Alternative Trial Designs Research Articles

Harms with placebo in trials of biological therapies and small molecules as induction therapy in inflammatory bowel disease: a systematic review and meta-analysis

Randomised placebo-controlled trials are the gold standard to assess novel drugs in ulcerative colitis and Crohn's disease. However, there might be risks associated with receiving placebo. We aimed to examine the harms associated with receiving placebo in trials of licensed biologics and small molecules for the induction of remission in ulcerative colitis and luminal Crohn's disease in a meta-analysis. We performed a systematic review and meta-analysis. We searched MEDLINE, Embase, Embase Classic, and the Cochrane Central Register of Controlled Trials from database inception to May 30, 2024, for randomised placebo-controlled trials of licensed biologics and small molecules for induction of remission in adults (≥18 years) with moderately to severely active ulcerative colitis or luminal Crohn's disease reporting data on adverse events over a minimum treatment period of 4 weeks. There were no prespecified study exclusion criteria. We extracted summary data and pooled data using a random-effects model for any treatment-emergent adverse event, any drug-related adverse event, infection, worsening of inflammatory bowel disease (IBD) activity, withdrawal due to adverse events, serious adverse events, serious infection, serious worsening of IBD activity, or venous thromboembolic events (VTEs), reporting relative risks (RRs) with 95% CIs. The protocol for this meta-analysis was registered with PROSPERO (CRD42024527341). The search identified 10 826 citations, of which 47 trials including 20 987 patients (14 267 [68·0%] receiving active drug and 6720 [32·0%] receiving placebo) were eligible. The risk of any treatment-emergent adverse event was no different with active drug than with placebo (7660/14 267 [53·7%] patients on active drug vs 3758/6720 [55·9%] on placebo; RR 0·97, 95% CI 0·94-1·00; I2 =36%). However, the risks of worsening of IBD activity (563/13 473 [4·2%] vs 530/6252 [8·5%]; 0·48, 0·40-0·59; I2 =54%), withdrawal due to adverse event (401/13 363 [3·0%] vs 299/6267 [4·8%]; 0·62, 0·48-0·79; I2 =46%), serious adverse event (682/14 267 [4·8%] vs 483/6720 [7·2%]; 0·69, 0·59-0·80; I2 =30%), serious infection (140/14 194 [1·0%] vs 91/6647 [1·4%]; 0·67, 0·50-0·89; I2 =0%), serious worsening of IBD activity (187/11 271 [1·7%] vs 189/5056 [3·7%]; 0·45, 0·34-0·60; I2 =27%), or VTEs (13/7542 [0·2%] vs 12/2981 [0·4%]; 0·45, 0·21-0·94; I2 =0%) were all significantly lower with active drug than placebo. Numbers needed to treat with active drug to avoid these potentially serious adverse events ranged from 23 for worsening of IBD activity to 452 for VTEs. 27 randomised controlled trials were judged as low risk of bias across all domains. Patients with moderately to severely active IBD receiving placebo are more likely to experience significant worsening of IBD activity and some serious adverse events, which might relate to a reduction in risk of these events with active drug. Patients should be counselled about these potential harms, and alternative trial designs to mitigate these harms should be considered. None.

Variable Duration Trial as an Alternative Design for Continuous Endpoints.

Clinical trials with continuous primary endpoints typically measure outcomes at baseline, at a fixed timepoint (denoted Tmin), and at intermediate timepoints. The analysis is commonly performed using the mixed model repeated measures method. It is sometimes expected that the effect size will be larger with follow-up longer than Tmin. But extending the follow-up for all patients delays trial completion. We propose an alternative trial design and analysis method that potentially increases statistical power without extending the trial duration or increasing the sample size. We propose following the last enrolled patient until Tmin, with earlier enrollees having variable follow-up durations up to a maximum of Tmax. The sample size at Tmax will be smaller than at Tmin, and due to staggered enrollment, data missing at Tmax will be missing completely at random. For analysis, we propose an alpha-adjusted procedure based on the smaller of the p values at Tmin and Tmax, termed . This approach can provide the highest power when the powers at Tmin and Tmax are similar. If the power at Tmin and Tmax differ significantly, the power of is modestly reduced compared with the larger of the two powers. Rare disease trials, due to the limited size of the patient population, may benefit the most with this design.

