellular carcinoma, performance status 0–2 and Child–Pugh A/B7 liver function. Intervention Preconditioning cyclophosphamide on Day 1 and Day 29 followed by chemoembolisation on Day 31 (± dendritic cell infusion), followed by further preconditioning cyclophosphamide on Days 60, 90 and 120 (± additional dendritic cell infusions on Days 62, 92 and 122). Main outcome measures The primary endpoint was progression-free survival time using Response Evaluation Criteria in Solid Tumours v1.1 criteria. Secondary endpoints were progression-free survival time based on modified (m) Response Evaluable Criteria in Solid Tumours criteria, overall survival time, radiological response according to Response Evaluable Criteria in Solid Tumours 1.1 criteria, radiological response based on Modified Response Evaluable Criteria in Solid Tumours criteria, change in the serum alpha-fetoprotein tumour marker, toxicity using Common Terminology Criteria for Adverse Events v4.0 and immune response. Results Between March 2016 and October 2019, 55 patients were randomised of whom 48 are evaluable (24 in each group). The progression-free survival time using Response Evaluable Criteria in Solid Tumours criteria was 18.6 months in patients treated with chemoembolisation plus preconditioning cyclophosphamide plus dendritic cell infusions (Group 2) compared to 10.4 months in those treated with chemoembolisation plus preconditioning cyclophosphamide alone (Group 1) (hazard ratio 0.43, upper value of one-sided 80% confidence interval 0.57; p = 0.016). Although not statistically powered, the progression-free survival time using Modified Response Evaluable Criteria in Solid Tumours criteria showed a similar magnitude of benefit (18.6 vs 10.8 months: hazard ratio 0.48, 95% confidence interval 0.22 to 1.02). The overall response rate (complete response and partial response) by Response Evaluable Criteria in Solid Tumours was 54% in Group 2 and 29% in Group 1 and the disease control rate (complete response, partial response and stable disease) was 92% in Group 2 and 67% in Group 1. Treatment with dendritic cell vaccination was associated with an enhanced antigen-specific immune response. Treatment was well tolerated with few additional adverse events from the additional dendritic cell infusions. Conclusions Chemoembolisation plus preconditioning cyclophosphamide plus dendritic cell infusions merit further investigation in a randomised Phase III trial but the trial design will need to take into account the current evolving hepatocellular carcinoma treatment landscape. Limitations The current dendritic cell manufacturing process limits large-scale use and further validation and automation of the process will be needed prior to testing in a randomised Phase III trial. Future Work Further testing in a randomised Phase III trial is warranted. Trial registration This trial is registered as ISRCTN11889464; EudraCT number: 2011-001690-62. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 09/160/24) and is published in full in Efficacy and Mechanism Evaluation; Vol. 12, No. 9. See the NIHR Funding and Awards website for further award information. Plain language summary Transarterial chemoembolisation is the standard treatment for patients with liver cancer that is confined to the liver. As part of this treatment, chemotherapy is given into the blood vessel feeding the tumour and the blood supply to the tumour is then blocked with small particles. In the study, we tested whether a cancer vaccine could control liver cancer for longer when given with transarterial chemoembolisation, to see if it would be worth testing this treatment in a larger trial. The vaccine was prepared by taking immune cells from patients and activating them to recognise and kill the cancer cells. We also gave all patients low doses of a chemotherapy drug called cyclophosphamide which has been shown to help destroy negative immune cells that stop the immune system from being able to recognise cancer cells. This gives the vaccine the best chance of being able to activate the immune system against the liver cancer cells. Patients entering this study were randomly chosen to have treatment with transarterial chemoembolisation plus low-dose chemotherapy or to treatment with transarterial chemoembolisation plus low-dose chemotherapy plus the cancer vaccine. We injected the first vaccine directly into the liver cancer at the time of transarterial chemoembolisation. A further three vaccines were given monthly as a drip into the patients’ veins. Fifty-five patients took part in this study. We found that the cancer remained controlled for longer in the group of patients who had the additional cancer vaccine treatment. However, there was no difference in how long patients remained alive for. We found that the cancer vaccine was well tolerated with only mild side effects in general. The results from this trial are encouraging and suggest that it is worth testing this cancer vaccine in more patients with liver cancer in a larger clinical trial. Scientific summary Background Transarterial chemoembolisation (TACE) is the recommended first line treatment for patients with intermediate stage hepatocellular carcinoma (HCC) who are of good performance status and have good liver synthetic function. However, this treatment remains palliative and disease progression is inevitable such that combination with novel therapies is attractive. Since TACE may liberate an abundance of tumour antigens it may lend itself to combination with immunotherapeutic strategies. Dendritic cells (DC) are potent antigen presenting cells which exist in peripheral tissues where they take up and process antigens, short peptide fragments of which (epitopes) are presented on the cell surface in association with the major histocompatibility complex. A previous study by our group using DCs pulsed ex vivo with the lysate of the HepG2 cell line showed clinical benefit with evidence of antigen-specific T-cell responses in some patients with advanced HCC. This trial set out to investigate the activity of this DC vaccine in combination with chemoembolisation compared to chemoembolisation alone in patients with intermediate stage HCC. All patients also received a conditioning regimen comprising low-dose cyclophosphamide. Objectives To determine whether the addition of DC vaccine to chemoembolisation and preconditioning cyclophosphamide prolongs progression-free survival and warrants further investigation. Primary outcome measure: Progression-free survival time (defined as the time from randomisation to date of progression or death, whichever was earlier, using RECIST 1.1 criteria). Secondary outcome measures: Progression-free survival at 12 months based on modified RECIST (mRECIST) criteria. Overall survival time. Radiological response based on RECIST 1.1 criteria. Radiological response based on mRECIST criteria. Change in the tumour marker serum alpha-fetoprotein (AFP). Assessment of toxicity using NCI-CTCAE version 4. Immune response. Methods This was an open-label, multicentre, randomised Phase II clinical trial conducted in three hospitals in the UK. Eligible patients were aged 18 years or older, had histologically or cytologically confirmed diagnosis of HCC or met the American Association for Study of Liver Diseases (AASLD) non-invasive diagnostic criteria, at least one uni-dimensional lesion measurable according to RECIST 1.1, were suitable for TACE treatment, had received no previous chemotherapy, radiotherapy, immunotherapy or other experimental treatment for HCC prior to entry into the trial, had an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2, a Child–Pugh score of ≤ 7, suitable veins for access with 17G fistula needle and adequate renal and hepatic function. Randomisation was performed using the Cancer Research UK Clinical Trial Unit’s ‘electronic Remote Data Capture’ system. Patients were randomly assigned on a 1 : 1 basis to TACE therapy + preconditioning cyclophosphamide therapy only (Group 1) or to TACE therapy + preconditioning cyclophosphamide therapy + DC infusions (Group 2), using a computer-generated minimisation algorithm with an error component to prevent allocation predictions. Randomisation was stratified by viral hepatitis versus non-viral aetiology, and treatment centre. Patients randomised to Group 2 underwent leukapheresis initially on Day 24 (for the first five Group 2 patients) as the first DC vaccine was infused as a fresh product at the time of TACE on Day 31. Following a protocol amendment, all subsequent patients underwent leukapheresis prior to Day 1 cyclophosphamide treatment, and the first DC infusion was a frozen product that was thawed just prior to infusion. Production of the DC vaccine was via differentiation of autologous monocytes derived from the immunomagnetic separation of CD14+ monocytes from non-mobilised leukapheresis. This was followed by the differentiation of CD14+ monocytes into immature DC by culturing the cells in interleukin 4 and granulocyte-macrophage colony-stimulating factor for 5 days in DendriMACS media. Immature DC were then loaded with HepG2 tumour lysate and keyhole limpet haemocyanin (for immune monitoring), which act as the antigen and immunogenic molecules respectively. Following antigen loading, the DC were matured with monophosphoryl lipid A (MPLA). The final product of autologous DC pulsed with HepG2 lysate matured with MPLA was resuspended in cryopreservation fluid and frozen at ≤−140 °C prior to release for use. All patients received conditioning cyclophosphamide intravenously at a dose of 250 mg/m2 on Day 1 and Day 29 followed by TACE on Day 31 as the standard treatment. TACE was performed as per standard of care. Patients received further cyclophosphamide at a dose of 250 mg/m2 on Days 60, 90 and 120. Patients in Group 2 additionally received DC vaccination, the first of which was via the intrahepatic route at the time of chemoembolisation on Day 31. Three further vaccinations were given intravenously at monthly intervals (Days 62, 92 and 122) following a single dose of cyclophosphamide at a dose of 250 mg/m2 2 days before each vaccination (Days 60, 90 and 120). Primary and secondary analyses were performed using a modified intention-to-treat population, defined as all patients enrolled on to the trial who had received at least one TACE treatment, retaining patients in their randomised treatment groups and including patients who had deviated from the protocol. Results Between March 2016 and October 2019, 55 patients were randomised of whom 48 (24 in each group) had TACE and were evaluable. The progression-free survival time using RECIST 1.1 criteria was 18.6 months in patients treated with chemoembolisation plus preconditioning cyclophosphamide plus DC infusions (Group 2) compared to 10.4 months in those treated with chemoembolisation plus preconditioning cyclophosphamide alone (Group 1) [hazard ratio (HR) 0.43, upper value of one-sided 80% confidence interval (CI) 0.57; p = 0.016]. Although not statistically powered, the progression free survival time using mRECIST criteria showed a similar magnitude of benefit (18.6 vs 10.8 months: HR 0.48, 95% CI 0.22 to 1.02). There was no difference in median overall survival (25.7 vs. 21.5 months: HR 0.61, 95% CI 0.27 to 1.28) although the number of patients randomised was small and patients in Group 1 received more additional treatments. The overall response rate (complete response and partial response) by RECIST was 54% in Group 2 and 29% in Group 1 and the disease control rate (complete response, partial response and stable disease) was 92% in Group 2 and 67% in Group 1. The addition of DC infusions did not appear to significantly increase the incidence or severity of adverse events (AEs): the incidence of any AE in both arms was very similar and the incidence of ≥ grade 3 AEs in both arms were low. The most common AEs related to DCs were chills (30%), fatigue (22%) and nausea (22%) but these were all grade 1 or 2 only. Immune responses were assessed using an ELISpot assay of interferon (IFN-γ) release. A significantly increased AFP-specific T- cell response was observed in patients in Group 2. Post hoc rank sign testing with Bonferroni correction for multiple testing identified this was due to a statistically significant increase in IFN--γ production at Day 45. Conclusion Chemoembolisation plus preconditioning cyclophosphamide plus DC infusions merit further investigation in a randomised Phase III trial but the trial design will need to take into account the current evolving HCC treatment landscape. The current DC manufacturing process limits large-scale use and further validation and automation of the process will also be needed prior to testing in a randomised Phase III trial. Trial registration This trial is registered as ISRCTN11889464; EudraCT number: 2011-001690-62. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 09/160/24) and is published in full in Efficacy and Mechanism Evaluation; Vol. 12, No. 9. See the NIHR Funding and Awards website for further award information.
Background Almost all large-scale trials of disease-modifying therapeutic agents in critical care have failed to show benefit for patients, which may be explained in part by the clinical and biological heterogeneity inherent in virtually all critical illness syndromes. Enrichment strategies have been developed to separate responders from non-responders and better target treatments. In patients with the acute respiratory distress syndrome, a critical illness syndrome involving severe lung inflammation, latent class analysis and other clustering approaches have led to the discovery of subgroups (phenotypes) that appear to respond differently to treatment based on retrospective analyses of published clinical trials and observational cohorts. The next step is to test these phenotypes in a prospective trial. Rapid, point-of-care analytical methods have now made such a trial possible. There is a need to advance treatment for patients with acute respiratory distress syndrome and other critical illness syndromes by incorporating a phenotype-based approach into prospective trial design. The hyperinflammatory and hypoinflammatory phenotypes, that have been identified in acute respiratory distress syndrome, will be the first to be included in such a trial, with scope for further phenotypes to be studied over time. Future work This Efficacy and Mechanism Evaluation report, through expert consensus, describes a new Phase II, multiarm, adaptive platform randomised controlled trial design that tests multiple pharmacological therapies in a population of patients with acute respiratory distress syndrome stratified by baseline inflammatory phenotype. This report also reviews issues to be considered in developing precision medicine trials in critical care, which are designed with newly developed clinical phenotypes in mind. This work has been used to develop the Precision medicine Adaptive Network platform Trial in Hypoxaemic acutE respiratory failuRe precision medicine trial in acute respiratory distress syndrome, which has been funded and will begin recruitment in June 2025. Limitations This report is the result of expert consensus review, rather than utilising strict review methodologies (e.g. Delphi consensus process). However, expert consensus has been found to generate similar results to consensus processes when a high degree of agreement is reached and > 70% agreement was reached for all included recommendations. Funding This article presents independent research funded by the (NIHR) Efficacy and Mechanism Evaluation programme as award number NIHR154493.
