Design and rationale for an empirical investigation of the resource use and costs of investigator-initiated randomized trials in Switzerland, the UK, and Germany.

BACKGROUND: Conducting high-quality randomized clinical trials (RCTs) is challenging, time consuming, and resource intense. Academic investigators usually depend on scarce financial resources; however, current literature lacks systematically collected empirical data on the detailed resource use and costs of investigator-initiated RCTs. METHODS: The aim of this study is to generate a database of detailed empirical resource use and cost data from 100 investigator-initiated RCTs in Switzerland, Germany, and the UK. Investigators enter their empirical costs data into an online data collection form, which is followed by a short interview and a detailed cost report. We plan to investigate cost patterns and cost drivers and examine planned versus actual RCT costs as well as explore different strata of costs across the planning, conduct, and finalization phases, in drug and non-drug trials, and across medical fields and countries. DISCUSSION: This study will add detailed empirical data to the limited research on investigator-initiated RCT costs currently available. A study limitation will be that cost data will be retrospective and self-reported, which might be inaccurate depending on how costs were recorded. TRIAL REGISTRATION: Open Science Framework (OSF) https://doi.org/10.17605/OSF.IO/QY2GU . Registered on June 4, 2021.

Resource use and costs of investigator-sponsored randomised clinical trials in Switzerland, Germany and the United Kingdom: a meta-research study.

BACKGROUND: Conducting high-quality randomised clinical trials (RCTs) is challenging and resource intensive. Funders and academic investigators depend on limited financial resources and, therefore, need empirical data for optimal budget planning. However, current literature lacks detailed empirical data on resource use and costs of investigator-sponsored RCTs. The aim of this study is to systematically collect cost data from investigator-sponsored RCTs from Switzerland, Germany, and the United Kingdom (UK). METHODS: Principal investigators were asked to share their RCT cost and resource use data and enter it into an online case report form. We assessed cost patterns, cost drivers, and specific cost items, examined costs by study phase (planning-, conduct-, and finalisation phase), compared planned with actual RCT costs, and explored differences in cost patterns across countries, medical fields, and intervention types. RESULTS: We included 93 RCTs which were initiated in Switzerland (n=53; including 8 conducted in low- and lower middle-income countries), Germany (n=22), and the UK (n=18). The median total trial cost in our RCT sample was $645,824 [Interquartile range (IQR), $269,846 to $1,577,924]. The median proportion of the total costs spent for planning phase was 27.5% [IQR, 20.6 to 39.7%], for conduct phase 57.3% [IQR, 44.4%-66.3%], and for finalisation phase 12.7% [IQR, 8.5% to 19.3%] with little variation across countries. The items that contributed most to the total costs were protocol writing (7.2%; IQR 3.8% to 10.6%), data management (5.0%; IQR 2.2% to 8.1%) and follow up (4.5%; IQR 2.3% to 8.4%). Of the 66 RCTs with an available original budget, 46 (69.7%) exceeded the budget by over 50%. Use of routinely collected data to assess primary outcomes was independently associated with lower per patient- and lower total trial costs. CONCLUSIONS: Over a quarter of total trial costs were incurred in the planning phase, which is typically not fully funded. Two thirds of RCTs exceeded their budget by more than 50%. Investigators and funders should consider empirical cost data to improve budgeting and funding practices.

Characteristics, consent patterns, and challenges of randomized trials using the Trials within Cohorts (TwiCs) design - A scoping review.

