Background Progression-free survival and objective response rate assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), are based on serial radiographic assessments of tumor burden. We quantified case-level discordance between investigator and blinded independent central review (BICR)-determined progressive disease (PD) and objective response (OR) to provide benchmarks that can help clinical study teams judge whether observed discordance rates are expected or a data quality concern. Methods We performed a pooled analysis of 39 phase 2 and 3 solid-tumor trials of pembrolizumab-based regimens in which radiographic images were reviewed by investigators and BICR and RECIST v1.1 was used to assess response. Case-level discordance of PD, confirmed OR, and unconfirmed OR were calculated from 2×2 tables. Results Case-level discordance was 17.7% (95% CI 17.2–18.2) for PD (n=20,908), 12.2% (11.8–12.7) for confirmed OR (n=21,520), and 14.7% (14.1–15.3) for unconfirmed OR (n=15,209). Discordance varied by cancer type, ranging from 11.8% (melanoma) to 22.8% (hepatocellular carcinoma [HCC]) for PD, from 5.4% (HCC) to 20.0% (cervical cancer) for confirmed OR, and from 6.3% (HCC) to 19.7% (cervical cancer) for unconfirmed OR. Trials with real-time verification of progression showed lower PD discordance than those without (17.3% [95% CI 16.7-17.8] vs 20.2% [18.8-21.7]). PD discordance was similar in double-blind and open-label trials (17.6% [95% CI 16.9-18.3] vs 17.8% [17.0-18.6]). Confirmed OR discordance was more common in double-blind trials (13.3% [12.7-13.9] vs 10.9% [10.3-11.6]). Conclusion This analysis of trials of pembrolizumab-based regimens addresses a critical gap in oncology trial methodology by establishing empirical benchmarks for site–central discordance of RECIST v1.1 response assessment, enabling study teams to distinguish expected variability from potential data quality signals. While the underlying sources of discordance characterized here are not specific to immunotherapy, the reported magnitude of discordance should be applied cautiously to trials of non-immunotherapy agents.
Background Children undergoing cancer treatment are at high risk for malnutrition, poor diet quality, and early cardiometabolic risk due to treatment-related side effects, disrupted appetite, and household-level barriers to healthy eating. Caregivers play a central role in nutritional support during treatment but often experience substantial burden, time constraints, and nutrition insecurity. Food-as-medicine strategies, including medically tailored meals (MTMs), have shown promise in adult populations but remain underexplored in pediatric oncology, particularly during active treatment and within family-centered models. Objective The primary objective of this study is to evaluate the feasibility, acceptability, and adherence of From Kitchen to Clinic, a 12-week, family-centered food-as-medicine intervention that integrates MTM delivery with caregiver coaching for caregivers of children undergoing cancer treatment. Secondary objectives include collecting exploratory data on patient dietary intake, weight and lean body mass trajectories, treatment tolerance, household food and nutrition security, and caregiver burden and distress to inform a future definitive trial. Methods This prospective, single-arm feasibility study will enroll 60 caregiver–child dyads (N=120) recruited from two outpatient pediatric oncology clinics at a large children’s hospital. The 12-week intervention includes an intensive phase (weeks 1–8) with weekly MTM delivery and caregiver coaching, followed by a tapered phase (weeks 9–12) with reduced meal frequency and bi-weekly coaching. Feasibility outcomes include recruitment, retention, assessment completion, intervention adherence, and acceptability, evaluated against predefined progression criteria. Exploratory outcomes will be assessed at baseline and at 3, 6, and 12 months post-intervention using validated dietary, anthropometric, clinical, and caregiver-reported measures. Trial registration NCT07454902
Background Hypersensitivity Pneumonitis (HP) is an interstitial lung disease caused by an inhalational environmental exposure. Patients living with HP experience significant stress, uncertainty, and hypervigilance about the management of their disease and prognosis. These factors lead to reduced health-related quality of life (HRQOL), an important outcome that no interventions currently target. Objective The goal of this behavioral and educational intervention, RISE-HP, is to improve HRQOL in people who have HP. The objective of this pilot study is to assess feasibility, acceptability, and preliminary effectiveness of the RISE-HP intervention. Methods This pilot randomized controlled trial will be conducted in patients over the age of 18 with a diagnosis of HP. Forty participants will be randomly assigned to receive either the RISE-HP intervention (meetings with a peer coach focused on living well with their HP using cognitive behavioral techniques and motivational interviewing) or an attention control (general health education sessions with a research assistant) for 10 weeks. Participants will complete four additional study visits (enrollment, 5 weeks, 10 weeks, and 14 weeks after intervention start) for patient reported outcome measure completion. Primary implementation outcomes will be feasibility and acceptability. Secondary patient-centered effectiveness clinical outcomes will be improvement in HRQOL as measured by the Kings Brief Interstitial Lung Disease (KBILD) questionnaire. Additional secondary patient-reported clinical outcomes include fatigue, anxiety, depression, and self-efficacy. Conclusion Overall, this study addresses an important gap in HP care by targeting HRQOL and offers a novel non-pharmacologic patient-centered approach to therapy in patients with HP.