Background Thrombosis with thrombocytopenia syndrome is a rare condition known to occur spontaneously or after heparin use. With the advent of COVID-19 vaccines during the pandemic, thrombosis with thrombocytopenia syndrome cases emerged post administration of adenoviral vaccines, termed vaccine-induced immune thrombosis and thrombocytopenia. In response, the thrombosis with thrombocytopenia syndrome consortium was formed to deepen our understanding of this syndrome post vaccination. Methods The consortium employed a comprehensive approach across five work packages. This included designing cohort studies covering the entire English population and analysing local linked regional data sets to detect thrombosis with thrombocytopenia syndrome occurrences in real time. Various patient and healthy control specimens, including those from vaccinated individuals, underwent testing for antiplatelet factor 4 antibodies using three different assays. Patients who developed vaccine-induced immune thrombosis and thrombocytopenia after the AstraZeneca (AZD1222) COVID-19 vaccine underwent whole-genome and ribonucleic acid sequencing to identify genetic susceptibility factors. Multiple studies were conducted to investigate the mechanism of antiplatelet factor 4 antibody formation, including assessments of adenoviral vector structure and binding to platelet factor 4. Detailed studies were also conducted to understand the immune response to vaccines, the role of immune complexes involving platelet factor 4 and their effects on proinflammatory cytokines, neutrophil extracellular traps and platelets in the pathogenesis of the syndrome. Results Cohort studies revealed a higher risk of arterial and venous thromboses after COVID-19 infection compared to vaccination. Specifically, regarding vaccines, the risk of thrombosis and/or thrombocytopenia was higher after the first dose of the AZD1222 vaccine but not with subsequent doses of. Regional linked data indicated that real-time ascertainment of diseases across multiple acute hospital sites’ secure data environments is not yet feasible at scale. The overall background seroprevalence of antiplatelet factor 4 antibodies was low in healthy individuals, vaccinated individuals and those infected with COVID-19. Whole-genome sequencing did not identify significant variants predisposing to vaccine-induced immune thrombosis and thrombocytopenia, with ongoing work on ribonucleic acid sequencing. An electrostatic interaction between the hexon hypervariable regions of the ChAdOx1 capsid and platelet factor 4 was suggested as a possible mechanism for antiplatelet factor 4 antibody development. Strong immune response drove the formation of neutrophil extracellular traps, significant inflammatory responses and clot formation in distant organs. Platelet activation post immune complex formation against platelet factor 4 was dependent on FcγRIIa but independent of complement, also occurring through binding with c-Mpl. T-cell reactivity against the AZD1222 vaccine indicates potential cross-reactivity with prevalent human adenoviruses. Conclusions The consortium’s comprehensive work has uncovered new potential mechanisms of vaccine-induced immune thrombosis and thrombocytopenia and identified novel biomarkers and therapeutic strategies for further development and validation. This is crucial, as the combination of thrombosis and thrombocytopenia, alongside antiplatelet factor 4 antibodies, can occur without exposure to heparin or adenovirus vaccines. Future considerations Recommendations include the development of a national reference laboratory and registry for diagnosis and further study of thrombosis with thrombocytopenia syndrome; future vaccine development using the adenoviral vector platform to focus on the reduction of the electrostatic interaction between viral hexons and platelet factor 4; international genomics collaboration; and studies focused on understanding the symptoms suffered by patients as well as strategies to ameliorate them. Limitations Direct identification of vaccine-induced immune thrombosis and thrombocytopenia patients was hindered by poor recording. The rarity of vaccine-induced immune thrombosis and thrombocytopenia limited the number of patients recruited for genomic and mechanistic studies. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme as award number NIHR135073. Plain language summary Thrombosis with thrombocytopenia syndrome is rare: it is characterised by thrombosis and lowered platelet counts together with the development of an antibody against a protein called platelet factor 4. This syndrome has been linked to heparin use or can occur spontaneously. With COVID-19 vaccines, a new form called vaccine-induced immune thrombosis and thrombocytopenia appeared. The thrombosis with thrombocytopenia syndrome consortium formed to better understand this syndrome. The consortium used various methods, like studying the data of the entire English population and analysing local data in real time. They tested patient and healthy control samples for antiplatelet factor 4 antibodies and sequenced genes from patients who got vaccine-induced immune thrombosis and thrombocytopenia after the AZD1222 COVID-19 vaccine. They also studied how these antibodies form and their effects, including changes in cytokines and platelet involvement. Our studies showed a higher thrombosis risk after COVID-19 infection compared to vaccination. The first dose of the AZD1222 vaccine had higher risks of thrombosis and lowered platelets (occurring separately), but subsequent doses or mRNA vaccines were safer. Identifying vaccine-induced immune thrombosis and thrombocytopenia patients directly was difficult due to poor records. Real-time tracking of diseases across hospitals was not yet possible at scale. The prevalence of antiplatelet factor 4 antibodies was low in healthy, vaccinated and COVID-19-infected individuals. Genetic sequencing didn’t find significant variants causing vaccine-induced immune thrombosis and thrombocytopenia, but there are ongoing ribonucleic acid studies. Our studies found a possible mechanism for antiplatelet factor 4 antibody development involving the AZD1222 vaccine. The immune response caused generalised inflammation and clotting in distant organs. Platelet activation was influenced by certain factors. T-cell reactivity against the AZD1222 vaccine hinted at potential cross-reactivity with common human viruses. The consortium’s work has uncovered new insights into vaccine-induced immune thrombosis and thrombocytopenia, suggesting potential new diagnostic and treatment strategies. This is crucial, as thrombosis with thrombocytopenia syndrome can occur without exposure to heparin or adenovirus vaccines.