OBJECTIVES: Trials within Cohorts (TwiCs) is a pragmatic design approach that may overcome frequent challenges of traditional randomized trials such as slow recruitment, burdensome consent procedures, or limited external validity. This scoping review aims to identify all randomized controlled trials using the TwiCs design and to summarize their design characteristics, ways to obtain informed consent, output, reported challenges and mitigation strategies. STUDY DESIGN AND SETTING: Systematic search of Medline, Embase, Cochrane, trial registries and citation tracking up to December 2022. TwiCs were defined as randomized trials embedded in a cohort with postrandomization consent for the intervention group and no specific postrandomization consent for the usual care control group. Information from identified TwiCs was extracted in duplicate from protocols, publications, and registry entries. We analyzed the information descriptively and qualitatively to highlight methodological challenges and solutions related to nonuptake of interventions and informed consent procedure. RESULTS: We identified a total of 46 TwiCs conducted between 2005 and 2022 in 14 different countries by a handful of research groups. The most common medical fields were oncology (11/46; 24%), infectious diseases (8/46; 17%), and mental health (7/46; 15%). A typical TwiCs was investigator-initiated (46/46; 100%), publicly funded (36/46; 78%), and recruited outpatients (27/46; 59%). Excluding eight pilot trials, only 16/38 (42%) TwiCs adjusted their calculated sample size for nonuptake of the intervention, anticipating a median nonuptake of 25% (interquartile range 10%-32%) in the experimental arm. Seventeen TwiCs (45%) planned analyses to adjust effect estimates for nonuptake. Regarding informed consent, we observed three patterns: 1) three separate consents for cohort participation, randomization, and intervention (17/46; 37%); 2) combined consent for cohort participation and randomization and a separate intervention consent (10/46; 22%); and 3) consent only for cohort participation and intervention (randomization consent not mentioned; 19/46; 41%). CONCLUSION: Existing TwiCs are globally scattered across a few research groups covering a wide range of medical fields and interventions. Despite the potential advantages, the number of TwiCs remains small. The variability in consent procedures and the possibility of substantial nonuptake of the intervention warrants further research to guide the planning, implementation, and analysis of TwiCs.

Antibody and T-Cell Response to Bivalent Booster SARS-CoV-2 Vaccines in People With Compromised Immune Function: COVERALL-3 Study.

BACKGROUND: Bivalent messenger RNA (mRNA) vaccines, designed to combat emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, incorporate ancestral strains and a new variant. Our study assessed the immune response in previously vaccinated individuals of the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS) following bivalent mRNA vaccination. METHODS: Eligible SHCS and STCS participants received approved bivalent mRNA SARS-CoV-2 vaccines (mRNA-1273.214 or BA.1-adapted BNT162b2) within clinical routine. Blood samples were collected at baseline, 4 weeks, 8 weeks, and 6 months postvaccination. We analyzed the proportion of participants with anti-spike protein antibody response ≥1642 units/mL (indicating protection against SARS-CoV-2 infection), and in a subsample T-cell response (including mean concentrations), stratifying results by cohorts and population characteristics. RESULTS: In SHCS participants, baseline anti-spike antibody concentrations ≥1642 units/mL were observed in 87% (96/112), reaching nearly 100% at follow-ups. Among STCS participants, 58% (35/60) had baseline antibodies ≥1642 units/mL, increasing to 80% at 6 months. Except for lung transplant recipients, all participants showed a 5-fold increase in geometric mean antibody concentrations at 4 weeks and a reduction by half at 6 months. At baseline, T-cell responses were positive in 96% (26/27) of SHCS participants and 36% (16/45) of STCS participants (moderate increase to 53% at 6 months). Few participants reported SARS-CoV-2 infections, side-effects, or serious adverse events. CONCLUSIONS: Bivalent mRNA vaccination elicited a robust humoral response in individuals with human immunodeficiency virus (HIV) or solid organ transplants, with delayed responses in lung transplant recipients. Despite a waning effect, antibody levels remained high at 6 months and adverse events were rare. Clinical Trials Registration . NCT04805125.

Community-based management of arterial hypertension and cardiovascular risk factors by lay village health workers for people with controlled and uncontrolled blood pressure in rural Lesotho: joint protocol for two cluster-randomized trials within the ComBaCaL cohort study (ComBaCaL aHT Twic 1 and ComBaCaL aHT TwiC 2).

