Aim: To better understand the motivations and needs of healthy volunteers in clinical trials. Methods: The European Federation for Exploratory Medicines Development (EUFEMED) devised a Survey of 58 questions on motivations of volunteers to participate, as well as on needs at the level of convenience, risk/benefit, social interaction, partnership and altruism. The Survey was shared with European Clinical Research Units (CRUs) who agreed to conduct the Survey in volunteers taking part in their phase 1 trials. Results: The Survey generated responses from 4349 healthy volunteers. In 54% (95% CI: 52,55) of cases contributing to new treatments was the primary motivation to participate, vs. monetary compensation in 41% (95% CI: 39,42) of responders. Volunteer requirements during overnight stays defined as important were well-functioning showers (89%, 95% CI: 87,90), ability to spend some time outside (78%, 95% CI: 76,80), the meal quality (76%, 95% CI 73,78), access to high-speed internet (73%, 95% CI: 71,75), a place to read/work alone (69%, 95% CI: 66,71) and a good night rest (69%, 95% CI: 67,71). The opportunity to socialize with staff was important for 85% (95% CI: 83,87), a unit with a cozy interior for 70% (95% CI 67,72) and socializing with other participants for 63% (95% CI 61,66) of responders. Conclusion: Healthy volunteers in clinical trials have specific needs during their stay in the Clinical Research Unit. Volunteer recruitment, compliance and retainment, as well as an ethical and a subject-centric approach to trial design and conduct can benefit from understanding these needs.

Background:∼5-10% of patients with asthma have severe disease. A proportion remain symptomatic despite suppression of T2-related inflammation but what drives persistent symptoms remains unclear. Eicosanoids exert a functional role in pulmonary inflammation. We explored the relationship between urinary eicosanoids, asthma symptoms, obesity and T2-biomarker status. Methods:Urine was sampled during a randomised controlled trial assessing corticosteroid optimisation using T2-biomarker directed care at scheduled study visits (n=728) and at exacerbation (n=103). Urine eicosanoid concentrations were measured by mass spectrometry, then log2-transformed, z-scored and concatenated by biosynthetic pathway generating six pathway scores. Results were stratified by T2 status (T2-low: exhaled nitric oxide fraction (F ENO) <20 ppb and blood eosinophil count (BEC) <0.15×109 cells·L-1; versus T2-high: F ENO ≥20 ppb and BEC ≥0.15×109 cells·L-1), symptoms (symptom-low: Asthma Control Questionnaire-7 (ACQ-7) <1.5; versus symptom-high: ACQ-7 ≥1.5) and obesity. Results:Isoprostane (pathway score p=0.02) and thromboxane (pathway score p=0.04) levels were higher in symptom-high versus symptom-low, T2-low participants. Isoprostane levels were greater in symptom-high versus symptom-low participants, irrespective of T2 status (pathway score p=0.01). Cysteinyl-leukotriene E4 levels (LTE4) were elevated in T2-high versus T2-low participants (pathway score p=0.0007), irrespective of symptoms. Corticosteroid exposure, obesity and exacerbations were not associated with increased eicosanoid levels (p≥0.05). Conclusion:Raised urinary eicosanoid levels of isoprostanes and thromboxanes were associated with increased symptoms in T2-low severe asthma. Elevated excretion of these metabolites in T2-low participants could reflect increased thromboxane-receptor (TP) activation, which may be promoting increased asthma severity and bronchoconstriction. Further research and interventions are needed to explore the role of TP modulation in T2-low severe asthma.

Background: Globally, ∼5% of patients have severe asthma. Despite new treatments, many remain symptomatic (ACQ>1.5) with low levels of Type-2 inflammation (T2-low: FeNO<20ppb & Blood Eosinophil count [BEC]<0.15x109cells/L). Aims: To profile urinary eicosanoids in "T2-low" severe asthma. Methods: Urine samples were analysed, from T2-low patients, by liquid-chromatography/mass-spectrometry, during a multi-centre, 48-week RCT enabling corticosteroid optimisation. Results: Urinary concentrations of isoprostanes, thromboxane and PGD2 metabolites are elevated in "symptom-high" [SH: uncontrolled] v "symptom-low" [SL: controlled], T2-low patients (Table 1) and are associated with a reduced FEV1 (71.7% v 88.5%, P<0.0001). After adjusting for obesity, thromboxane 2,3-dinor-TXB2 (0.32 v 0.16ng/mL, P=0.0337) and isoprostane 8,12-iso-iPF2a-VI (3.73 v 2.10ng/mL, P=0.0234) remain elevated in "SH" v "SL", T2-low patients and are associated with a reduced FEV1(88.0% v 70.6%, P=0.002). Conclusion: Elevated urinary eicosanoids in "SH/T2-low" patients are in part due to obesity, however, some thromboxane and prostaglandin metabolites are independently associated with persistent symptoms. Table 1: Lung-function, eicosanoids & biomarkers in "SH" v "SL", T2-low patients *P <0.05; **P <0.0001