Background Overweight and obesity affect over 60% of the United Kingdom population and constitute a major risk factor for the development of comorbidities. Preventing weight gain in periods of life where there is an elevated risk of adipose tissue expansion could be beneficial in preventing associated diseases in later life. This study investigated the impact of inulin-propionate ester on the prevention of weight gain in young people who were at risk of gaining weight. Objectives To investigate the impact of increasing colonic production of the short-chain fatty acid propionate on preventing body weight gain, in younger adults, over 12 months. Several underpinning mechanisms were investigated in a substudy. Design iPREVENT was a randomised, parallel-group, placebo-controlled, double-blind trial, designed with 90% power to detect a 2 kg between-arm difference in weight gain at 12 months. Setting This trial was performed at the Imperial Clinical Research Facility in London and the University of Glasgow Clinical Research Facility. Participants Participants were 20–40 years old, with a body mass index of 24.0–27.0 kg/m2 if of South Asian ethnicity or 25.0–30.0 kg/m2 if non-South Asian. Participants were also required to have at least one of the following risk factors: weight gain in the past year, low physical activity, low intake of fruit and vegetables or high intake of sugar-sweetened beverages. A total of 270 participants (135 per arm) were randomised. Intervention Participants were randomised to either 10 g/day inulin-propionate ester or 10 g/day inulin control (fermentable oligosaccharide) consumed daily for 12 months. Main outcome measure The primary outcome was weight gain from baseline to 12 months. Results The mean (± standard deviation) body weight at baseline for inulin was 79.1 kg ± 10.6 (n = 135) and inulin-propionate ester 79.6 kg ± 10.9 (n = 135). At 12 months body weight was 78.9 kg ± 11.8 (n = 114) and 81.4 kg ± 11.9 (n = 112) for inulin and inulin-propionate ester, respectively. The baseline-adjusted mean difference in weight gain was 1.02 (95% confidence intervals −0.37 to 2.41) kg for inulin-propionate ester versus inulin control. Of the secondary outcomes, the confidence interval cautiously supports differences in fat-free mass; 1.07 kg (0.21 to 1.93) (N = 226), body water; 0.72 kg (0.1 to 1.33) (N = 226) and fasting glucose; 0.11 mmol/l (0.01 to 0.21) (N = 191). Compliance with inulin-propionate ester treatment of ≥ 50% over 12 months was 63% (n = 135). There were no unexpected adverse or serious adverse events. Limitations This study aimed to explore the efficacy of enhanced propionate production above background fermentation. It could be argued a negative control (a non-fermentable substrate e.g. cellulose) would have been more suitable. Metabolomic analysis of compliance could only be conducted on a subsection of the study population. There was no intention to conduct follow-up assessments on participants beyond their 12-month visit. Conclusions In adults below the age of 40 years, inulin-propionate ester did not affect weight gain compared with the control. Future work Previously we observed that inulin-propionate ester prevented weight gain in older adults, but not in this younger cohort. We aim to investigate the variation in responses between these age groups. Trial registration This trial is registered as ISRCTN16299902. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 15/185/16) and is published in full in Efficacy and Mechanism Evaluation; Vol. 12, No. 8. See the NIHR Funding and Awards website for further award information. Plain language summary Obesity is the storage of fat within the body to the degree that causes poor health outcomes. The percentage of people with overweight or obesity continues to increase in all global populations. The prevention of obesity is a major public health goal. Evidence suggests that high-fibre diets prevent weight gain. Fibre leads to increased production of short-chain fatty acids by bacteria in the colon. Short-chain fatty acids appear to have a beneficial effect on metabolic health. However, most people do not consume enough fibre and forfeit these effects. We have combined inulin (a type of dietary fibre) and propionate (a short-chain fatty acid) to form inulin-propionate ester. This novel food ingredient can deliver propionate to the colon. Inulin was chosen as the control to explore propionate independent of any effect that inulin may have on body weight. In previous studies, inulin-propionate ester has prevented further weight gain in middle-aged adults who are overweight. Here, we now investigate whether inulin-propionate ester prevents weight gain in younger adults compared with inulin. We undertook this study because evidence suggests that rapid weight gain in young adults is related to obesity and other chronic diseases in later life. We recruited 270 participants aged 20–40 years with an overweight body mass index (25–30 kg/m2) and behaviours associated with weight gain. Participants were randomly allocated to 2 groups of 135 participants each to take 10 g inulin-propionate ester or 10 g inulin daily for 12 months. Our main interest was the change in body weight after 1 year. Other measurements of interest were changes in body fat, fasting blood biomarkers, which can indicate chronic disease risk (e.g. blood sugar and cholesterol), and blood pressure. There were no differences in body weight gain, most measures of body composition and fasting blood biomarkers, between the two groups at 12 months. In conclusion, neither inulin-propionate ester nor inulin prevented weight gain in young adults. Scientific summary Background Obesity is a major global health concern and over 60% of UK adults are obese or overweight. Most research focuses on obesity treatment rather than the prevention of initial weight gain and fat deposition. Young people aged between 20 and 35 years have the fastest rates of weight gain at an average of approximately 1 kg/year. Weight gain during early adulthood increases the likelihood of poor metabolic health outcomes like elevated fasting glucose or hypertension, which contribute to chronic metabolic disease risk. Epidemiological and intervention studies have shown that dietary fibre is associated with lower body weight and better metabolic outcomes. Dietary fibre has a range of impacts on the gastrointestinal tract and gut microbiota. The fermentation of fibre by bacteria in the colon produces short-chain fatty acids (SCFAs) which may have beneficial effects on appetite and substrate metabolism. A collaboration between Scottish Universities Environmental Research Centre and Imperial College London led to the creation of inulin-propionate ester (IPE), a compound consisting of inulin (fibre) and propionate (SCFA) to