Background:Low back pain (LBP) is a leading cause of disability and healthcare utilization worldwide, yet management in primary care often remains inconsistent with clinical guidelines, with underuse of high-value care and persistent use of low-value interventions. The primary objective of this study is to evaluate the effectiveness of PRIME (PRImary care MultilEvel intervention for low back pain) compared with usual care in terms of cost-effectiveness (system level), back-related imaging rates (practitioner level), and self-reported disability (patient level), while concurrently examining implementation processes. Methods:This study uses an effectiveness-implementation hybrid type 1 design (NCT07137065). Effectiveness will be evaluated through a pragmatic cluster randomized controlled superiority trial conducted in primary care in Switzerland, recruiting 500 patients with LBP from February 2026 to June 2027. General practitioner quality circles will be randomized to PRIME or usual care. PRIME combines clinician training, patient education resources, automated decision support, and a stepped care pathway aligned with patients' risk of chronicity. Implementation outcomes and determinants will be assessed in the intervention group using quantitative and qualitative methods guided by established implementation frameworks. Discussion:This trial will provide a comprehensive evaluation of a multilevel intervention targeting both clinical and implementation gaps in LBP care. By integrating effectiveness and implementation outcomes, the study aims to generate actionable evidence on how high-value LBP care can be sustainably implemented in routine primary care and inform future scale-up strategies.
Background:Low back pain is often influenced by unhealthy lifestyle factors, such as physical inactivity, poor sleep, unhealthy diet, and excess weight. Despite their impact, these factors are rarely addressed in routine care for non-specific low back pain. In the Netherlands, adults with overweight or obesity can access a combined lifestyle intervention targeting physical activity, diet, sleep and stress. Integrating this intervention into standard care for non-specific low back pain may improve patient outcomes. Methods:The Back2Health study is a two-armed randomised controlled trial with parallel economic and process evaluations evaluating the (cost-)effectiveness of an integrated lifestyle intervention versus usual care on physical functioning and physical activity over 36 months in patients with persistent non-specific low back pain and overweight or obesity. In total, 318 adults will be recruited from Dutch hospitals and randomised (1:1) to either the integrated lifestyle intervention, delivered by physiotherapists trained as lifestyle coaches, or usual care.Co-primary outcomes are physical functioning and physical activity (steps/day) over 36 months. Secondary outcomes include pain intensity, systemic inflammation markers, sleep, and diet. Participants complete questionnaires every 3-6 months and attend in-person physical assessments at five timepoints. Data will be analysed according to both 'intention-to-treat' and 'per-protocol' principles. Additionally, a process and economic evaluation will be performed. Ethics and dissemination:The study protocol was approved by a medical ethics committee (METC Brabant: NL85373.028.23). Results will be published in peer-reviewed journals and presented at (inter)national conferences. Trial registration number:ClinicalTrials.gov (NCT06594796).