BACKGROUND: Arterial hypertension (aHT) is a major cause for premature morbidity and mortality. Control rates remain poor, especially in low- and middle-income countries. Task-shifting to lay village health workers (VHWs) and the use of digital clinical decision support systems may help to overcome the current aHT care cascade gaps. However, evidence on the effectiveness of comprehensive VHW-led aHT care models, in which VHWs provide antihypertensive drug treatment and manage cardiovascular risk factors is scarce. METHODS: Using the trials within the cohort (TwiCs) design, we are assessing the effectiveness of VHW-led aHT and cardiovascular risk management in two 1:1 cluster-randomized trials nested within the Community-Based chronic disease Care Lesotho (ComBaCaL) cohort study (NCT05596773). The ComBaCaL cohort study is maintained by trained VHWs and includes the consenting inhabitants of 103 randomly selected villages in rural Lesotho. After community-based aHT screening, adult, non-pregnant ComBaCaL cohort participants with uncontrolled aHT (blood pressure (BP) ≥ 140/90 mmHg) are enrolled in the aHT TwiC 1 and those with controlled aHT (BP < 140/90 mmHg) in the aHT TwiC 2. In intervention villages, VHWs offer lifestyle counseling, basic guideline-directed antihypertensive, lipid-lowering, and antiplatelet treatment supported by a tablet-based decision support application to eligible participants. In control villages, participants are referred to a health facility for therapeutic management. The primary endpoint for both TwiCs is the proportion of participants with controlled BP levels (< 140/90 mmHg) 12 months after enrolment. We hypothesize that the intervention is superior regarding BP control rates in participants with uncontrolled BP (aHT TwiC 1) and non-inferior in participants with controlled BP at baseline (aHT TwiC 2). DISCUSSION: The TwiCs were launched on September 08, 2023. On May 20, 2024, 697 and 750 participants were enrolled in TwiC 1 and TwiC 2. To our knowledge, these TwiCs are the first trials to assess task-shifting of aHT care to VHWs at the community level, including the prescription of basic antihypertensive, lipid-lowering, and antiplatelet medication in Africa. The ComBaCaL cohort and nested TwiCs are operating within the routine VHW program and countries with similar community health worker programs may benefit from the findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05684055. Registered on January 04, 2023.

Characteristics, Progression, and Output of Randomized Platform Trials: A Systematic Review.

Importance: Platform trials have become increasingly common, and evidence is needed to determine how this trial design is actually applied in current research practice. Objective: To determine the characteristics, progression, and output of randomized platform trials. Evidence Review: In this systematic review of randomized platform trials, Medline, Embase, Scopus, trial registries, gray literature, and preprint servers were searched, and citation tracking was performed in July 2022. Investigators were contacted in February 2023 to confirm data accuracy and to provide updated information on the status of platform trial arms. Randomized platform trials were eligible if they explicitly planned to add or drop arms. Data were extracted in duplicate from protocols, publications, websites, and registry entries. For each platform trial, design features such as the use of a common control arm, use of nonconcurrent control data, statistical framework, adjustment for multiplicity, and use of additional adaptive design features were collected. Progression and output of each platform trial were determined by the recruitment status of individual arms, the number of arms added or dropped, and the availability of results for each intervention arm. Findings: The search identified 127 randomized platform trials with a total of 823 arms; most trials were conducted in the field of oncology (57 [44.9%]) and COVID-19 (45 [35.4%]). After a more than twofold increase in the initiation of new platform trials at the beginning of the COVID-19 pandemic, the number of platform trials has since declined. Platform trial features were often not reported (not reported: nonconcurrent control, 61 of 127 [48.0%]; multiplicity adjustment for arms, 98 of 127 [77.2%]; statistical framework, 37 of 127 [29.1%]). Adaptive design features were only used by half the studies (63 of 127 [49.6%]). Results were available for 65.2% of closed arms (230 of 353). Premature closure of platform trial arms due to recruitment problems was infrequent (5 of 353 [1.4%]). Conclusions and Relevance: This systematic review found that platform trials were initiated most frequently during the COVID-19 pandemic and declined thereafter. The reporting of platform features and the availability of results were insufficient. Premature arm closure for poor recruitment was rare.

Methods proposed for monitoring the implementation of evidence-based research: a cross-sectional study.

OBJECTIVES: Evidence-based research (EBR) is the systematic and transparent use of prior research to inform a new study so that it answers questions that matter in a valid, efficient, and accessible manner. This study surveyed experts about existing (e.g., citation analysis) and new methods for monitoring EBR and collected ideas about implementing these methods. STUDY DESIGN AND SETTING: We conducted a cross-sectional study via an online survey between November 2022 and March 2023. Participants were experts from the fields of evidence synthesis and research methodology in health research. Open-ended questions were coded by recurring themes; descriptive statistics were used for quantitative questions. RESULTS: Twenty-eight expert participants suggested that citation analysis should be supplemented with content evaluation (not just what is cited but also in which context), content expert involvement, and assessment of the quality of cited systematic reviews. They also suggested that citation analysis could be facilitated with automation tools. They emphasized that EBR monitoring should be conducted by ethics committees and funding bodies before the research starts. Challenges identified for EBR implementation monitoring were resource constraints and clarity on responsibility for EBR monitoring. CONCLUSION: Ideas proposed in this study for monitoring the implementation of EBR can be used to refine methods and define responsibility but should be further explored in terms of feasibility and acceptability. Different methods may be needed to determine if the use of EBR is improving over time.