specifically increase the production of propionate in the colon. This facilitates a more targeted investigation of the role of individual SCFAs on weight gain compared with general fibre supplementation. In previous work, IPE has prevented weight gain, lowered visceral fat mass (FM) and improved insulin sensitivity in middle-aged cohorts. However, the effect of increasing colonic propionate production using IPE in younger adults at risk of weight gain has not been explored. Therefore, this multicentre, randomised, placebo-controlled, double-blind trial was designed to investigate the effect of IPE on body weight in younger adults (20–40 years) with self-reported behaviours linked with phenotypic susceptibility to weight gain (e.g. low physical activity). Main study objectives The primary objective was to investigate whether IPE has a superior effect on preventing body weight gain, compared with inulin, in younger adults over 12 months. The secondary objectives were to: Assess the effect of IPE compared to inulin on blood pressure, fasting biochemistry, and body composition. Determine the safety profile of IPE via adverse events (AEs), compliance and withdrawal reporting. The substudy objectives were to assess the mechanisms by which IPE affects: Energy balance by measuring whole-body energy expenditure, hepatic lipid metabolism and whole-body lipid oxidation. Appetite by measuring peptide YY (PYY) and glucagon-like peptide 1 (GLP-1) concentrations, subjective appetite ratings and ad libitum energy intake. The colonic environment via 16S ribosomal ribonucleic acid (rRNA) and metabolite analysis. The urinary, faecal and serum metabolite profile using nuclear magnetic resonance (NMR) spectroscopic analyses. Breath hydrogen as a surrogate measure of colonic bacteria fermentation. Methods Trial design iPREVENT was a randomised, placebo-controlled, double-blind trial to investigate the efficacy of IPE versus inulin control upon weight gain prevention and to determine the safety profile of IPE. Participants were randomised to take 10 g/day of either IPE or inulin control daily for 12 months, with study visits at baseline, and 2, 6 and 12 months after randomisation. A subset of participants consented, before study randomisation, to participate in further assessments of mechanistic measures in a substudy. Study settings The trial was performed at two UK sites: National Institute for Health and Care Research Imperial Clinical Research Facility (CRF) in London, Imperial College Healthcare NHS Trust, and University of Glasgow CRF (NHS Research Scotland). Participants A total of 270 participants were enrolled and randomised using Sealed Envelope software (open-source software, www.sealedenvelope.com), of whom 52 also took part in the mechanistic substudy. The study recruited participants who were males and females aged 20–40 years with a body mass index (BMI) of 24.0–27.0 kg/m2 if of South Asian ethnicity or 25.0–30.0 kg/m2 if non-South Asian. Potential participants had to meet at least one of the following criteria at screening: a self-reported weight gain of 2 kg or more over the last 12 months low self-reported physical activity low self-reported fruit and vegetable intake (< 2 servings per day) high self-reported intake of sugar-sweetened beverages (> 1 serving per day). Participants were excluded if they: were diagnosed with chronic disease; type 2 and type 2 diabetes, cancer, renal failure, heart disease, organic acidaemia (propionic acidaemia, methylmalonic acidaemia) were diagnosed with gastrointestinal conditions including coeliac disease, inflammatory bowel disease and irritable bowel syndrome had previous bowel reconstruction surgery were pregnant or lactating had used antibiotics at any time in the past 3 months had untreated vitamin B12 deficiency (< 160 ng/l) were taking part in a weight loss programme or consuming a weight loss product had lost 3 kg or more in the last 3 months (self-reported) had diarrhoea, constipation, bloating or abdominal cramping in the last 2 weeks (self-reported). Substudy exclusion criteria included: anaemia or as per screening haemoglobin levels of < 130 g/l for males and < 110 g/l for females allergies or intolerances to any of the ingredients in the set substudy meals. Recruitment Study recruitment ran from July 2019 to October 2021 and was paused from March to September 2020 due to coronavirus disease 2019 (COVID-19). Trial participants were recruited from the following sources which are ranked from most to least productive: contacting NHS trusts contacting local general practices social media adverts posters newspaper adverts pop-up events. Interventions Participants received unlabelled, identical-looking trial interventions of IPE and inulin in 10 g pre-packed, foil-backed sachets, and they were instructed to take one sachet per day, mixed in a cold drink/water, at any time with their normal diet. Study procedures At the screening visit, the study rationale and protocol were explained. Participants were then asked to provide informed consent. Body weight and body composition (body water, FM, lean mass) were measured. A blood sample was taken for a full blood count to rule out the risk of B12 deficiency or anaemia. Participants were asked about their medical history, current medications, physical activity, alcohol intake, smoking or vaping, and recreational drug use. Blood pressure and waist and hip circumference were also measured. Participants who were asked to attend their baseline (randomisation) study visit fasted for 12 hours and had abstained from intense physical activity and alcohol the day before. A blood sample was taken for fasting glucose, insulin, cholesterol and lipids. The participants were randomised via Sealed Envelope software and provided with IPE or inulin sachets lasting them for 2 months. The same measurements were taken at the 2-, 6- and 12-month visits. No blood samples were taken at the 2-month visit. Compliance was measured by counting used and unused inulin/IPE sachets and the occurrence of AE or serious adverse events (SAEs) was documented. Outcomes Primary outcome: Weight gain from baseline to 12 months Secondary outcomes: Occurrence of AEs and SAEs over the duration of the study. Changes in fasting biochemistry from baseline to 6 and 12 months: Glucose. Insulin. Triglycerides. Total cholesterol. Low-density lipoprotein cholesterol. High-density lipoprotein cholesterol. Changes in blood pressure from baseline to 2, 6 and 12 months. Changes in body weight from baseline to 2 and 6 months. Changes in waist/hip/BMI/body composition measurements – FM, fat mass index (FMI), per cent body fat (fat%), fat-free mass (FFM) and FM/FFM ratio, from baseline to 2, 6 and 12 months. Changes in compliance (sachet count) from baseline to 2, 6 and 12 months. Exploratory/mechanistic study outcomes Gut microbiota: 16S rRNA profiles from stool sample. Impact on neuroendocrine cell number: Proliferation in intestinal organoids using the level of SCFA and other metabolites identified from NMR spectroscopic analyses of stool. Appetite regulation: Measured by visual analogue scales, food diaries, ad libitum intake, and appetite-regulating gut hormones PYY, GLP-1, gastrin and cholecystokinin. Energy expenditure: Open-loop indirect calorimetry. Hepatic lipid