Optimizing the Interdisciplinary Design of Adaptive Platform Trials

Adaptive platform trials (APTs) are often complex clinical trials that, ideally, are well suited to answer the motivating clinical questions effectively and efficiently, with the motivating clinical questions and associated treatment arms expected to evolve over time as evidence accumulates. Recently, APTs have played a pivotal role in informing public health policy by efficiently generating compelling evidence regarding the effectiveness of therapies for COVID-19. For APTs to be maximally effective in informing future public health policy, they must be carefully tailored to address the right clinical questions, with the right balance of size, scope, rigor, and flexibility. The design process requires input from clinical and statistical domain experts and often includes input from trial implementation personnel, ethicists, and patient representatives. The design process is inherently iterative, with proposed designs evaluated through trial simulation, the identification of strengths and weaknesses of the proposed design, and revision by the team to address weaknesses. This iterative design process requires effective communication and collaboration between the statistical and clinical domain experts. This session is intended to present a current best practice in facilitating and enhancing the collaborative design process for APTs, including how best to present simulation-based trial performance to the design team and ensure effective interdisciplinary communication. The speakers have extensive experience in leading the design of APTs across multiple therapeutic areas, in both academic and industry settings. The session will begin with a brief presentation by Dr. Lewis on the basic structure of an APT and the tasks and challenges associated with the multidisciplinary design process. The subsequent discussion will be organized by the following themes: (1) considerations in the selection of the study population and primary outcome metric;(2) selecting treatment domains and factors to be compared;(3) trial simulation and communication of performance metrics to both statistical and non-statistical team members;and (4) defining and calibrating interim decision rules. Each of the 4 panel members will outline a recommended approach to facilitating 1 of the 4 design tasks, with examples drawn from their experience. The remaining time (15 min) will be available for a panel question-and-answer period. At the end of the session, the audience will have an understanding of the general organization of, and a process for facilitating, the design process for an adaptive platform trial. Panel Members Roger J Lewis, MD, PhD, is a Senior Physician in the Los Angeles County Department of Health Services, Professor of Emergency Medicine at the David Geffen School of Medicine at UCLA, and the Senior Medical Scientist at Berry Consultants, LLC, a group that specializes in innovative clinical trial design. He is also the former Chair of the Department of Emergency Medicine at Harbor-UCLA Medical Center. Dr. Lewis' expertise centers on adaptive and Bayesian clinical trials, including platform trials;translational, clinical, health services and outcomes research methodology;data and safety monitoring boards, and the oversight of clinical trials. Dr. Lewis was elected to membership in the National Academy of Medicine in 2009. He has authored or coauthored over 270 original research publications, reviews, editorials, and chapters. Dr. Lewis is a Past President of the Society for Academic Emergency Medicine (SAEM) and served on the Board of Directors for the Society for Clinical Trials. He is a fellow of the American College of Emergency Physicians, the American Statistical Association, and the Society for Clinical Trials. Juliana Tolles, MD, MHS, is an Assistant Professor of Emergency Medicine at the Harbor-UCLA Medical Center and the David Geffen School of Medicine at UCLA, and a Medical and Statistical Scientist at Berry Consultants, LLC. Her academic research interests include emergency medical services, resuscitation medicine, and trau a care. She has authored several reviews for Journal of the American Medical Association (JAMA) on statistical methodology and has lectured nationally on research methodology for the Society for Academic Emergency Medicine Advanced Research Methodology Evaluation and Design (ARMED) course. She is also a co-investigator for the Strategies to Innovate Emergency Clinical Care Trials (SIREN) network Southern California site. Kert Viele, PhD, is a Director and Senior Statistical Scientist with Berry Consultants, where he leads Berry Consultants' research enterprise. He is a leader in clinical trial implementation of Bayesian hierarchical modeling, with expertise in platform and basket trials as well as clinical trials incorporating the use of historical information. Prior to joining Berry Consultants in 2010, he was a faculty member at the University of Kentucky, where he received the Provost's Award for Outstanding Teaching and was an investigator for NSF and NIH-funded research. He has developed over 100 custom Bayesian adaptive clinical trials for clients in industry, government, and academia, and currently serves on several data safety monitoring boards for randomized clinical trials. A former editor of the journal Bayesian Analysis, Dr. Viele is also an author of FACTS (Fixed and Adaptive Clinical Trial Simulator), clinical trial simulation software currently licensed to multiple pharmaceutical, academic, and government organizations. William Meurer, MD, MS, is an Associate Professor of Emergency Medicine and Neurology at the University of Michigan Health System. In addition, he serves as a Medical and Statistical Scientist for Berry Consultants, LLC. He works to improve the care of patients with acute neurological disease both through his work on the acute stroke team and as a researcher. His work in the field focuses on the design of clinical trials with adaptive and flexible components. In addition, he is a principal investigator of the National Institutes of Neurological Disorders and Stroke (NINDS) Clinical Trials Methodology Course (http:// neurotrials.training) and a co-investigator in the clinical coordinating center of the Strategies to Innovate Emergency Care Clinical Trials (SIREN) network- also funded by NIH). He was a co-investigator on the Adaptive Designs Accelerating Promising Treatments into Trials (ADAPT-IT) project, as part of the FDA Advancing Regulatory Science initiative with NIH.