Bridging the gap: identifying factors impacting mRNA severe acute respiratory syndrome coronavirus 2 vaccine booster response in people with HIV-1.

OBJECTIVES: This study aimed to investigate the association of demographic and clinical characteristics, including HIV-specific parameters with the antibody response to a third dose of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine in people with HIV-1 (PWH). DESIGN: Post hoc analysis of data collected during the observational extension of the COrona VaccinE tRiAL pLatform trial (COVERALL-2) nested into the Swiss HIV Cohort Study (SHCS). METHODS: Serological measurements were conducted on a total of 439 PWH who had received a third dose of either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) SARS-CoV-2 vaccine. Antibody reactivity was assessed using the multifactorial ABCORA immunoassay that defines SARS-CoV-2 seroconversion and predicts neutralization activity. The association between log transformed antibody reactivity and various baseline factors, including vaccine type, demographics, immune and viral status, smoking status, comorbidities, infection history, and co-medication with chemotherapy and immunosuppressive drugs, was investigated using a multivariable linear regression model. RESULTS: Antibody response to third SARS-CoV-2 vaccination was significantly lower among PWH with CD4 + cell count less than 350 cells/µl [ratio of means 0.79; 95% confidence interval (CI) 0.65-0.95]. Having a detectable HIV-1 viral load at least 50 copies/ml and being on concurrent chemotherapy was associated with an overall lower humoral immune response (ratio of means 0.75; 95% CI 0.57-1.00 and 0.34; 95% CI 0.22-0.52, respectively). CONCLUSION: The study highlights the importance of optimal antiretroviral treatment for PWH, emphasizing the need for timely intervention to enhance the vaccine immunogenicity in this population. Moreover, it underscores the significance of sequential mRNA vaccination and provides important evidence for informing vaccine guidelines.

Compelling evidence from meta-epidemiological studies demonstrates overestimation of effects in randomized trials that fail to optimize randomization and blind patients and outcome assessors.

OBJECTIVES: To investigate the impact of potential risk of bias elements on effect estimates in randomized trials. STUDY DESIGN AND SETTING: We conducted a systematic survey of meta-epidemiological studies examining the influence of potential risk of bias elements on effect estimates in randomized trials. We included only meta-epidemiological studies that either preserved the clustering of trials within meta-analyses (compared effect estimates between trials with and without the potential risk of bias element within each meta-analysis, then combined across meta-analyses; between-trial comparisons), or preserved the clustering of substudies within trials (compared effect estimates between substudies with and without the element, then combined across trials; within-trial comparisons). Separately for studies based on between- and within-trial comparisons, we extracted ratios of odds ratios (RORs) from each study and combined them using a random-effects model. We made overall inferences and assessed certainty of evidence based on Grading of Recommendations, Assessment, development, and Evaluation and Instrument to assess the Credibility of Effect Modification Analyses. RESULTS: Forty-one meta-epidemiological studies (34 of between-, 7 of within-trial comparisons) proved eligible. Inadequate random sequence generation (ROR 0.94, 95% confidence interval [CI] 0.90-0.97) and allocation concealment (ROR 0.92, 95% CI 0.88-0.97) probably lead to effect overestimation (moderate certainty). Lack of patients blinding probably overestimates effects for patient-reported outcomes (ROR 0.36, 95% CI 0.28-0.48; moderate certainty). Lack of blinding of outcome assessors results in effect overestimation for subjective outcomes (ROR 0.69, 95% CI 0.51-0.93; high certainty). The impact of patients or outcome assessors blinding on other outcomes, and the impact of blinding of health-care providers, data collectors, or data analysts, remain uncertain. Trials stopped early for benefit probably overestimate effects (moderate certainty). Trials with imbalanced cointerventions may overestimate effects, while trials with missing outcome data may underestimate effects (low certainty). Influence of baseline imbalance, compliance, selective reporting, and intention-to-treat analysis remain uncertain. CONCLUSION: Failure to ensure random sequence generation or adequate allocation concealment probably results in modest overestimates of effects. Lack of patients blinding probably leads to substantial overestimates of effects for patient-reported outcomes. Lack of blinding of outcome assessors results in substantial effect overestimation for subjective outcomes. For other elements, though evidence for consistent systematic overestimate of effect remains limited, failure to implement these safeguards may still introduce important bias.