metabolism: Stable isotope tracers of fat oxidation (13C palmitate) and de novo lipogenesis. Total body water through dilution analysis of deuterated water. Other data observations: Changes in physical activity from baseline to 2, 6 and 12 months. Changes in other lifestyle factors (drinking, smoking, recreational drugs) from baseline to 2, 6 and 12 months. Changes in diet from baseline to 2, 6 and 12 months (via food diaries). Statistical analysis The sample size for this study was 270 participants, based on the randomised proof-of-concept trial, the difference between arms in the change in body weight over 24 weeks was 1.4 kg [95% confidence interval (CI) −0.3 to 3.1], p = 0.099. A 2 kg between-arm 12-month effect size was therefore chosen. This agreed with a weight gain prevention trial over 9 months in young adults which aimed to detect a 2 kg effect and achieved 4.3 kg, with a pooled standard deviation (SD) for body weight change of 4.35 kg, and 81% retention. The analysis of the primary end point incorporates the earlier correlated interim measurements of body weight in a linear mixed-effects (LME) model and is adjusted for baseline continuous body weight and other categorical randomisation stratifiers with further specification of the role of time point, and correlation structure, detailed in the statistical analysis plan. The implicit ‘missing at random’ assumption has been challenged through a set of sensitivity analyses. As these involve all randomised participants, the LME model and the sensitivity analyses taken together therefore constitute an intention-to-treat strategy. Where possible, continuous secondary end points have been adjusted for their baseline to improve the precision of estimated intervention effects. Repeated measures have been analysed using LME models adjusting also for randomisation stratifiers. Comparisons between arms for binary outcomes are summarised as differences in proportions. Ninety-five per cent CIs have been used to make inferences from estimated effect sizes. Results Participants were recruited for the study from July 2019 and the target sample size was reached in October 2021 with 135 participants randomly allocated into 2 arms. Recruitment was paused from March 2020 to September 2020 during COVID-19. Participant retention was in line with estimates, with 16% (42/270) participants completely withdrawing from trial interventions. At 12 months, a compliance threshold of ≥ 50% was reached by 53% (72/135) of the inulin control arm and 63% (85/135) of the IPE arm. A high threshold of ≥ 80% was reached by 32% (43/135) of the inulin control arm and 48% (65/135) of the IPE arm, resulting in a total of 40% (108/270) of participants. Participant baseline characteristics were similar between trial arms. Primary outcome was provided for 84% (227/270) of participants. Primary outcome Mean (± SD) body weight at baseline was 79.1 kg ± 10.6 (n = 135) for inulin and 79.6 kg ± 10.9 (n = 135) for IPE. At 12 months, body weight was 78.9 kg ± 11.8 (n = 114) and 81.4 kg ± 11.9 (n = 112), for inulin and IPE, respectively. The baseline-adjusted difference was 1.02 (95% CI −0.37 to 2.41) kg (p = 0.15), between the groups. Secondary outcomes Lifestyle factors were comparable by study arm. There were no significant differences in measures of fasting biochemistry outcomes, except for glucose: 0.11 (0.01 to 0.21). There was a difference between arms for body water of 0.72 (0.17 to 1.28) and FFM of 1.08 (0.29 to 1.86). No changes in FM, FMI, fat%, FFM and FM/FFM ratio were detected after 12 months of IPE intake. The AE and SAE reporting was similar between the two arms. There were a greater number of moderate-severity gastrointestinal-related AEs in the inulin control arm than in the IPE arm. The effect of COVID-19 During the COVID-19 lockdowns, researchers pivoted to collecting participants’ self-reported body weight at home. Participants were encouraged to attend the clinic for their next visit, so a clinic-reported weight could be taken. Researchers also attempted to take clinic weights when participants had self-reported their 12-month weight but could attend the clinic within the 1-month measurement window. However, we cannot discount our results were affected by the pandemic given several studies reported increased weight gain occurred during the COVID-19 lockdowns. Conclusions This was the first long-term study to investigate the efficacy of increasing colonic propionate production using IPE on weight gain prevention in younger adults recruited specifically due to their risk of further weight gain. IPE did not significantly alter weight gain trajectory compared with inulin. This contrasts with previous findings demonstrating that IPE prevented weight gain, lowered body fat mass and improved insulin sensitivity in middle-aged participants who were overweight or obese. Notably, despite this population being at increased risk of weight gain, neither group exhibited significant increases in body weight nor reached the predicted 2 kg weight gain. These results are encouraging given that the study was conducted during the COVID-19 pandemic, and a recent systematic review reported that the average adult gained 1.57 kg weight from March to May 2020. The role of dietary fibre in preventing weight gain warrants further investigation. The outcomes of this trial were not influenced by unaccounted confounding variables, such as compliance rates. High compliance at 12 months was seen in 40% of participants. The safety profile of both the intervention and control appears comparable. There were no unexpected AEs or SAEs, and complete withdrawal rates were similar for both study arms. Supplement cessation was less balanced, 42 participants and 61 participants stopped intake of IPE and inulin, respectively. The study was not confounded by high rates of gastrointestinal disturbance from IPE or inulin. The results differ from our previous observations that IPE prevented weight gain in middle-aged people with a BMI ≥ 25 kg/m2. At present, it is not possible to understand this difference, but we could hypothesise that young adults may be less sensitive to increased propionate production and may require a larger dose of IPE for an effect to be seen. In our previous work, 10 g was determined to be the minimally effective dose of IPE to promote weight maintenance in middle-aged participants. On the other hand, it is possible that young adults are more responsive to the effects of microbial fermentation of inulin on appetite regulation, as indicated by the lack of weight gain in the inulin control group. Discrepancies in results between older and younger adults could partially be attributed to differences in diet and lifestyle. Younger adults have a greater tendency to eat sporadically or snack throughout the day, whereas older people tend to have more regular meal patterns and settled routines. Previous studies using stable isotopes indicate that IPE releases propionate 3–4 hours post ingestion. As propionate is a short-term signalling molecule, it may have no effect on appetite and energy intake in individuals with less consistent meal patterns. Further, evidence indicates that circulating concentrations of satiety hormones, including PYY, are lower in younger adults. These habits, powerful external