A workshop held at the 18th Annual Conference of the Pharmaceutical Contract Management Group in Krakow on 9 September 2022 asked over 200 delegates what the clinical trial landscape would look like in 2050. Issues considered included who will be running the pharmaceutical industry in 2050; how 'health chips', wearables and diagnostics will impact on finding the right patients to study; how will artificial intelligence be designing and controlling clinical trials; and what will the role of the Clinical Research Associate, the critical observer, documenter and conductor of a clinical trial need to look like by 2050. The consensus was that, by 2050, if you are working in clinical trials, you will be a data scientist. We can expect to see an increasing role of new technologies and a new three-phase registration model for novel therapies. The first phase will involve an aspect of quality evaluation and biological proof-of-concept probably involving more preclinical modelling and engineered human cell lines and fewer animal studies than currently used. Once registered, new products will enter a period of adaptive clinical development (delivered as a single study) intended to establish safety. This phase will most likely take around 1-2 years and explore tailored options for administration. Investigations will most likely be conducted in patients, possibly in a 'patient-in-a-box' setting (hospital or healthcare centre, virtual or microsite). On completion of safety licencing, drugs will begin an assessment of efficacy in partnership with those responsible for reimbursement - testing will be performed in patients, possibly where individual patient involvement in safety testing will offer some reimbursement deal for future treatment. Change is coming, though its precise form will likely depend on the creativity and vision of sponsors, regulators and payers.

Background: Patients with type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2 inflammation with corticosteroids.Objectives: We sought to analyze whole blood transcriptome from 738 samples in T2-biomarker-high/-low patients with severe asthma to relate transcriptomic signatures to T2 biomarkers and asthma symptom scores.Methods: Bulk RNA-seq data were generated for blood samples (baseline, week 24, week 48) from 301 participants recruited to a randomized clinical trial of corticosteroid optimization in severe asthma. Unsupervised clustering, differential gene expression analysis, and pathway analysis were performed. Patients were grouped by T2-biomarker status and symptoms. Associations between clinical characteristics and differentially expressed genes (DEGs) associated with biomarker and symptom levels were investigated.Results: Unsupervised clustering identified 2 clusters; cluster 2 patients were blood eosinophil-low/symptom-high and more likely to be receiving oral corticosteroids (OCSs). Differential gene expression analysis of these clusters, with and without stratification for OCSs, identified 2960 and 4162 DEGs, respectively. Six hundred twenty-seven of 2960 genes remained after adjusting for OCSs by subtracting OCS signature genes. Pathway analysis identified dolichyl-diphosphooligosaccharide biosynthesis and assembly of RNA polymerase I complex as significantly enriched pathways. No stable DEGs were associated with high symptoms in T2-biomarker-low patients, but numerous associated with elevated T2 biomarkers, including 15 that were upregulated at all time points irrespective of symptom level.Conclusions: OCSs have a considerable effect on whole blood transcriptome. Differential gene expression analysis demonstrates a clear T2-biomarker transcriptomic signature, but no signature was found in association with T2-biomarker-low patients, including those with a high symptom burden. (J Allergy Clin Immunol 2023;152:876-86.)