Adjunct prednisone in community-acquired pneumonia: 180-day outcome of a multicentre, double-blind, randomized, placebo-controlled trial.

BACKGROUND: Several trials and meta-analyses found a benefit of adjunct corticosteroids for community-acquired pneumonia with respect to short-term outcome, but there is uncertainty about longer-term health effects. Herein, we evaluated clinical outcomes at long term in patients participating in the STEP trial (Corticosteroid Treatment for Community-Acquired Pneumonia). METHODS: This predefined secondary analysis investigated 180-day outcomes in 785 adult patients hospitalized with community-acquired pneumonia included in STEP, a randomised, placebo-controlled, double-blind trial. The primary endpoint was time to death from any cause at 180 days verified by telephone interview. Additional secondary endpoints included pneumonia-related death, readmission, recurrent pneumonia, secondary infections, new hypertension, and new insulin dependence. RESULTS: From the originally included 785 patients, 727 were available for intention-to-treat analysis at day 180. There was no difference between groups with respect to time to death from any cause (HR for corticosteroid use 1.15, 95% CI 0.68 to 1.95, p = 0.601). Compared to placebo, corticosteroid-treated patients had significantly higher risks for recurrent pneumonia (OR 2.57, 95% CI 1.29 to 5.12, p = 0.007), secondary infections (OR 1.94, 95% CI 1.25 to 3.03, p = 0.003) and new insulin dependence (OR 8.73, 95% CI 1.10 to 69.62, p = 0.041). There was no difference regarding pneumonia-related death, readmission and new hypertension. CONCLUSIONS: In patients with community-acquired pneumonia, corticosteroid use was associated with an increased risk for recurrent pneumonia, secondary infections and new insulin dependence at 180 days. Currently, it is uncertain whether these long-term adverse effects outweigh the short-term effects of corticosteroids in moderate CAP. TRIAL REGISTRATION: This trial was registered with ClinicalTrials. gov, number NCT00973154 before the recruitment of the first patient. First posted: September 9, 2009. Last update posted: April 21, 2015.

Antibody Response After the Third SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients and People Living With HIV (COVERALL-2).

Background: After basic immunization with 2 mRNA SARS-CoV-2 vaccine doses, only a small proportion of patients who are severely immunocompromised generate a sufficient antibody response. Hence, we assessed the additional benefit of a third SARS-CoV-2 vaccine in patients with different levels of immunosuppression. Methods: In this observational extension of the COVERALL trial (Corona Vaccine Trial Platform), we recruited patients from the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study (ie, lung and kidney transplant recipients). We collected blood samples before and 8 weeks after the third SARS-CoV-2 vaccination with either mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech). The primary outcome was the proportion of participants showing an antibody response (Elecsys Anti-SARS-CoV-2 S test; threshold ≥100 U/mL) 8 weeks after the third SARS-CoV-2 vaccination. We also compared the proportion of patients who reached the primary outcome from basic immunization (the first and second vaccines) to the third vaccination. Results: Nearly all participants (97.2% [95% CI, 95.9%-98.6%], 564/580) had an antibody response. This response was comparable between mRNA-1273 (96.1% [95% CI, 93.7%-98.6%], 245/255) and BNT162b2 (98.2% [95% CI, 96.7%-99.6%], 319/325). Stratification by cohort showed that 99.8% (502/503) of people living with HIV and 80.5% (62/77) of recipients of solid organ transplants achieved the primary endpoint. The proportion of patients with an antibody response in solid organ transplant recipients improved from the second vaccination (22.7%, 15/66) to the third (80.5%, 62/77). Conclusions: People living with HIV had a high antibody response. The third vaccine increased the proportion of solid organ transplant recipients with an antibody response. Clinical Trials Registration. NCT04805125 (ClinicalTrials.gov).

Community-based type 2 diabetes care by lay village health workers in rural Lesotho: protocol for a cluster-randomized trial within the ComBaCaL cohort study (ComBaCaL T2D TwiC).