cues and lower baseline concentrations of satiety hormones could overcome any satiety signal driven by IPE. Consistent intake of IPE may have resulted in adaptations to the colonic environment and reduced sensitivity to propionate. Chronic IPE intake may have contributed to the desensitisation of free fatty acid receptors 2 and 3 located on enteroendocrine cells in the gastrointestinal tract, diminishing secretion of GLP-1 and PYY and a reducing satiety response. Further investigation is required to determine whether receptor desensitisation or alterations to certain associated proteins (e.g. those involved in gut hormone degradation) contribute to the diminished impact. This clinical trial has some limitations. Due to the COVID-19 lockdowns and pivot to collection of self-reported weight data, the ‘Principal weight’ measurement for the primary outcome consists of 38% self-reported weight data. Self-reported data introduce inherent bias. Additionally, discrepancies in calibration between home weight scales and those used in the CRF may introduce further variability in the measurements. There was no plan to follow up with the participants after their final visit at the 12-month point to identify changes in their weight gain trajectory after stopping the supplement. Future studies should aim to understand the differential effects of IPE and inulin between population groups and explore drivers of appetite regulation in younger adults. Trial registration This trial is registered as ISRCTN16299902. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 15/185/16) and is published in full in Efficacy and Mechanism Evaluation; Vol. 12, No. 8. See the NIHR Funding and Awards website for further award information.
Background Primary aldosteronism due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured or greatly improved by adrenal surgery. However, the invasive nature of the standard presurgical investigation contributes to fewer than 1% of patients with primary aldosteronism being offered the chance of a cure. Objectives The primary objective of our prospective study was to compare the accuracy of a non-invasive test, [11C]metomidate positron emission tomography computed tomography scanning, with adrenal vein sampling in predicting the biochemical remission of primary aldosteronism and the resolution of hypertension after surgery. Design and methods All participants of the study underwent both investigations, in random order, as determined by minimisation. Individuals were recommended for surgery if one or both investigations indicated unilateral primary aldosteronism. Biochemical and clinical outcomes were assessed at 6 months post surgery, or after 9–12 months of medical therapy. In November 2019, the MATCH extension study was added to address two study limitations. Firstly, the short (20-minute) half-life of [11C]-metomidate, which currently limits its use to centres with an on-site cyclotron. Secondly, the short, 6-month interval between surgery and primary outcome determination. Development of para-chloro-2-[18F]fluoroethyletomidate, an 18F analogue of [11C]-metomidate with a 109-minute half-life, allowed an within-patient comparison of para-chloro-2-[18F]fluoroethyletomidate and [11C]metomidate positron emission tomography in 31 participants in the extension study. The extension also allowed assessment of outcomes at 2 years post intervention. Results In the original MATCH study, a total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. The accuracies of [11C]metomidate positron emission tomography and computed tomography at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7% and 65.4%. For adrenal vein sampling, the accuracies were 63.6% and 61.5%. [11C]metomidate positron emission tomography and computed tomography was not significantly superior, but the differences of 9.1% (95% confidence interval −6.5% to 24.1%) and 3.8% (95% confidence interval −11.9% to 9.4%) lay within the pre-specified−17% margin for non-inferiority (p = 0.00055 and p = 0.0077, respectively). At 2 years post surgery, partial/complete or complete clinical success were achieved in 78/96 (81%) and 24/96 (25%) of patients, respectively. Comparing patients whose systolic blood pressure was ≤ 135 or > 135 mmHg on spironolactone, complete clinical success occurred in 9/19 and 6/44, respectively (odds ratio 5.7, 95% confidence interval 1.6 to 19.8; p = 0.008); 10/14 (71%) patients harbouring KCNJ5 mutations achieved complete clinical success at 2 years (odds ratio 16.9, 95% confidence interval 3.5 to 80.7; p = 0.0002), compared with 0/16 with CACNA1D and 4/15 with other mutations. There was high agreement in prediction of unilateral primary aldosteronism: [11C]metomidate positron emission tomography and computed tomography 18/31 (58.1%), para-chloro-2-[18F]fluoroethyletomidate 17/31 (54.8%), κ = 0.850, 95% confidence interval (0.676 to 1.000). Limitations Accuracy of [11C]metomidate positron emission tomography and computed tomography and adrenal vein sampling could only be assessed in the surgical group. The assumption was made that if both investigations indicated bilateral disease, this was accurate; which is a limitation of the study. Furthermore, the accuracy of para-chloro-2-[18F]fluoroethyletomidate was assessed against [11C]metomidate positron emission tomography, which we know from the overall study is not perfect as a small proportion of aldosterone-producing adenomas were diagnosed by only one investigation. Further work is required to ascertain reasons for this discrepancy. Conclusions Overall, [11C]metomidate positron emission tomography is non-inferior to adrenal vein sampling in detecting unilateral primary aldosteronism. Favourable clinical Primary Aldosteronism Surgical Outcome study outcomes seen at 6 months post adrenalectomy are sustained at 2 years and are predicted by genotype and preoperative response to spironolactone. Para-chloro-2-[18F]fluoroethyletomidate is a valid alternative to [11C]metomidate positron emission tomography in primary aldosteronism subtyping. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation programme as award number 14/145/09. Plain language summary Hypertension (high blood pressure) causes heart attacks and strokes. The commonest curable cause of hypertension is primary aldosteronism, where excess production of the hormone aldosterone from one/both adrenal glands leads to an excess of sodium (salt) in the body. In approximately half of cases the cause is a benign tumour, an aldosterone-producing adrenal adenoma, which can be removed by surgery. However, the current diagnostic test (adrenal vein sampling) for such a tumour is difficult, invasive and only available at a handful of centres in the UK. This, with several other factors not addressed in this study, contributes to only 1% of patients with primary aldosteronism being appropriately investigated and treated. [11C]-Metomidate positron emission tomography and computed tomography is a new scan which will light-up if an aldosterone-producing adenoma is present. The aim of the MATCH study was to compare the accuracy of [11C]metomidate positron emission tomography and computed tomography with adrenal vein sampling. One disadvantage of [11C]metomidate positron emission tomography and computed tomography is the