The Association for Human Pharmacology in the Pharmaceutical Industry’s annual meeting focused on current and impending challenges facing the United Kingdom’s (UK) pharmaceutical industry and how these opportunities can inspire innovation and best practice. The UK pharmaceutical landscape is still evolving following Brexit and learnings from the coronavirus disease 2019 (COVID-19) pandemic. As such, the UK’s clinical community is in a unique position to steer innovation in a meaningful direction. With the continuation of remote forms of working, further opportunities have arisen to support novel practices away from the clinic. The keynote speaker reflected on clinical development over the past 40 years and how the industry must continue to concentrate on patient welfare. The future of drug development was discussed regarding challenges associated with developing translational gene therapies, and the status of investment markets analyzed from a business strategy and consulting perspective. The patient viewpoint was a core theme throughout the conference with patient-centric blood sampling and decentralized clinical trials providing suggestions for how the industry can save costs and increase efficiency. Moreover, the patient perspective was central to a debate over whether ethics requirements should be the same for oncology patients taking part in first-in-human studies as those for healthy subjects. Discussions continued around the changing roles of the Qualified Person and Principal Investigators which underpins how sponsors may want to run future trials in the UK. Lessons learned from conducting challenge trials in healthy volunteers and patients were discussed following a presentation from the serving Chair of the COVID-19 challenge ethics committee. The current state of interactions with the Medicines and Healthcare products Regulatory Agency were also explored. It was considered how the immediate future for the UK clinical trials community is inevitably still linked with Europe; the newly implemented European Medicines Agency Clinical Trials Information System has been met with lukewarm responses, providing a promising opportunity to ensure UK Phase I units continue to play a vital role in global research.

Rationale: The past 25 years have seen huge progress in understanding of the pathobiology of type-2 (T2) asthma, identification of measurable biomarkers, and the emergence of novel monoclonal antibody treatments. Although present in a minority of patients with severe asthma, very little is known about the mechanisms underlying T2-low asthma, making it a significant unmet need in asthma research. Objectives: The objective of this study was to explore the differences between study exacerbators and nonexacerbators, to describe physiological changes at exacerbation in those who are T2HIGH and T2LOW at the time of exacerbation, and to evaluate the stability of inflammatory phenotypes when stable and at exacerbation. Methods: Exacerbation assessment was a prespecified secondary analysis of data from a 48-week, multicenter, randomized controlled clinical study comparing the use of biomarkers and symptoms to adjust steroid treatment in a T2-low severe asthma-enriched cohort. Participants were phenotyped as T2LOW (fractional exhaled nitric oxide ⩽ 20 ppb and blood eosinophil count ⩽ 150 cells/µl) or T2HIGH (fractional exhaled nitric oxide > 20 or blood eosinophil count > 150) at study enrollment and at each exacerbation. Here, we report the findings of the exacerbation analyses, including comparison of exacerbators and nonexacerbators, the physiological changes at exacerbation in those who had evidence of T2 biology at exacerbation versus those that did not, and the stability of inflammatory phenotypes when stable and at exacerbation. Measurements and Main Results: Of the 301 participants, 60.8% (183) had one or more self-reported exacerbations (total of 390). Exacerbators were more likely to be female, have a higher body mass index, and have more exacerbations requiring oral corticosteroid and unscheduled primary care attendances for exacerbations. At enrollment, 23.6% (71) were T2LOW and 76.4% (230) T2HIGH. The T2LOW group had more asthma primary care attendances, were more likely to have a previous admission to HDU (high dependency unit)/ICU and to be receiving maintenance oral corticosteroids. At exacerbation, the T2LOW events were indistinguishable from T2HIGH exacerbations in terms of lung function (mean fall in T2LOW FEV1, 200 [400] ml vs. T2HIGH 200 [300] ml; P = 0.93) and symptom increase (ACQ5: T2LOW, 1.4 [0.8] vs. T2HIGH, 1.3 [0.8]; P = 0.72), with no increase in T2 biomarkers from stable to exacerbation state in the T2LOW exacerbations. The inflammatory phenotype within individual patients was dynamic; inflammatory phenotype at study entry did not have a significant association with exacerbation phenotype. Conclusions: Asthma exacerbations demonstrating a T2LOW phenotype were physiologically and symptomatically similar to T2HIGH exacerbations. T2LOW asthma was an unstable phenotype, suggesting that exacerbation phenotyping should occur at the time of exacerbation. The clinically significant exacerbations in participants without evidence of T2 biology at the time of exacerbation highlight the unmet and pressing need to further understand the mechanisms at play in non-T2 asthma. Clinical trial registered with www.clinicaltrials.gov (NCT02717689).

In T2‐mediated severe asthma, biologic therapies, such as mepolizumab, are increasingly used to control disease. Current biomarkers can indicate adequate suppression of T2 inflammation, but it is unclear whether they provide information about airway microbial composition. We investigated the relationships between current T2 biomarkers and microbial profiles, characteristics associated with a ProteobacteriaHIGH microbial profile and the effects of mepolizumab on airway ecology.