Clinical trial designs to assess treatment effects on glomerular filtration rate decline

Glomerular filtration rate (GFR) decline is used as surrogate endpoint for kidney failure. Interventions that reduce chronic kidney disease (CKD) progression often exert acute GFR reductions which differ from their long-term benefits and complicate the estimation of long-term benefit. Here, we assessed the utility of two alternative trial designs (wash-out design and active run-in randomized withdrawal design) that attempt to exclude the impact of acute effects. Post-hoc analyses of two clinical trials that characterized the effect of an intervention with acute reductions in GFR were conducted. The two trials included a wash-out period (EMPAREG-Outcome testing empagliflozin vs placebo) or an active run-in period with a randomized withdrawal (SONAR testing atrasentan vs placebo). We compared the drug effect on GFR decline calculated from the first on-treatment visit to the end-of-treatment (chronic effect in a standard randomized trial design) with GFR change calculated from randomization to end-of-wash-out, or GFR change from treatment specific baseline GFR values (GFR at start-of-run-in for placebo and end-of-run-in for atrasentan) until end-of-treatment. The effect of empagliflozin versus placebo on chronic GFR slope was 1.72 (95% confidence interval 1.49-1.94) mL/min/1.73m2 /year, similar to total GFR decline from baseline to the end of wash-out period using a linear mixed model 1.64 (1.44-1.85) mL/min/1.73m2 /year). The effect of atrasentan versus placebo on chronic GFR slope was 0.72 (0.32-1.11) mL/min/1.73m2 /year, similar to total slope from a single slope model when estimated from treatment specific baseline GFR values 0.77 (0.39-1.14) mL/min/1.73m2 /year). Statistical power of the two designs outperformed the standard randomized design. Thus, wash-out and active-run-in randomized-withdrawal trial designs are appropriate models to compute treatment effects on GFR decline.

Time to prerandomization seizure count design sufficiently assessed the safety and tolerability of perampanel for the treatment of primary generalized tonic-clonic seizures.

Static assignment of participants in randomized clinical trials to placebo or ineffective treatment confers risk from continued seizures. An alternative trial design of time to exceed prerandomization monthly seizure count (T-PSC) has replicated the efficacy conclusions of traditionally designed trials, with shorter exposure to placebo and ineffective treatment. Trials aim to evaluate efficacy as well as safety and tolerability; therefore, we evaluated whether this T-PSC design also could replicate the trial's safety and tolerability conclusions. We retrospectively applied the T-PSC design to analyze treatment-emergent adverse events (TEAEs) from a blinded, placebo-controlled trial of perampanel for primary generalized tonic-clonic seizures (NCT01393743). The safety analysis set consisted of 81 and 82 participants randomized to perampanel and placebo arms, respectively. We evaluated the incidences of TEAEs, treatment-related TEAEs, serious TEAEs, and TEAEs of special interest that occurred before T-PSC relative to those observed during the full-length trial. Of the 67 and 59 participants who experienced TEAEs in the perampanel and placebo arms during full-length trial, 66 (99%) and 54 (92%) participants experienced TEAEs with onset occurring before T-PSC, respectively. When limited to treatment-related TEAEs, 55 of 56 (98%) and 32 of 37 (86%) participants reported treatment-related TEAEs that occurred before T-PSC in the perampanel and placebo arms, respectively. There were more TEAEs after T-PSC with placebo as compared to perampanel (Fisher exact odds ratio = 8.6, p = .035), which resulted in overestimation of the difference in TEAE rate. There was a numerical reduction in serious TEAEs (3/13 occurred after T-PSC, one in placebo and two in perampanel). Almost all TEAEs occurred before T-PSC. More treatment-related TEAEs occurred after T-PSC for participants randomized to placebo than perampanel, which may be due to either a shorter T-PSC or delayed time to TEAE for placebo.

Perceptions of non-disclosure of results in clinical trial designs for multicancer detection tests.