Background:Asthma is a leading cause of childhood morbidity. In 2020, the National Heart, Lung, and Blood Institute codified a different paradigm of asthma management, single maintenance and reliever therapy (SMART), as guideline-recommended care for children ages 5 and above requiring Step 3-4 asthma therapy. Strategies for implementing SMART and its real-world effectiveness-have not been studied in U.S. children. Methods:This hybrid type-II effectiveness-implementation trial will compare effects of two successive, cumulative implementation strategies to usual care using a clinic-level, cluster-randomized design in a large pediatric primary care network. Participating clinics will be randomized to usual care or active implementation strategies. Active implementation strategy clinics will first receive electronic health record-based clinical decision support plus education. After one year, nurse care coordinator and community health worker support will be added in active strategy clinics to help families overcome system-level barriers (e.g., insurance prior authorization, social needs support) for one year, followed by a 6-month sustainment phase. The primary implementation outcome will be visit-level SMART adoption among SMART-eligible children in a repeated cross-sectional sample assessed using difference-in-differences. The study will also assess real-world clinical effectiveness of SMART in reducing severe asthma exacerbations using target trial emulation and mechanisms of SMART implementation and effectiveness using mediation analyses. Discussion:This pragmatic hybrid effectiveness-implementation trial will test strategies for improving SMART adoption and evaluate SMART's impact on asthma outcomes. Findings will inform efforts to scale implementation and dissemination strategies nationally and build real-world evidence base for SMART effectiveness in U.S. pediatric populations. Trial registration:ClinicalTrials.gov identifiers: NCT07137923; NCT07138027. There are two ClinicalTrials.gov records, one to evaluate each implementation strategy. Registration dates: August 22, 2025.
Purpose:The PROMISE Registry is a U.S. decentralized, 20-year prospective prostate cancer germline genetic registry. Here, we examine the effectiveness of different recruitment strategies, including institutional partnerships, direct-to-patient marketing outreach, and community engagement grants (CEGs). Methods:Recruitment efforts were categorized into: (1) Institutional outreach through physician referrals, (2) Direct-to-patient marketing outreach, through online vehicles, including a PROMISE website and sponsored content, webinars, media relations, and other efforts to drive traffic to this site. Events and conferences were used on a limited basis, and (3) CEGs supported local organizations in reaching disproportionately affected populations. Effectiveness of each category was assessed through enrollment data, demographic diversity, and overall cost. Results:From May 2021 to December 2024, 5649 individuals enrolled. Marketing outreach accounted for 61% of enrollment compared to other outreach methods. Non-White and Hispanic individuals consisted of 9.4% and 2.3%, of all consented participants, respectively. Almost one-fifth (19%) of participants enrolled were estimated to face greater levels of disadvantage, as defined by the Area Deprivation Index (ADI). Conclusion:A multifaceted recruitment approach was key to exceeding recruitment goals. Online marketing and strategic partnerships with patient advocacy organizations were effective and impactful. Opportunities for future research may explore refinements in digital outreach and ways to overcome accessibility barriers to improve rates of engagement and proportional representation in clinical registries.
Introduction:The overall aim is to explore the impact of losing driving privileges and to estimate the effect of compensatory vision rehabilitation in Norwegian stroke survivors whose driver's licenses have been revoked due to VFL. Specifically, to evaluate the effect of vision rehabilitation on perceived and measured functional vision, and secondarily explore markers for perceived functional vision and functional visual field that may predict an effect of vision rehabilitation. Methods:This study is an open, randomized controlled trial (RCT) with delayed-start design. Stroke survivors aged 20-85 years (N = 52) will be recruited from a vision rehabilitation clinic in Norway and randomized into two arms: A) immediate start of eight-week home-based vision rehabilitation intervention and B) delayed start (eight weeks) of the same eight-week vision rehabilitation intervention. A quantitative and qualitative approach will be applied to assess changes in functional vision after eight weeks of vision rehabilitation, and at twelve weeks post-intervention in both groups. The quantitative analysis includes descriptive statistics, plots and inferential statistics of effects. In addition, ten participants will be recruited for qualitative individual interviews before and after the eight-week intervention to explore experiences of living with VFL and participating in the intervention. For the qualitative analysis, we will apply thematic analysis. Conclusions:The study is designed as an RCT that will give important insight into the effectiveness of vision rehabilitation for visual field loss after stroke on functional vision measured by a novel VR-vision test. Trial registration:ClinicalTrials.gov: NCT07147660.