BACKGROUND: Approximately 5% to 10% of patients with asthma have severe disease, with a consistent preponderance in females. Current asthma guidelines recommend stepwise treatment to achieve symptom control with no differential treatment considerations for either sex.OBJECTIVE: To examine whether patient sex affects outcomes when using a composite T2-biomarker score to adjust cortico-steroid (CS) treatment in patients with severe asthma compared with standard care.METHODS: This is a post hoc analysis, stratifying patient outcomes by sex, of a 48-week, multicenter, randomized controlled clinical trial comparing a biomarker-defined treat-ment algorithm with standard care. The primary outcome was the proportion of patients with a reduction in CS treatment (inhaled and oral corticosteroids). Secondary outcomes included exacerbation rates, hospital admissions, and lung function.RESULTS: Of the 301 patients randomized, 194 (64.5%) were females and 107 (35.5%) were males. The biomarker algorithm led to a greater proportion of females being on a lower CS dose versus standard care, which was not seen in males (effect estimate: females, 3.57; 95% CI, 1.14-11.18 vs males, 0.54; 95% CI, 0.16-1.80). In T2-biomarkerelow females, reducing CS dose was not associated with increased exacerbations. Females scored higher in all domains of the 7-item Asthma Control Question-naire, apart from FEV1, but with no difference when adjusted for body mass index/anxiety and/or depression. Dissociation be-tween symptoms and T2 biomarkers were noted in both sexes, with a higher proportion of females being symptom high/T2-biomarker low (22.8% vs 15.6%; P [ .0002), whereas males were symptom low/T2-biomarker high (22.3% vs 11.4%; P < .0001).CONCLUSIONS: This exploratory post hoc analysis identified that females achieved a greater benefit from biomarker-directed CS optimization versus symptom-directed treatment. (c) 2023 The Authors. Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). (J Allergy Clin Immunol Pract 2023;11:1233-42)

A systematic review of clinical trials conducted with a low-dose inactivated influenza vaccine adjuvanted by azoximer bromide (AZB, Polyoxidonium), was performed to compare vaccine reactogenicity against non-adjuvant vaccines. We also assessed whether lower amounts of antigen per viral strain in AZB-adjuvanted vaccines affected antibody responses. A robust search strategy identified scientific publications reporting 30 clinical trials, comprising data on 11,736 participants and 86 trial arms, for inclusion in the analysis. Local reaction rates (Rlr) appeared to be lower in AZB-adjuvanted vaccine treatment arms versus comparator vaccine treatment arms. Meta‑regression analysis revealed that AZB did not contribute to vaccine reactogenicity. Post-vaccination geometric mean titres in those exposed to AZB-adjuvanted vaccine and comparator vaccine treatment arms were similar in both children and adults aged 18–60 years, implying an antigen-sparing effect by AZB.

Background: The COVID-19 outbreak was declared to be a pandemic by the WHO in March 2020. Ongoing clinical trials were suspended, some never to re-start. A survey was conducted to get a better understanding of both the successes and failures in dealing with the pandemic.Methods: European contract research organisations (CROs) were asked to determine the extent to which the pandemic impacted on their operations in terms of the trial site conduct and investigator performance as well as its impact on subjects and patients involved in ongoing trials and the quality of data generated. Results: Forty-nine companies provided responses to the questionnaire. Data indicated that the challenges faced during the pandemic had a marked impact on clinical trial conduct and delivery. We saw an almost immediate decline in clinical trial activity associated with reduced subject/patient recruitment and a reluctance of study participants to undergo follow-up due to their fears of exposure to infection. There was insufficient data to determine the full extent of the pandemic on clinical trial performance and associated limitations in access to bed spaces and the resources necessary to perform procedures and subject follow-up. The introduction of remote monitoring by CROs provided the opportunity for essential activities associated with clinical trials to resume/continue. However, implementing these solutions required research organisations to implement changes to trial documentation and procedures. This placed marked burdens on budgets and clinical resources.Conclusions: Those involved in clinical trials advanced a flexible approach to addressing the challenges posed by COVID-19, with all parties working closely together to find solutions.