10546 Background: Multi-cancer detection tests (MCDs) are blood-based tests designed to detect multiple cancers. The National Cancer Institute (NCI) is planning a pilot study to ascertain the feasibility of recruitment and the necessary infrastructure, clinical workflow, and diagnostic pathways for conducting a large clinical trial to assess whether cancer screening using MCDs reduces cancer mortality. In preparation for these activities, the NCI conducted a qualitative focus group study with primary care physicians (PCPs) and laypersons to explore the acceptability of alternative MCD trial designs, including the disclosure vs. non-disclosure of MCD test results to study participants. Methods: Focus groups were conducted with convenience samples of PCPs (6 groups, N=45) and laypersons (4 groups, N=88) by a consumer research firm. Interviews used both open-ended questions and specific prompts to explore participants’ perceptions of alternative clinical trial designs. Interviews were audio-recorded and transcribed, and qualitative thematic analysis of interview transcripts was conducted to identify emergent themes. Results: In general, PCPs and laypersons reported a willingness to refer or participate in an MCD trial regardless of design, with the understanding that clear and transparent information would be provided in the consent process. However, both groups expressed concern with a trial design in which patients in the control arm would not receive their MCD test results—a design that would allow a marked reduction in sample size and time necessary to assess a mortality endpoint. PCPs noted that although this design might be ethically acceptable due to current clinical equipoise about MCD testing, they expressed concern about mistrust among patients and medical-legal liability. Laypersons had difficulty understanding the rationale for non-disclosure of MCD test results during a trial, and concerns about the ethics of non-disclosure. Some participants felt more comfortable if return of value with other information was included as part of routine study procedures. Participants were more comfortable with an alternative design involving delayed testing of stored blood samples from the control group after trial completion. PCPs also expressed concern about increased workloads if their patients enrolled. Conclusions: PCPs and laypersons had generally positive reactions to a trial to investigate diagnostic performance, pathways, and outcomes of MCDs. Concerns about study designs involving non-disclosure of results might be managed through return of value strategies, careful education, and clear communication of the benefits and risks of MCDs.

Delayed treatment effect predicting (DTEP) model for guiding immuno-oncology trial designs

BackgroundThe presence of delayed treatment effects (DTE) is common in immuno-oncology trials. However, conventional trial designs often overlook the potential presence of DTE, which can result in an underestimation of the required sample size and loss of statistical power. Conversely, when there is actually no apparent delay in treatment effects, alternative trial designs for addressing DTE may lead to an overestimation of sample size and unnecessary prolongation of the trial duration. To mitigate this challenge, we propose the use of a DTE predicting (DTEP) model to better guide immuno-oncology trial designs. MethodsThe DTEP model was developed and validated using data from 147 published randomized immuno-oncology trials. The eligible trials were divided into a training set (approximately 75% of the trials) and a test set (approximately 25%). We employed linear discriminant analysis (LDA) to develop the DTEP model for predicting the DTE status using baseline characteristics available at the trial design stage. The receiver operating characteristic (ROC) curve was utilized to assess the ability of the model to distinguish between trials with and without DTE. We further re-conducted the JUPITER-02 trial in a simulation setting, employing three design approaches to assess the potential benefits of utilizing the DTEP model. ResultsBaseline characteristics available during the trial design stage, including cancer type, line of treatment, and experimental and control arm regimens were incorporated, and high accuracy in predicting the DTE status in both the training set (area under the operating characteristic curve (AUC), 0.79; 95% confidence interval (CI), 0.71–0.88) and test set (AUC, 0.78; 95% CI, 0.66–0.90) was achieved. Notably, the model successfully predicted the DTE status in two randomized trials among the test sets that were conducted by our team (ESCORT-1st (absence of DTE) and JUPITER-02 (presence of DTE)). In silico re-conduct of the JUPITER-02 trial further showed that the statistical power would be markedly improved when trial designs were guided by the DTEP model. ConclusionsThe DTEP model can significantly enhance the precision and effectiveness of immuno-oncology trial designs, thereby facilitating the discovery of effective immunotherapeutics in a more streamlined and expedited manner.

Doing research in non-specialist mental health services for children and young people: lessons learnt from a process evaluation of the ICALM (Interpersonal Counselling for Adolescent Low Mood) feasibility randomised controlled trial

BackgroundThe rising prevalence of adolescent mild depression in the UK and the paucity of evidence-based interventions in non-specialist sectors where most cases present, creates an urgent need for early psychological interventions. Randomised controlled trials (RCTs) are considered the gold standard for obtaining unbiased estimates of intervention effectiveness. However, the complexity of mental health settings poses great challenges for effectiveness evaluations. This paper reports learning from an embedded process evaluation of the ICALM RCT which tested the feasibility of delivering Interpersonal Counselling for Adolescents (IPC-A) plus Treatment as Usual (TAU) versus TAU only for adolescent (age 12–18) mild depression by non-qualified mental health professionals in non-specialist sectors.MethodsA qualitative mixed methods process evaluation, drawing on Bronfenbrenner’s socioecological model to investigate key influences on trial delivery across macro-(e.g. policy), meso-(e.g. service characteristics) and micro-(e.g. on-site trial processes) contextual levels. Data collection methods included 9 site questionnaires, 4 observations of team meetings, policy documents, and 18 interviews with stakeholders including therapists, heads of service and managers. Thematic analysis focused on understanding how contextual features shaped trial implementation.ResultsThe ICALM trial concluded in 2022 having only randomised 14 out of the target 60 young people. At a macro-level, trial delivery was impacted by the COVID-19 pandemic, with services reporting a sharp increase in cases of (social) anxiety over low mood, and backlogs at central referral points which prolonged waiting times for mild cases (e.g. low mood). An interaction between high demand and lack of capacity at a meso-service level led to low prioritisation of trial activities at a micro-level. Unfamiliarity with research processes (e.g. randomisation) and variation in TAU support also accentuated the complexities of conducting an RCT in this setting.ConclusionsConducting a RCT of IPC-A in non-specialist services is not feasible in the current context. Failure to conduct effectiveness trials in this setting has clinical implications, potentially resulting in escalation of mild mental health problems. Research done in this setting should adopt pragmatic and innovative recruitment and engagement approaches (e.g. creating new referral pathways) and consider alternative trial designs, e.g. cluster, stepped-wedge or non-controlled studies using complex systems approaches to embrace contextual complexity.Trial registrationISRCTN registry, ISRCTN82180413. Registered on 31 December 2019.