BACKGROUND: Type 2 diabetes (T2D) poses a growing public health burden, especially in low- and middle-income countries (LMICs). Task-shifting to lay village health workers (VHWs) and the use of digital clinical decision support systems (CDSS) are promising approaches to tackle the current T2D care gap in LMICs. However, evidence on the effectiveness of lay worker-led T2D care models, in which VHWs initiate and monitor drug treatment in addition to community-based screening and referral services, is lacking. METHODS: We are conducting a cluster-randomized trial nested within the Community-Based Chronic Disease Care Lesotho (ComBaCaL) cohort study (NCT05596773) using the trial within cohort (TwiC) design to assess the effectiveness of a VHW-led, CDSS-assisted T2D care model in rural Lesotho. Participants are non-pregnant members of the ComBaCaL cohort study with T2D. The ComBaCaL cohort study is conducted in approximately 100 villages in two rural districts in Lesotho and is managed by trained and supervised VHWs. In intervention villages, VHWs offer a community-based T2D care package including lifestyle counselling, first-line oral antidiabetic, lipid-lowering, and antiplatelet treatment guided by a tablet-based CDSS to participants who are clinically eligible, as well as treatment support to participants who prefer or clinically require facility-based T2D care. In control clusters, all participants will be referred to a health facility for T2D management. The primary endpoint is the mean glycosylated haemoglobin (HbA1c) 12 months after enrolment. Secondary endpoints include the 10-year risk for cardiovascular events estimated using the World Health Organization risk prediction tool. DISCUSSION: The trial was launched on May 13, 2023, and has enrolled 226 participants at the date of submission (October 6, 2023). To our knowledge, the trial is the first to assess task-shifting of T2D care to VHWs at the community level, including the prescription of first-line antidiabetic, lipid-lowering, and antiplatelet medication in sub-Saharan Africa, and will thus provide the missing evidence on the effectiveness of such a T2D care model in this setting. The study is operating within the established Lesotho VHW programme. Similar community health worker programmes which exist across sub-Saharan Africa may benefit from the findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT05743387. Registered on February 24 2023.

Evaluating the impact of including non-randomised studies of interventions in meta-analysis of randomised controlled trials: a protocol for a meta-epidemiological study.

INTRODUCTION: Although interest in including non-randomised studies of interventions (NRSIs) in meta-analysis of randomised controlled trials (RCTs) is growing, estimates of effectiveness obtained from NRSIs are vulnerable to greater bias than RCTs. The objectives of this study are to: (1) explore how NRSIs can be integrated into a meta-analysis of RCTs; (2) assess concordance of the evidence from non-randomised and randomised trials and explore factors associated with agreement; and (3) investigate the impact on estimates of pooled bodies of evidence when NRSIs are included. METHODS AND ANALYSIS: We will conduct a systematic survey of 210 systematic reviews that include both RCTs and NRSIs, published from 2017 to 2022. We will randomly select reviews, stratified in a 1:1 ratio by Core vs non-Core clinical journals, as defined by the National Library of Medicine. Teams of paired reviewers will independently determine eligibility and abstract data using standardised, pilot-tested forms. The concordance of the evidence will be assessed by exploring agreement in the relative effect reported by NRSIs and RCT addressing the same clinical question, defined as similarity of the population, intervention/exposure, control and outcomes. We will conduct univariable and multivariable logistic regression analyses to examine the association of prespecified study characteristics with agreement in the estimates between NRSIs and RCTs. We will calculate the ratio of the relative effect estimate from NRSIs over that from RCTs, along with the corresponding 95% CI. We will use a bias-corrected meta-analysis model to investigate the influence on pooled estimates when NRSIs are included in the evidence synthesis. ETHICS AND DISSEMINATION: Ethics approval is not required. The findings of this study will be disseminated through peer-reviewed publications, conference presentations and condensed summaries for clinicians, health policymakers and guideline developers regarding the design, conduct, analysis, and interpretation of meta-analysis that integrate RCTs and NRSIs.

Reminding Peer Reviewers of Reporting Guideline Items to Improve Completeness in Published Articles: Primary Results of 2 Randomized Trials.