Successive waves of COVID-19 have altered opinions and working practices. We conducted a survey in early 2020 among 759 members of the medical communications community, recruited via our network, seeking their experiences, opinions, and insights. The survey was repeated 13 months later (N=925 respondents) using similar methodology. In both surveys respondents had a generally positive attitude to home working and appreciation for the lack of commute and time saved. In contrast, distractions in the home, inability to “switch off” at the end of the day, and concerns about potential impact on career development and/or connections with colleagues were highlighted. Notable findings include working longer hours as the pandemic progressed and an increase in feelings of isolation and loneliness in comparison to before the pandemic. Companies generally appear not to have used the time since the start of the pandemic to formally define home or hybrid working, including consideration of workplace health and safety requirements.

Background: Evidence-based therapies used to treat coronavirus disease (COVID-19) remain limited. Azoximer bromide (AZB; Polyoxidonium®) is an immunomodulating molecule frequently used in the Russian Federation. It offers demonstrable therapeutic benefit in upper respiratory tract infections. This study evaluated the safety and efficacy of AZB when used in combination with standard of care treatment in patients hospitalized with COVID-19. Methods: Hospitalized patients with COVID-19 (n=81; nine sites) received AZB 12 mg intravenously once daily for 3 days then intramuscularly every other day until day 17. The primary endpoint included clinical status at day 15 versus baseline. Historical control data of 100 patients from a randomized, controlled, open-label trial conducted in China were included to serve as a direct control group. Results: Notable clinical improvement, assessed by seven-point ordinal scale (OS) score and National Early Warning Score, was observed. Mean duration of hospitalization was 19.3 days. Indicators of pneumonia and lung function showed gradual recovery to normalization. No patients died but, by day 28, one patient still required respiratory support; this patient died on day 34. A higher proportion of patients receiving AZB required invasive or non-invasive ventilation (OS 5 or 6) at baseline compared with the historical control group. Improvement in mean OS score by day 14/15 was not notable in the control group (OS 3.99–3.87) but was clear in the AZB group (OS 4.36–2.90). Mean duration of hospitalization was similar in the control group (16.0 days); however, day 28 mortality was higher, at 25.0% (n=25). Conclusion: AZB combined with standard of care was safe and well tolerated. An apparent clinical improvement could not be fully evaluated due to the lack of a direct control group; further assessment of AZB for the treatment of COVID-19 in a randomized, placebo-controlled study is warranted.

A clinical need for aetiotropic coronavirus disease (COVID-19) treatments is required. The immune modulator azoximer bromide (AZB; Polyoxidonium®) is indicated in Russia for use against acute viral infections and during remission. In this study, adults hospitalized with COVID-19 (n=32) received AZB and standard of care in an open-label, multicentre, interventional study. All patients were symptomatic; 22 had severe disease (National Early Warning Score ≥5) and required mechanical ventilation or respiratory support and 19 patients had co-morbidities. Patients received AZB 12 mg intravenously once daily for 3 days, then intramuscularly every other day (approximately ten injections) until discharge. The primary endpoint was the patient's clinical status (7-point Ordinal Scale; OS) on day 15 versus that at baseline. The mean duration of hospitalization was 20 days. All patients were alive and discharged with normal oxygen saturation (SpO2) with no secondary infections or delayed mortality reported by the end-of-study visit (on day 28–72). A decrease in the mean OS and National Early Warning Score values was observed following treatment with AZB. A decrease in OS score was marked in patients identified as severe. Both sets of patients achieved similar scores, which can be classified as an improvement by day 9–10; SpO2 levels trended to normalization over time. By day 11–12, all patients had a normal body temperature. Serum C-reactive protein levels decreased in patients with severe and mild disease. Most patients had signs of pneumonia at baseline (n=27), with the majority recovering by days 10–12. No major toxicities were observed. AZB was safe and well tolerated when administered in addition to standard of care treatment for COVID-19. Further randomized, placebo-controlled studies are needed to elucidate any potential therapeutic effect in COVID-19.