Optimising the implementation of digital-supported interventions for the secondary prevention of heart disease: a systematic review using the RE-AIM planning and evaluation framework

BackgroundmHealth technologies are now widely utilised to support the delivery of secondary prevention programs in heart disease. Interventions with mHealth included have shown a similar efficacy and safety to conventional programs with improvements in access and adherence. However, questions remain regarding the successful wider implementation of digital-supported programs. By applying the Reach-Effectiveness-Adoption-Implementation-Maintenance (RE-AIM) framework to a systematic review and meta-analysis, this review aims to evaluate the extent to which these programs report on RE-AIM dimensions and associated indicators.MethodsThis review extends our previous systematic review and meta-analysis that investigated the effectiveness of digital-supported programs for patients with coronary artery disease. Citation searches were performed on the 27 studies of the systematic review to identify linked publications that reported data for RE-AIM dimensions. All included studies and, where relevant, any additional publications, were coded using an adapted RE-AIM extraction tool. Discrepant codes were discussed amongst reviewers to gain consensus. Data were analysed to assess reporting on indicators related to each of the RE-AIM dimensions, and average overall reporting rates for each dimension were calculated.ResultsSearches found an additional nine publications. Across 36 publications that were linked to the 27 studies, 24 (89%) of the studies were interventions solely delivered at home. The average reporting rates for RE-AIM dimensions were highest for effectiveness (75%) and reach (67%), followed by adoption (54%), implementation (36%) and maintenance (11%). Eleven (46%) studies did not describe relevant characteristics of their participants or of staff involved in the intervention; most studies did not describe unanticipated consequences of the intervention; the ongoing cost of intervention implementation and maintenance; information on intervention fidelity; long-term follow-up outcomes, or program adaptation in other settings.ConclusionsThrough the application of the RE-AIM framework to a systematic review we found most studies failed to report on key indicators. Failing to report these indicators inhibits the ability to address the enablers and barriers required to achieve optimal intervention implementation in wider settings and populations. Future studies should consider alternative hybrid trial designs to enable reporting of implementation indicators to improve the translation of research evidence into routine practice, with special consideration given to the long-term sustainability of program effects as well as corresponding ongoing costs.RegistrationPROSPERO—CRD42022343030.

Steps to Improve Precision Medicine in Epilepsy.

Precision medicine isan old concept, but it is not widely applied across human health conditions asyet. Numerous attempts have been made to apply precision medicine in epilepsy, this has beenbased on abetter understanding of aetiological mechanisms and deconstructing disease into multiple biological subsets. The scope of precision medicine is to provide effective strategies for treating individual patients with specific agent(s) that are likely to work best based on the causal biological make-up. We provide an overview of the main applications of precision medicine in epilepsy, including thecurrent limitations and pitfalls, and propose potential strategies for implementation and toachieve a higher rate of success in patient care. Such strategies include establishing adefinition of precision medicine and its outcomes; learning from past experiences, from failures and from other fields (e.g. oncology); using appropriate precision medicine strategies (e.g. drug repurposing versus traditional drug discovery process); and using adequate methods to assess efficacy (e.g. randomised controlled trials versus alternative trial designs). Although theprogress of diagnostic techniques now allows comprehensive characterisation of each individual epilepsy condition from a molecular, biological, structural and clinical perspective, there remain challenges in the integration of individual data in clinical practice to achieve effective applications of precision medicine in this domain.

Optimizing clinical nutrition research: the role of adaptive and pragmatic trials.