Importance: Numerous studies have shown that adherence to reporting guidelines is suboptimal. Objective: To evaluate whether asking peer reviewers to check if specific reporting guideline items were adequately reported would improve adherence to reporting guidelines in published articles. Design, Setting, and Participants: Two parallel-group, superiority randomized trials were performed using manuscripts submitted to 7 biomedical journals (5 from the BMJ Publishing Group and 2 from the Public Library of Science) as the unit of randomization, with peer reviewers allocated to the intervention or control group. Interventions: The first trial (CONSORT-PR) focused on manuscripts that presented randomized clinical trial (RCT) results and reported following the Consolidated Standards of Reporting Trials (CONSORT) guideline, and the second trial (SPIRIT-PR) focused on manuscripts that presented RCT protocols and reported following the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline. The CONSORT-PR trial included manuscripts that described RCT primary results (submitted July 2019 to July 2021). The SPIRIT-PR trial included manuscripts that contained RCT protocols (submitted June 2020 to May 2021). Manuscripts in both trials were randomized (1:1) to the intervention or control group; the control group received usual journal practice. In the intervention group of both trials, peer reviewers received an email from the journal that asked them to check whether the 10 most important and poorly reported CONSORT (for CONSORT-PR) or SPIRIT (for SPIRIT-PR) items were adequately reported in the manuscript. Peer reviewers and authors were not informed of the purpose of the study, and outcome assessors were blinded. Main Outcomes and Measures: The difference in the mean proportion of adequately reported 10 CONSORT or SPIRIT items between the intervention and control groups in published articles. Results: In the CONSORT-PR trial, 510 manuscripts were randomized. Of those, 243 were published (122 in the intervention group and 121 in the control group). A mean proportion of 69.3% (95% CI, 66.0%-72.7%) of the 10 CONSORT items were adequately reported in the intervention group and 66.6% (95% CI, 62.5%-70.7%) in the control group (mean difference, 2.7%; 95% CI, -2.6% to 8.0%). In the SPIRIT-PR trial, of the 244 randomized manuscripts, 178 were published (90 in the intervention group and 88 in the control group). A mean proportion of 46.1% (95% CI, 41.8%-50.4%) of the 10 SPIRIT items were adequately reported in the intervention group and 45.6% (95% CI, 41.7% to 49.4%) in the control group (mean difference, 0.5%; 95% CI, -5.2% to 6.3%). Conclusions and Relevance: These 2 randomized trials found that it was not useful to implement the tested intervention to increase reporting completeness in published articles. Other interventions should be assessed and considered in the future. Trial Registration: ClinicalTrials.gov Identifiers: NCT05820971 (CONSORT-PR) and NCT05820984 (SPIRIT-PR).

Development of a risk-tailored approach and dashboard for efficient management and monitoring of investigator-initiated trials.

BACKGROUND: Most randomized controlled trials (RCTs) in the academic setting have limited resources for clinical trial management and monitoring. Inefficient conduct of trials was identified as an important source of waste even in well-designed studies. Thoroughly identifying trial-specific risks to enable focussing of monitoring and management efforts on these critical areas during trial conduct may allow for the timely initiation of corrective action and to improve the efficiency of trial conduct. We developed a risk-tailored approach with an initial risk assessment of an individual trial that informs the compilation of monitoring and management procedures in a trial dashboard. METHODS: We performed a literature review to identify risk indicators and trial monitoring approaches followed by a contextual analysis involving local, national and international stakeholders. Based on this work we developed a risk-tailored management approach with integrated monitoring for RCTs and including a visualizing trial dashboard. We piloted the approach and refined it in an iterative process based on feedback from stakeholders and performed formal user testing with investigators and staff of two clinical trials. RESULTS: The developed risk assessment comprises four domains (patient safety and rights, overall trial management, intervention management, trial data). An accompanying manual provides rationales and detailed instructions for the risk assessment. We programmed two trial dashboards tailored to one medical and one surgical RCT to manage identified trial risks based on daily exports of accumulating trial data. We made the code for a generic dashboard available on GitHub that can be adapted to individual trials. CONCLUSIONS: The presented trial management approach with integrated monitoring enables user-friendly, continuous checking of critical elements of trial conduct to support trial teams in the academic setting. Further work is needed in order to show effectiveness of the dashboard in terms of safe trial conduct and successful completion of clinical trials.

Antibody Response After Third Vaccination With mRNA-1273 or BNT162b2: Extension of a Randomized Controlled SARS-CoV-2 Noninferiority Vaccine Trial in Patients With Different Levels of Immunosuppression (COVERALL-2).