Posttraumatic stress disorder (PTSD) and substance use disorders (SUDs) often co-occur and are associated with a more severe clinical profile than either disorder alone. Prolonged Exposure (PE) is empirically supported treatment for PTSD and has demonstrated effectiveness among those with a co-occurring SUD. However, PE is not typically offered in substance use treatment settings, in part due to concerns about feasibility, retention, and symptom exacerbation, as well as structural misfit with time-limited residential and outpatient programs. Massed Prolonged Exposure (M-PE), PE delivered multiple times per week and completed within a condensed timeframe, yields comparable treatment outcomes to PE and may better align with the structure of residential and outpatient care and address key barriers to implementation. Here, we describe an ongoing randomized controlled trial investigating the efficacy of M-PE versus trauma treatment as usual (TAU) delivered concurrent to SUD TAU, among individuals with co-occurring PTSD and substance use disorders enrolled in a comprehensive residential and outpatient SUD program. In addition to examining treatment outcomes, this trial utilizes qualitative methods to gain a deeper understanding of participants' experiences and evaluate M-PE implementation barriers and facilitators in an SUD treatment setting. We describe the development and implementation of this randomized clinical trial.
Background:Sexual minority cisgender women, transgender men and women, and nonbinary or gender diverse (SMW/TGD) people experience disproportionately high rates of hazardous drinking and posttraumatic stress symptoms, due in part to elevated exposure to trauma, stigma-related stressors and related adaptations, and barriers to accessing affirming care. Existing integrated alcohol-trauma interventions have rarely been evaluated or culturally adapted for SMW/TGD people, underscoring the need for scalable, culturally responsive approaches for this population. This protocol describes development and pilot testing of Recovery through Inhibitory learning, Self-Efficacy promoting, problem-solving, and community building (RISE), a brief, culturally responsive telehealth intervention integrating selected Unified Protocol modules with exposure-based expressive writing for trauma-exposed SMW/TGD adults with hazardous drinking and at least subthreshold PTSD symptoms. Methods:Guided by the ADAPT-ITT framework, Aim 1 will adapt RISE using community- and provider-engaged methods with 20 SMW/TGD community members and 10 mental/behavioral health providers. Aim 2 will pilot RISE in a randomized trial comparing immediate treatment (n = 30) versus 6-week waitlist control (n = 30). RISE includes four adapted Unified Protocol sessions followed by five days of expressive writing about trauma, stigma, or other adverse experiences with clinician check-ins. Feasibility, acceptability, implementation indicators, and preliminary clinical outcomes will be assessed through self-report and clinician-administered measures. Conclusion:This study will generate preliminary data regarding feasibility, acceptability, and clinical promise of a brief, scalable intervention addressing hazardous drinking, posttraumatic stress, and stigma-related stressors and related adaptations among SMW/TGD populations. Findings will inform refinement of RISE and a future fully powered randomized controlled trial. Trial registration number:Registered on 15 October 2025 (ClinicalTrials.gov identifier: NCT07217795).
Background: Antimicrobial resistance (AMR) is one of the top ten threats to global health. Over-prescription of antibiotics, a key driver of AMR, has been documented in many low- and middle-income countries. Low-cost interventions that do not add substantially to the physician workload, are consistent with good physician practices and WHO guidelines, and serve as a reminder on the risks of overprescribing antibiotics are critically needed. This protocol describes a study that aims to test the effect of two such interventions among junior physicians in Nepal. The first intervention requires physicians to specify the diagnosis in their prescription note—thus reminding them of the risks of over-prescription at the time of care. The second intervention provides individualized feedback on their actual prescription behavior. Methods: The study is a stepped-wedge randomized controlled trial among an anticipated 60 physicians in 5 hospitals in Nepal, with data collected from approximately 3600 patients over a 6-month period. Physicians in the hospitals will receive the first intervention (the mandate), sequentially, beginning at the end of the first month after a refresher training on AMR. They will receive the second intervention (the feedback), again sequentially, beginning at the end of the third month. The primary outcome is the antibiotics prescription rate, which will be assessed—for both interventions—using multilevel, mixed-effect regressions (random intercepts for physicians and fixed effects for hospitals) accounting for potential confounders. Conclusion: The study will contribute to current global efforts to combat AMR by utilizing low-cost, context-informed interventions to reduce inappropriate antibiotic prescribing in resource-limited settings.