Evidence-based nutritional recommendations address the health impact of suboptimal nutritional status. Efficacy randomized controlled trials (RCTs) have traditionally been the preferred method for determining the effects of nutritional interventions on health outcomes. Nevertheless, obtaining a holistic understanding of intervention efficacy and effectiveness in real-world settings is stymied by inherent constraints of efficacy RCTs. These limitations are further compounded by the complexity of nutritional interventions and the intricacies of the clinical context. Herein, we explore the advantages and limitations of alternative study designs (e.g., adaptive and pragmatic trials), which can be incorporated into RCTs to optimize the efficacy or effectiveness of interventions in clinical nutrition research. Efficacy RCTs often lack external validity due to their fixed design and restrictive eligibility criteria, leading to efficacy-effectiveness and evidence-practice gaps. Adaptive trials improve the evaluation of nutritional intervention efficacy through planned study modifications, such as recalculating sample sizes or discontinuing a study arm. Pragmatic trials are embedded within clinical practice or conducted in settings that resemble standard of care, enabling a more comprehensive assessment of intervention effectiveness. Pragmatic trials often rely on patient-oriented primary outcomes, acquire outcome data from electronic health records, and employ broader eligibility criteria. Consequently, adaptive and pragmatic trials facilitate the prompt implementation of evidence-based nutritional recommendations into clinical practice. Recognizing the limitations of efficacy RCTs and the potential advantages of alternative trial designs is essential for bridging efficacy-effectiveness and evidence-practice gaps. Ultimately, this awareness will lead to a greater number of patients benefiting from evidence-based nutritional recommendations.

Evolution and optimization of clinical trial endpoints and design in pulmonary arterial hypertension.

Selection of endpoints for clinical trials in pulmonary arterial hypertension (PAH) is challenging because of the small numbers of patients and the changing expectations of patients, clinicians, and regulators in this evolving therapy area. The most commonly used primary endpoint in PAH trials has been 6-min walk distance (6MWD), leading to the approval of several targeted therapies. However, single surrogate endpoints such as 6MWD or hemodynamic parameters may not correlate with clinical outcomes. Composite endpoints of clinical worsening have been developed to reflect patients' overall condition more accurately, although there is no standard definition of worsening. Recently there has been a shift to composite endpoints assessing clinical improvement, and risk scores developed from registry data are increasingly being used. Biomarkers are another area of interest, although brain natriuretic peptide and its N-terminal prohormone are the only markers used for risk assessment or as endpoints in PAH. A range of other genetic, metabolic, and immunologic markers is currently under investigation, along with conventional and novel imaging modalities. Patient-reported outcomes are an increasingly important part of evaluating new therapies, and several PAH-specific tools are now available. In the future, alternative statistical techniques and trial designs, such as patient enrichment strategies, will play a role in evaluating PAH-targeted therapies. In addition, modern sequencing techniques, imaging analyses, and high-dimensional statistical modeling/machine learning may reveal novel markers that can play a role in the diagnosis and monitoring of PAH.

Placebo Effects and Neuromodulation: Ethical Considerations and Recommendations.

Placebo-controlled trials are the gold standard of evaluating treatment efficacy in clinical research. Neuromodulation is emerging as an important treatment pathway for many neuropsychiatric conditions, and placebo control arms of these trials require careful design with unique considerations (e.g., sham devices that mimic active stimulation, blinding effectiveness). Inherent to placebo-controlled trials are ethical concerns, such as deception, and potential harm of not receiving the active treatment. In this article, we outline important ethical considerations of placebo-controlled trials across neuromodulation approaches and provide recommendations on how ethical principles can be adhered to going forward. We specifically address issues of autonomy and respect for persons, beneficence, and justice. Within the context of this ethical framework, we also discuss factors influencing placebo effects in neuromodulation, the importance of adequate blinding, and alternative trial designs that could be considered.

Estimating HIV Incident Diagnoses Among Men Who Have Sex With Men Eligible for Pre-exposure Prophylaxis but Not Taking It: Protocol and Feasibility Assessment of Data Sources and Methods