Why do some patients with severe asthma not follow healthcare provider (HCP) advice to adjust treatment? We explored possible barriers when adjusting asthma treatment in a secondary analysis of data from a randomised, controlled, single-blind (study participant), multi-centre, parallel group 48-week clinical study comparing biomarker directed treatment adjustment to standard care in severe asthma. The main outcome measure was patient choice not to follow HCP advice to adjust asthma treatment. Of 1572 treatment advisories (301 subjects) instructions were followed in 1,377 cases (87.6%). Patients were more likely to follow advice to remain on current treatment (96.7%) than to either reduce (70.3%) or increase (67.1%) their treatment, with 64% of patients following all treatment advice. Multivariate analysis showed belonging to an ethnic minority group (OR: 3.10; 95% CI: 1.68, 5.73) and prior study medication change (≥2 OR: 2.77, 95% CI: 1.51, 5.10) were associated with failure to follow treatment advice. Emergency room attendance (<1yr) (OR: 0.54, 95% CI: 0.32, 0.92) was associated with following treatment advice. The largest effect was seen with transition onto or off oral corticosteroids (OR: 29.28; 95% CI: 16.07, 53.36) vs. those requested to maintain treatment. Study centre was also an important determinant. Factors such as minority ethnic group and different patient behaviour in specialist clinical centres will require further focussed studies to explore the underlying mechanisms. These findings have implications for generalisability for models of care in severe asthma.

Background: United Kingdom Refractory Asthma Stratification Programme (RASP-UK) is a randomised trial of corticosteroid optimisation in severe asthma based on composite biomarkers [1]. TranSMART is an open-source data warehouse and analysis platform developed to store large amounts of clinical and omics data[2]. Using a data management platform ensures: accessibility, sustainability and transparency of data which is essential for future respiratory projects within the EU. Aim: Our aim was to deploy a tranSMART platform and to apply the extract-transform-load (ETL) process for RASP-UK datasets and with a 100% accuracy. Methods: TranSMART were deployed on the Data Science Institute (DSI) servers (https://rasp.dsi.ic.ac.uk/transmart/). After the ETL process data was uploaded to the tranSMART platform (Fig 1-A, C). The accuracy of the ETL process was confirmed by a full recompile of the study dataset from TranSMART and a field-by-field comparison with the index data (Fig 1-B). Fig1-A is a screenshot of the platform. B shows the ETL and the testing process. C shows a summary of the data. Results: A tranSMART platform were deployed and RASP-UK datasets were uploaded to the platform with a 100% accuracy. Conclusions: TranSMART platform contributes to the accessibility and sustainability of large data-centred projects.

Background Asthma treatment guidelines recommend increasing corticosteroid dose to control symptoms and reduce exacerbations. This approach is potentially flawed because symptomatic asthma can occur without corticosteroid responsive type-2 (T2)-driven eosinophilic inflammation, and inappropriately high-dose corticosteroid treatment might have little therapeutic benefit with increased risk of side-effects. We compared a biomarker strategy to adjust corticosteroid dose using a composite score of T2 biomarkers (fractional exhaled nitric oxide [FENO], blood eosinophils, and serum periostin) with a standardised symptom-risk-based algorithm (control). Methods We did a single-blind, parallel group, randomised controlled trial in adults (18-80 years of age) with severe asthma (at treatment steps 4 and 5 of the Global Initiative for Asthma) and FENO of less than 45 parts per billion at 12 specialist severe asthma centres across England, Scotland, and Northern Ireland. Patients were randomly assigned (4:1) to either the biomarker strategy group or the control group by an online electronic case-report form, in blocks of ten, stratified by asthma control and use of rescue systemic steroids in the previous year. Patients were masked to study group allocation throughout the entirety of the study. Patients attended clinic every 8 weeks, with treatment adjustment following automated treatment-group-specific algorithms: those in the biomarker strategy group received a default advisory to maintain treatment and those in the control group had their treatment adjusted according to the steps indicated by the trial algorithm. The primary outcome was the proportion of patients with corticosteroid dose reduction at week 48, in the intention-to-treat (ITT) population. Secondary outcomes were inhaled corticosteroid (ICS) dose at the end of the study; cumulative dose of ICS during the study; proportion of patients on maintenance oral corticosteroids (OCS) at study end; rate of protocol-defined severe exacerbations per patient year; time to first severe exacerbation; number of hospital admissions for asthma; changes in lung function, Asthma Control Questionnaire-7 score, Asthma Quality of Life Questionnaire score, and T2 biomarkers from baseline to week 48; and whether patients declined to progress to OCS. A secondary aim of our study was to establish the proportion of patients with severe asthma in whom T2 biomarkers remained low when corticosteroid therapy was decreased to a minimum ICS dose. This study is registered with ClinicalTrials.gov, NCT02717689 and has been completed. Findings Patients were recruited from Jan 8, 2016, to July 12, 2018. Of 549 patients assessed, 301 patients were included in the ITT population and were randomly assigned to the biomarker strategy group (n=240) or to the control group (n=61). 28.4% of patients in the biomarker strategy group were on a lower corticosteroid dose at week 48 compared with 18.5% of patients in the control group (adjusted odds ratio [aOR] 1.71 [95% CI 0.80-3.63]; p=0.17). In the per-protocol (PP) population (n=121), a significantly greater proportion of patients were on a lower corticosteroid dose at week 48 in the biomarker strategy group (30.7% of patients) compared with the control group (5.0% of patients; aOR 11.48 [95% CI 1.35-97.83]; p=0.026). Patient choice to not follow treatment advice was the principle reason for loss to PP analysis. There was no difference in secondary outcomes between study groups and no loss of asthma control among patients in the biomarker strategy group who reduced their corticosteroid dose. Interpretation Biomarker-based corticosteroid adjustment did not result in a greater proportion of patients reducing corticosteroid dose versus control. Understanding the reasons for patients not following treatment advice in both treatment strategies is an important area for future research. The prevalence of T2 biomarker-low severe asthma was low.