Background Values are considered central to psychological well-being and mental health, yet the effects of brief interventions targeting valued living remain underexamined. Mobile phone-based delivery may offer a feasible way to implement values-based microinterventions in daily life, while photography may help make values more concrete and accessible. This protocol describes a randomized controlled trial evaluating three values-based microinterventions with and without photography on mental health and values-related outcomes, while also exploring the role of values practice quality as a moderating variable. Methods A three-arm, single-blind randomized controlled trial with university students will be conducted. Participants will be randomized to one of three groups: (1) Reading What Matters, a standard written values-based microintervention condition; (2) Capturing What Matters, a photography-supported version of the same microinterventions; or (3) a control group completing only the assessment protocol. Distal outcomes will be assessed at baseline, post-intervention, and two-week follow-up, and will include mental health outcomes, values-related outcomes, and baseline mental imagery ability. Proximal outcomes will be assessed repeatedly through ecological momentary assessments during the intervention period and will include momentary mental health states, momentary valued living processes, and values practice quality. Discussion This study will provide initial evidence on the effects of values-based microinterventions on mental health and valued living, the potential contribution of photography, and the role of practice quality in values-focused work.
Background Lung resection is the gold standard and the most effective curative treatment for lung cancer, especially in early-stage non-small cell lung cancer, improving long-term survival and quality of life. The growing body of evidence from randomized controlled trials supports the efficacy of prehabilitation in reducing both the incidence and severity of postoperative pulmonary complications and shortening the length of hospital stay. Objective The general objective is to compare the effects of a single education session with different prehabilitation programs in patients undergoing lung resection surgery. Methods Two hundred lung cancer patients who are going to be submitted to a lung resection surgery will be randomized into: (1) Inspiratory Muscle Training Group (n = 50), Expiratory Muscle Training Group (n = 50), Global Exercise Training Group (n = 50), and Control Group (n = 50). All patients will receive a single session in-person education session and written information regarding healthy habits to follow before, during, and after hospital discharge, and those from the IMT-G, EMT-G, and GET-G will start their 2-week prehabilitation interventions at ULS São João. Patients will be evaluated at baseline, after completing the prehabilitation program (post-intervention assessment), and 30 days post-discharge (follow-up assessment). Discussion Despite diverse intervention strategies, prehabilitation consistently proves effective in bolstering patients' functional capacity. It may also help strengthen the respiratory muscles, which in turn affect lung function and cough effectiveness after thoracic surgery. This randomized trial has been designed to compare different prehabilitation programs and analyze their inherent costs.
Background Translating clinical trials into routine healthcare remains fractured and inconsistent, reflecting an enduring challenge in bridging research and practice. Implementation science can be applied to the clinical trial context, to better understand and improve how evidence is adopted and adapted in practice. Building the clinical trial workforce capability in implementation science for clinical trial design, conduct, and dissemination has the potential to address challenges of evidence translation at a much earlier stage of the research pipeline. Aim To determine, across the Australian and New Zealand clinical trials workforce (including consumers), familiarity with and understanding of implementation science, interest to upskill in methodologies, and barriers to and preferences for, accessing support. Method Online survey developed with Likert scale and open-ended responses. Snowball recruitment from clinical trial networks and centres, and QR code promotion. Results 353 responses received across diverse geographies, professions, and clinical areas. Over 40% were unsure how to define their understanding of implementation science in the context of clinical trials. Most participants (56.7%) were familiar with some methodologies but had limited experience of using them. Training interests were moderate to high, particularly on embedding implementation science in trial design, recruitment strategies, sustainment, and scalability. Over 80% believed competency in implementation science will become essential to the clinical trial workforce in the future. Conclusion This needs assessment of a clinically, professionally and geographically diverse clinical trial workforce reflects that implementation science is an emerging field of value in this context and there is an appetite for training and support.