HIV incidence estimates are published each year for all Ending the HIV Epidemic (EHE) counties, but they are not stratified by the demographic variables highly associated with risk of infection. Regularly updated estimates of HIV incident diagnoses available at local levels are required to monitor the epidemic in the United States over time and could contribute to background incidence rate estimates for alternative clinical trial designs for new HIV prevention products. We describe methods using existing, robust data sources within areas in the United States to reliably estimate longitudinal HIV incident diagnoses stratified by race and age categories among men who have sex with other men (MSM) eligible for pre-exposure prophylaxis (PrEP) but not taking it. This is a secondary analysis of existing data sources to develop new estimates of incident HIV diagnoses in MSM. We reviewed past methods used to estimate incident diagnoses and explored opportunities to improve these estimates. We will use existing surveillance data sources and population sizes of HIV PrEP-eligible MSM estimated from population-based data sources (eg, US Census data and pharmaceutical prescription databases) to develop metropolitan statistical area-level estimates of new HIV diagnoses among PrEP-eligible MSM. Required parameters are number of new diagnoses among MSM, estimates of MSM with an indication for PrEP, and prevalent PrEP use including median duration of use; these parameters will be stratified by jurisdiction and age group or race or ethnicity. Preliminary outputs will be available in 2023, and updated estimates will be produced annually thereafter. Data to parameterize new HIV diagnoses among PrEP-eligible MSM are available with varying levels of public availability and timeliness. In early 2023, the most recent available data on new HIV diagnoses were from the 2020 HIV surveillance report, which reports 30,689 new HIV infections in 2020, and 24,724 of them occurred in an MSA with a population of ≥500,000. Updated estimates for PrEP coverage based on commercial pharmacy claims data through February 2023 will be generated. The rate of new HIV diagnoses among MSM can be estimated from new diagnoses within each demographic group (numerator) and the total person-time at risk of diagnosis for each group (denominator) by metropolitan statistical area and year. To estimate time at risk, the person-time of individuals on PrEP or person-time after incident HIV infection but before diagnosis should be removed from stratified population size estimates of the total number of person-years with indications for PrEP. Reliable, serial, cross-sectional estimates for rates of new HIV diagnoses for MSM with PrEP indications can serve as benchmark community estimates of failures of HIV prevention and opportunities to improve services and will support public health epidemic monitoring and alternative clinical trial designs. DERR1-10.2196/42267.

A180 PLACEBO RATES IN MICROSCOPIC COLITIS RANDOMIZED TRIALS: APPLICATIONS FOR FUTURE DRUG DEVELOPMENT USING A HISTORICAL CONTROL ARM

Abstract Background There remains a need to develop effective medical therapies for patients with microscopic colitis (MC) who do not respond, are intolerant, or relapse on budesonide. Conducting randomized trials in MC is logistically and ethically challenging: budesonide is highly effective, and therefore, some institutional review boards have not allowed trials that randomize MC patients to placebo. However, comparing an investigational drug to budesonide is statistically infeasible: powering a non-inferiority study against a budesonide comparator arm with 90% power for a 10% non-inferiority margin would require over 700 subjects, yet fewer than 400 patients have been randomized in all historical MC trials. Therefore, alternative trial designs should be explored in MC, including the use of a historical control arm. Purpose To conduct a systematic review and meta-analysis to determine the proportion of placebo responders in MC trials that will inform future trials using a historical placebo comparator, and evaluate factors associated with placebo response. Method EMBASE, MEDLINE, and CENTRAL were searched from inception to January 7, 2022, and supplemented with conference abstracts to identify randomized controlled trials (RCTs) using a placebo comparator in adult patients with confirmed MC (either lymphocytic, collagenous, or mixed populations but excluding incomplete MC). The proportion of clinical and histologic responders in the placebo arms were pooled using random-effect models, statistical heterogeneity was evaluated using the I2 method, and the Freeman-Tukey double arcsine transformation was used to compute 95% confidence intervals (CI) using the score statistic and exact binomial method. All analyses were conducted in Stata 17.0. Result(s) Twelve placebo controlled RCTs were included, evaluating a total of 391 patients (163 randomized to placebo). The pooled placebo clinical response rate was 24.4% [95% CI 12.4%, 38.4%] (Figure 1), with substantial heterogeneity (I2=60.8%, p<0.01). The pooled histologic response rate was 19.9% [95% CI: 5.3%, 39.0%], with substantial heterogeneity (I2=66.4%, p<0.01). Subgroup analysis demonstrated higher placebo responses in lymphocytic colitis (39.9% [95% CI: 23.9%, 56.7%]) compared to collagenous colitis (19.8% [95% CI: 5.9%, 37.8%]), but not by allowance of baseline anti-diarrheals. Leave-one-out meta-analysis showed a reduction in heterogeneity after removal of Miehlke et al. 2014 (placebo response 21.0% [95% CI: 11.5%, 32.1%], I2=28.6%, p=0.17). Image Conclusion(s) Approximately 1 in 4 patients in MC trials will respond clinically to placebo and 1 in 5 will demonstrate a histologic response, although with substantial heterogeneity. T his highlights the need for standardized outcome definitions in MC trials and can serve to inform a Bayesian prior estimate for future trials that may consider using a historical placebo comparator. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest P. Hamilton: None Declared, K. Buhler: None Declared, G. Kaplan Grant / Research support from: Ferring, Janssen, AbbVie, GlaxoSmith Kline, Merck, and Shire, Consultant of: AbbVie, Janssen, Pfizer, Amgen, Takeda, and Gilead, C. Lu Consultant of: Abbvie, Janssen, Ferring, and Takeda, Speakers bureau of: Janssen and Abbvie, C. Seow Consultant of: Advisory Boards: Janssen, Abbvie, Takeda, Ferring, Shire, Pfizer, Sandoz, Pharmascience, Fresenius Kabi, Amgen, Speakers bureau of: Janssen, Abbvie, Takeda, Ferring, Shire, Pfizer, Pharmascience, K. Novak Grant / Research support from: AbbVie and Janssen, Consultant of: Advisory board fees from AbbVie, Janssen, Pfizer, Ferring, and Takeda, speaker’s fees from AbbVie, Janssen, and Pfizer, R. Panaccione Consultant of: Abbott, AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, UCB. Advisory Boards for: AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, SandozShire, Sublimity Therapeutics, Takeda Pharmaceuticals, Speakers bureau of: AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, Takeda Pharmaceuticals, C. Ma Grant / Research support from: Ferring, Pfizer, Consultant of: AbbVie, Alimentiv, American College of Gastroenterology, Amgen, AVIR Pharma Inc, BioJAMP, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Sanofi/Regeneron, Takeda, Pendopharm, Pfizer, Roche, Speakers bureau of: : AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Takeda, Pendopharm, and Pfizer