Extension of the COVERALL (COrona VaccinE tRiAL pLatform) randomized trial showed noninferiority in antibody response of the third dose of Moderna mRNA-1273 vaccine (95.3% [95% confidence interval {CI}, 91.9%-98.7%]) compared to Pfizer-BioNTech BNT162b2 vaccine (98.1% [95% CI, 95.9%-100.0%]) in individuals with different levels of immunosuppression (difference, -2.8% [95% CI, -6.8% to 1.3%]).

GRADE guidance 36: updates to GRADE's approach to addressing inconsistency.

OBJECTIVES: To update previous Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance by addressing inconsistencies and interpreting subgroup analyses. STUDY DESIGN AND SETTING: Using an iterative process, we consulted with members of the GRADE working group through multiple rounds of written feedback and discussions at GRADE working group meetings. RESULTS: The guidance complements previous guidance with clarification in two areas: (1) assessing inconsistency and (2) assessing the credibility of possible effect modifiers that might explain inconsistency. Specifically, the guidance clarifies that inconsistency refers to variability in results, not in study characteristics; that inconsistency assessment for binary outcomes requires consideration of both relative and absolute effects; how to decide between narrower and broader questions in systematic reviews and guidelines; that, with the same evidence, ratings of inconsistency may differ depending on the target of certainty rating; and how GRADE inconsistency ratings relate to a statistical measure of inconsistency I2 depending on the context in which one views results. The second part of the guidance illustrates, based on a worked example, the use of the instrument to assess the credibility of effect modification analyses. The guidance explains the stepwise process of moving from a subgroup analysis to assessing the credibility of effect modification and, if found credible, to subgroup-specific effect estimates and GRADE certainty ratings. CONCLUSION: This updated guidance addresses specific conceptual and practical issues that systematic review authors frequently face when considering the degree of inconsistency in estimates of treatment effects across studies.

Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials.

BACKGROUND: Interpretation of the evidence from randomised controlled trials (RCTs) of remdesivir in patients treated in hospital for COVID-19 is conflicting. We aimed to assess the benefits and harms of remdesivir compared with placebo or usual care in these patients, and whether treatment effects differed between prespecified patient subgroups. METHODS: For this systematic review and meta-analysis, we searched PubMed, Embase, the Cochrane COVID-19 trial registry, ClinicalTrials.gov, the International Clinical Trials Registry Platform, and preprint servers from Jan 1, 2020, until April 11, 2022, for RCTs of remdesivir in adult patients hospitalised with COVID-19, and contacted the authors of eligible trials to request individual patient data. The primary outcome was all-cause mortality at day 28 after randomisation. We used multivariable hierarchical regression-adjusting for respiratory support, age, and enrollment period-to investigate effect modifiers. This study was registered with PROSPERO, CRD42021257134. FINDINGS: Our search identified 857 records, yielding nine RCTs eligible for inclusion. Of these nine eligible RCTs, individual data were provided for eight, covering 10 480 patients hospitalised with COVID-19 (99% of such patients included in such RCTs worldwide) recruited between Feb 6, 2020, and April 1, 2021. Within 28 days of randomisation, 662 (12·5%) of 5317 patients assigned to remdesivir and 706 (14·1%) of 5005 patients assigned to no remdesivir died (adjusted odds ratio [aOR] 0·88, 95% CI 0·78-1·00, p=0·045). We found evidence for a credible subgroup effect according to respiratory support at baseline (pinteraction=0·019). Of patients who were ventilated-including those who received high-flow oxygen-253 (30·0%) of 844 patients assigned to remdesivir died compared with 241 (28·5%) of 846 patients assigned to no remdesivir (aOR 1·10 [0·88-1·38]; low-certainty evidence). Of patients who received no oxygen or low-flow oxygen, 409 (9·1%) of 4473 patients assigned to remdesivir died compared with 465 (11·2%) of 4159 patients assigned to no remdesivir (0·80 [0·70-0·93]; high-certainty evidence). No credible subgroup effect was found for time to start of remdesivir after symptom onset, age, presence of comorbidities, enrolment period, or corticosteroid use. Remdesivir did not increase the frequency of severe or serious adverse events. INTERPRETATION: This individual patient data meta-analysis showed that remdesivir reduced mortality in patients hospitalised with COVID-19 who required no or conventional oxygen support, but was underpowered to evaluate patients who were ventilated when receiving remdesivir. The effect size of remdesivir in patients with more respiratory support or acquired immunity and the cost-effectiveness of remdesivir remain to be further elucidated. FUNDING: EU-RESPONSE.