radioactivity from the tracer given during the scan has a short half-life, meaning the scan can only be performed where there are facilities to manufacture the tracer on site. A similar scan using a dye with a much longer half-life (para-chloro-2-[18F]fluoroethyletomidate positron emission tomography and computed tomography) was developed more recently, therefore in the MATCH extension study 31 participants had an additional para-chloro-2-[18F]fluoroethyletomidate positron emission tomography and computed tomography scan to allow comparison with [11C]metomidate positron emission tomography and computed tomography. We also looked for clues which could help predict which individuals were more likely to be cured by surgery. The MATCH study demonstrated that [11C]metomidate positron emission tomography and computed tomography is as accurate as adrenal vein sampling in diagnosing patients with PA confined to one adrenal. Para-chloro-2-[18F]fluoroethyletomidate positron emission tomography and computed tomography gave equivalent imaging data as [11C]metomidate positron emission tomography and computed tomography, suggesting that it is also a valid alternative to adrenal vein sampling. Participants whose blood pressure responded well to spironolactone (medication which blocks aldosterone) were more likely to be pill-free at both 6 and 24 months after surgery. Certain gene mutations (DNA ‘spelling mistakes’) in aldosterone-producing adenomas were associated with cure of hypertension: KCNJ5 and GNA&CTNNB1; while others (CACNA1D mutations) were associated with poorer outcomes.
Introduction Reduced antibiotic consumption due to better self-management could change the profile of bacteria present in the airway, which might benefit the health of chronic obstructive pulmonary disease patients. To test this, we planned to use sputum samples already being collected from Colour-COPD trial patients for mechanistic work. The trial will test whether a sputum colour chart is non-inferior to usual self-management, and has a primary outcome of chronic obstructive pulmonary disease-specific hospital admission. Secondary outcomes include antibiotic consumption and quality of life. Since only half of exacerbations of chronic obstructive pulmonary disease (acute exacerbation of chronic obstructive pulmonary disease) are bacterial, and sputum colour has a good positive predictive value for bacterial presence, it is likely that our intervention will reduce antibiotic consumption. The main route by which our intervention could improve patient outcomes is that it could alter the airway microbiome, and subsequent pathological processes; this add-on study tried to assess that concept. Methods We used all sputum samples submitted by Colour-COPD trial patients and processed and stored them for microbiome and cytokine analyses. Sputum plugs were split with one-half being diluted in phosphate-buffered saline, dispersed using glass beads and stored for quantitative polymerase chain reaction/16S analysis. The second portion was dispersed using sequential phosphate-buffered saline and dithiothreitol treatment, generating supernatants and cytospins. Analysis of the microbial patterns, which would have been obtained from the respiratory microbiome, will be compared to antibiotic consumption for acute exacerbation of chronic obstructive pulmonary disease (days/year) steroid load (days/year and mg/year), acute exacerbation of chronic obstructive pulmonary disease rate, forced expiratory volume in 1 second and longitudinally within individuals to determine the impact of frequent courses of antibiotics at group and individual level. This work will now be completed outside the duration of this award. Selected inflammatory markers linked to neutrophilic and eosinophilic inflammation were planned to be measured, but this work was abandoned when the study was terminated early. Results and study limitations The trial was stopped prematurely due to low recruitment. This was due to a combination of insufficient trial sites, the impact of COVID-19 on research infrastructure and a reduced rate of acute exacerbation of chronic obstructive pulmonary disease during the COVID-19 pandemic, which affected eligibility in primary care sites, in particular. Since analysis of the microbiome was planned to occur only after trial results, this was abandoned within this award at the termination of the trial. However, since the research questions remained, could be answered in other ways, and patients had consented to the use of their samples for the proposed work, alternative ways to collect samples and fund microbiome analyses were sought. We are now at a point where we expect to have sufficient samples to have adequate power to answer two of our research questions by the time the trial ends, and will conduct their analysis thereafter. Conclusion Although we are not able to address our objectives of describing the airway microbiome in a primary care chronic obstructive pulmonary disease population, and describing the relationship between antibiotic consumption and changes in airway microbiome during the term of the award, we were able to learn lessons about matching mechanistic work to trials. Future work We stored samples for a separately funded study to meet our objectives. Funding This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme as award number NIHR130938. Plain language summary Chronic obstructive pulmonary disease is a common lung problem mostly affecting adults over the age of 40. It causes breathlessness and cough, and patients often experience flare ups of their symptoms, known as exacerbations. One way of recognising an infectious exacerbation is to look at sputum colour, and compare this to a colour chart – antibiotics are only suggested if the colour indicates an infection. This study added laboratory work to a trial of sputum colour charts in chronic obstructive pulmonary disease (Colour-COPD Trial), to see if it affected basic processes in the lung that could determine how patients feel. We separated sputum from saliva and stored it to preserve genetic material (deoxyribonucleic acid) from bacteria and viruses. Antibiotics patients take affect patterns in bacterial deoxyribonucleic acid. If the Colour-COPD Trial had been able to show a difference in either quality of life or antibiotic use, we would have proceeded to look at the microbiome related to these outcomes. However, the trial was stopped early due to problems recruiting, mostly related to the effects of the COVID-19 pandemic, so we have had to find other ways to answer our questions. This has involved recruiting patients and collecting their sputum from other studies, which will complete next year. We decided it was important to try and complete the study, independent of the trial, because if helpful effects are seen within airway bacteria or inflammation that relate to aspects of chronic obstructive pulmonary disease care that can be collected from other sources (not just the trial) then we may be able to start personalising care for chronic obstructive pulmonary disease patients based on how their sputum looks. It may also enable us to design new treatments that alter the same basic processes and help patients. These results will be submitted as a separate publication in 2024.