Letter to the Editor: Survival in placebo-treated patients with severe alcohol-associated hepatitis.

To the editor, With great interest, we read the recent article of Szabo et al,1 reporting a negative randomized controlled trial (RCT) in patients with severe alcoholic hepatitis (sAH) and the accompanying editorial of Lucey and Thursz.2 We share the concern for future trial design in sAH regarding the sample size needed to demonstrate the survival benefit of a specific therapy. Insight into the survival of placebo-treated patients, as a surrogate for the natural history of the disease, is crucial herein. Therefore, we performed a systematic review and meta-analysis of all RCTs in sAH that included a placebo-controlled group (>10 patients). A systematic search on Pubmed, Embase, Cochrane library, and Web of Science (until March 2021) retrieved 4874 studies. Eleven RCTs reporting 30-day survival (568 placebo-treated patients) and 2 studies reporting 90-day survival (269 placebo-treated patients) were included (Figure 1). Data were analyzed at study-level using a linear mixed model (DerSimonian and Laird), with the arcsin-transformed survival rates as outcome.FIGURE 1: Pooled 30-day and 90-day survival in placebo-treated patients with severe alcohol-associated hepatitis. Data analyzed using a linear mixed model (DerSimonian and Laird) with arcsin-transformed survival rates as outcome. Median with 95% CI plotted.Pooled 30-day survival was 72.93% (95% CI: 67.09%–78.39%) and pooled 90-day survival was 73.61% (95% CI: 68.18%–78.69%) in placebo-treated sAH patients. A more recent year of publication was positively associated with 1-month survival (regression coefficient 0.0053, p=0.0037). Notably, the last 2 Western trials (n=289), demonstrated a 30-day survival of 80% and 83%, respectively, of placebo-treated sAH patients. If a given therapy would reduce mortality (30 or 90-day) in sAH-patients by 25% (comparable with the 28.7% used in the power analysis of the STOPAH trial), this would be of great added value to clinical practice. However, with a 27% mortality rate, this would mean that 622 patients need to be included in each treatment group in a 2-armed study (power calculated with a log-rank test, power=80%, alpha=0.05), which results in a study population of 1244 patients without taking into account drop-outs. This number of patients is larger than that reported in any RCT in sAH so far, including the STOPAH trial where patients were included in 65 different hospitals over 3 years.3 Not even to mention the study patient number we would need if the 30-day mortality rate is less than 20% as in the recent RCTs. In conclusion, the shown survival figures of placebo-treated sAH patients have major implications for the required sample size of future trials in sAH, questioning the feasibility of demonstrating superiority over placebo in a classical RCT design. Therefore, we fully agree with the conclusion of Lucey and Thursz that alternative trial designs should be explored to identify effective new treatments for this extremely vulnerable patient population.2

Optimizing patient recruitment into clinical trials of antimicrobial-resistant pathogens.