Background Despite the availability of high-impact maternal survival interventions along the continuum of care strategies, maternal mortality remains the major tragedy in resource poor settings. In low income countries interventions addressing role of husband and its effect on maternal health is not well studied, particularly in rural set up of Ethiopia. Therefore this study is designed to evaluate the effect of couple-based maternity education on husband involvement on maternity continuum of care. Methods We will use a cluster randomized controlled trial of two parallel groups to evaluate the effectiveness of couple-based maternity education on improving husband involvement in maternity continuum of care. Sample size is calculated by using G-power 3.1 and a 1:1 allocation ratio will be used. Sixteen kebeles will be randomly assigned to 8 interventions and 8 control groups with 248 couples in each group. Women who are in the early stages of their second trimester with their husbands will participate in the study. Group maternity education and home visits will be the intervention packages. Data analysis will be performed with an intention-to-treat analysis approach and will be analyzed using SPSS version 25.0 software. An independent effect of the intervention on the outcome of the interest will be assessed using multivariable logistic regression with generalized estimating equation model. Conclusion This trial result will generate conclusive evidence to policy makers about the effectiveness of couple-based maternity education to empower husband involvement in maternity continuum of care in rural Ethiopia. Trial registration This trial was prospectively registered with the African Clinical Trials Registry on 04 December 2025 (PACTR202512868895726).
Introduction:Obstructive sleep apnea (OSA) is highly prevalent, yet current treatment remains limited. Poor adherence to positive airway pressure (PAP) and barriers associated with injectable therapies can limit potential therapeutic options for moderate-to-severe OSA. The SURMOUNT-OSA trials demonstrated that tirzepatide contributes to OSA severity improvements; however, the injectable mode of administration introduces barriers that may limit accessibility and long-term adherence. Orforglipron, a once daily oral glucagon-like-peptide-1 receptor agonist, may offer a more feasible and accepted therapeutic option. ATTAIN-OSA was developed to evaluate the efficacy and safety of oral orforglipron in adults with moderate-to-severe OSA. Methods:ATTAIN-OSA is a master protocol with two multicenter, randomized, double-blind, placebo-controlled Phase 3 trials enrolling adults with moderate-to-severe OSA and obesity or overweight. Study 1 includes participants unable or unwilling to use PAP. Study 2 includes participants who use PAP and complete a protocol-mandated washout before baseline polysomnography. Participants are randomly assigned to placebo or orforglipron capsule formulation at maximum tolerated dose (12, 24, or 36 mg) for 52 weeks following a standardized dose escalation schedule. Results:The primary endpoint is change in Apnea-Hypopnea Index (AHI) at Week 52. Key secondary endpoints include sleep apnea-specific hypoxic burden, Patient-Reported Outcomes Measurement Information System sleep-related impairment, high-sensitivity C-reactive protein, and body weight, and other AHI-related endpoints. Overall, 712 participants have been randomized to orforglipron or placebo (Study 1, n = 363; Study 2, n = 349). Conclusion:ATTAIN-OSA evaluates if once-daily oral orforglipron can provide an effective and more accessible therapeutic approach to treat moderate-to-severe OSA in adults with obesity or overweight. Trial registration:ClinicalTrials.gov, NCT06649045.
Background Time-to-event endpoints, such as progression-free survival (PFS), are used to evaluate clinical activity in early-phase RCTs in cancer research. Because the power to detect a reduction in the hazard rate depends on the number of events observed, recruiting enough patients with a rare cancer can be difficult. Bayesian designs that leverage historical control data to augment the control arm are sought in rare cancers because there is a practical and ethical willingness to trade modest increases in bias and Type 1 error, particularly under prior-new data conflict, for meaningful reductions in variance and improved feasibility. Purpose The purpose is to provide a real-world, from beginning to end application to design a time-to-event hybrid-controlled trial for a rare cancer with best alternative care (BAC) as the control that uses robust borrowing from six BAC PFS data sources and explicitly evaluates the operating characteristics across degrees of prior-new data conflict. Methods A simulation-based approach for Bayesian sample size determination was used and calibrated to possess good frequentist Type 1 and 2 error properties. Results A Bayesian hybrid-controlled RCT resulted in a 28% reduction in the number of participants needed to detect a 50% reduction in the hazard rate compared with a traditional frequentist design with the same power. Conclusions Utilizing historical BAC PFS data from 309 patients with liver-predominant metastasis from primary ocular melanoma can enhance trial efficiency by assigning fewer subjects to the control arm and potentially lead to the earlier availability of effective therapies to patients with this rare cancer.