Purpose A discussion forum was hosted by the Association for Applied Human Pharmacology (AGAH e.V.) to critically debate how to interpret and optimise the Investigator’s Brochure (IB) for meaningful risk assessment of early clinical trials. Materials and Methods Four topics were specifically discussed: deficiencies/uncertainties in IBs, guidance for the investigator, reference safety information, and potential risks for human subjects associated with inadequate non-clinical safety assessment in the IB. In each case, 43 participants took part in a real-time online survey with pre-defined questions to capture the audience’s opinion. Results The ‘Summary of Data and Guidance for the Investigator’ was considered as the section of the IB with the highest need for improvement with emphasis on readability, comprehensibility, timeliness of data, and appropriateness for risk assessment. It was suggested that the IB should at least be signed by the sponsor’s scientist responsible for the content on pharmacology and toxicology. It was agreed that sponsors should consider thoroughly whether changes to an IB constitute a substantial amendment, and that the IB should include a section on the change history. Non-clinical pharmacology studies with negative outcomes should be reported in the IB in order to avoid assessment bias. The reference safety information for expectedness assessment of suspected serious adverse reactions should be provided as a stand-alone section of the IB. Conclusion The overall consensus was that an optimised presentation of data will ensure the best possible understanding of a compound’s characteristics and an optimal benefit-risk assessment which will safeguard the participants in clinical trials.

Phenotype-specific omic expression patterns in people with frailty could provide invaluable insight into the underlying multi-systemic pathological processes and targets for intervention. Classical approaches to frailty have not considered the potential for different frailty phenotypes. We characterized associations between frailty (with/without disability) and sets of omic factors (genomic, proteomic, and metabolomic) plus markers measured in routine geriatric care. This study was a prevalent case control using stored biospecimens (urine, whole blood, cells, plasma, and serum) from 1522 individuals (identified as robust (R), pre-frail (P), or frail (F)] from the Toledo Study of Healthy Aging (R=178/P=184/F=109), 3 City Bordeaux (111/269/100), Aging Multidisciplinary Investigation (157/79/54) and InCHIANTI (106/98/77) cohorts. The analysis included over 35,000 omic and routine laboratory variables from robust and frail or pre-frail (with/without disability) individuals using a machine learning framework. We identified three protective biomarkers, vitamin D3 (OR: 0.81 [95% CI: 0.68-0.98]), lutein zeaxanthin (OR: 0.82 [95% CI: 0.70-0.97]), and miRNA125b-5p (OR: 0.73, [95% CI: 0.56-0.97]) and one risk biomarker, cardiac troponin T (OR: 1.25 [95% CI: 1.23-1.27]). Excluding individuals with a disability, one protective biomarker was identified, miR125b-5p (OR: 0.85, [95% CI: 0.81-0.88]). Three risks of frailty biomarkers were detected: pro-BNP (OR: 1.47 [95% CI: 1.27-1.7]), cardiac troponin T (OR: 1.29 [95% CI: 1.21-1.38]), and sRAGE (OR: 1.26 [95% CI: 1.01-1.57]). Three key frailty biomarkers demonstrated a statistical association with frailty (oxidative stress, vitamin D, and cardiovascular system) with relationship patterns differing depending on the presence or absence of a disability.