Recruitment of patients with critical priority antimicrobial-resistant (AMR) bacteria into drug approval randomized controlled trials (RCTs) has not been successful to date. Approaching from the viewpoint of clinician-investigators and learning from the experience of AMR-focused investigator-initiated trials, we present suggestions to improve feasibility and efficiency of RCTs evaluating patients with severe infections caused by carbapenem-resistant Gram-negative or other AMR bacteria. Considerations address the trials' eligibility criteria, whether the focus of the trial is pathogen- or syndrome-targeted, trials' case report forms and monitoring, informed consent strategies for the recruitment of extremely ill patients, team dedication and incentives to run the trial and alternative trial designs. Evidence on the effects of new drugs against the AMR that these drugs target is weak and needs to be improved through better industry-academic collaboration, taking advantage of the different strengths of industry-led and investigator-initiated research.

The Second Nutrition and Cancer Networking Meeting Nutrition and Breast Cancer: Translating Evidence into Practice.

The 2nd Nutrition and Cancer Networking Meeting 'Nutrition and Breast Cancer: Translating Evidence into Practice' was held at Newcastle University in May 2022, with support from the Nutrition Society and British Association for Cancer Research. The first meeting in this series was held in Sheffield in 2019. The aim of this joint meeting was to bring together researchers with an interest in nutrition and breast cancer, with the programme spanning topics from risk and prevention to nutrition during treatment and beyond. Several key themes emerged, including the importance of engaging patients in the development of interventions and trials, making trials more accessible to diverse communities; training of clinical staff in nutrition and latest evidence; wider range of compounds should be considered in food composition tables; and alternative trial designs can be considered for prevention research to reduce financial burden and increase power.

The use of milrinone in neonates with persistent pulmonary hypertension of the newborn - a randomised controlled trial pilot study (MINT 1).

To assess the impact of milrinone administration on time spent on nitric oxide (iNO) in infants with acute pulmonary hypertension (aPH). We hypothesized that intravenous milrinone used in conjunction with iNO would reduce the time on iNO therapy and the time spent on invasive ventilation in infants ≥34 weeks gestation with a diagnosis of aPH. We aimed to assess the practicality of instituting the protocol and contributing to a sample size calculation for a definitive multicentre study. This was a multicentre, randomized, double-blind, two arm pilot study, with a balanced (1:1) allocation. Infants with a gestation ≥34 weeks and a birth weight ≥2000 grams aPH, an oxygenation index of ≥10, and commenced on iNO were eligible. Participants on iNO were assigned to either a milrinone infusion (intervention) or a normal saline infusion (placebo) for up to 35 h. The primary outcome was time on iNO and feasibility of conducting the protocol. The trial was terminated early after 4 years of enrollment due to poor recruitment. Four infants were allocated to the intervention arm and 5 to the placebo arm. The groups were well matched for baseline variables. No differences were seen in any of the primary or secondary outcomes. Conducting an interventional trial in the setting of acute pulmonary hypertension in infants is not feasible using our current approach. Future studies in this area require alternative trial design to improve recruitment as this topic remains understudied in the neonatal field. www.isrctn.com ; ISRCTN:12949496; EudraCT Number:2014-002988-16.

Clinical Trial Diversity in Oncology: FDA Takes Action with Post-Marketing Requirements or Commitments.

In recent years, there has been a renewed focus on promoting the inclusion of patients from racial and ethnic minority groups in oncology clinical trials. FDA Oncology has long pointed to the underrepresentation of racial minorities in registration trials leading to approval. US FDA's Guidance on diversity discusses how diversity could be handled within clinical trials, giving recommendations on broadening eligibility criteria, inclusive trial practices, and alternative trial designs. While there is no specific guidance from the FDA on cancer clinical trials, the recommendation is to include a representative population applicable to the US population. With the recent renewed focus on diversity in oncology clinical trials, FDA Oncology has recently asked for the completion of a Diversity Plan during drug development and has issued post-marketing commitments and requirements at the time of approval. As FDA has started to issue post-marketing requirements or commitments regarding diversity in 2020, we sought to analyze the post-marketing studies asking for a study of racial and ethnic minorities issued by the FDA's Office of Oncologic Diseases (OOD). The analysis demonstrated the need to increase the enrollment of a diverse patient population in cancer clinical trials.

Clinical research challenges posed by difficult-to-treat depression.

Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of 'difficult-to-treat depression' (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.