Optimizing Precision Medicine Cancer Clinical Trials

With the advent of precision medicine, getting the right treatment for the right patient at the right time has illuminated a variety of challenges and opportunities for innovation in trial design and conduct. Although there is no onesize- fits-all approach to precision medicine, a number of approaches, particularly basket and umbrella trial platforms that permit simultaneous evaluation of multiple treatments in multiple patient cohorts, have evolved to improve trial efficiency. The novel coronavirus pandemic has illuminated the need for, and feasibility of, conducting trials with fewer requirements, greater flexibility, and more decentralization. Through the lens of precision medicine cancer clinical trials, successes and challenges will be discussed to share practical solutions of how to improve evidence generation in the era of precision medicine. Through discussion of precision medicine cancer clinical trials within the United States, this session will provide an overview of how best to optimize these clinical trials. This session comprises the following three main topic areas: matching treatments to patients, including the use of novel patient identification strategies, genomic matching rules, molecular tumor boards (MTBs), decision-support tools, incorporating precision medicine trials into a research portfolio, and how to overcome challenges;accelerating evidence development, including the use of adaptive trial designs, cohort management strategies and data sharing plans;and improving diversity of trial participants and increasing generalizability of study results through expanded eligibility criteria and site selection strategies. This topic will be explored through 90 min of invited talks and a panel discussion with Q&A. Moderator and session chair, Richard L Schilsky, MD, FACP, FSCT, FASCO, will introduce the session and speakers and provide an introduction on the basics of precision oncology. Timothy Cannon, MD, a medical oncologist and clinical trial researcher, will present a case study of two patients with the same alteration and discuss how the care for each differed based on access to a precision medicine cancer clinical trial. Dr. Cannon will also discuss how to implement precision medicine trials within a research portfolio and how to identify patients at a site. Christine Walko, PharmD, BCOP, FCCP, a pharmacist and researcher, will then discuss the basics of matching therapies to genomics, how to use decision support tools, the role of an MTB, and identifying therapeutic options for patients. Edward S Kim, MD, MBA, FACP, FASCO, a medical oncologist, will talk about MTBs from a clinician perspective and precision medicine cancer clinical trials from a community practice perspective. Dr. Kim will also speak about how to extend the research team to create an adequate community research portfolio and about using broader eligibility criteria that might facilitate enrollment of diverse populations. Jane Perlmutter, PhD, MBA, FASCO, a cancer survivor and patient advocate, will discuss what pragmatic trials are, how they increase the opportunity for diversity and generalizability, and patient perspectives regarding pragmatic and precision cancer clinical trials. Susan Halabi, PhD, FASCO, FSCT, a researcher and professor of biostatistics and bioinformatics, will talk about the best ways to design an adaptive trial, especially its role in real-world settings, how these types of designs can be used for efficient signal finding in rare populations, and how these trials can create opportunities for data sharing and collaboration. Pam K Mangat, MS, a research scientist and the Director of Clinical Research for American Society of Clinical Oncology's (ASCO) Targeted Agent and Profiling Utilization Registry (TAPUR) Study, will discuss the operations behind a precision medicine study, advantages and disadvantages of a pragmatic trial, cohort closing and collapsing rules to help with management of large numbers of small cohorts, and contributing knowledge to other trials. The session will conclude with a panel di cussion moderated by session chair, Richard L Schilsky, MD, FACP, FSCT, FASCO, for approximately 10 min, with 5 min for a Q&A session.

Real-World Experience in Conducting Adaptive Platform Trials

Platform trials like RECOVERY, SOLIDARITY, REMAP-CAP, TOGETHER, PRINCIPLE, and many others have dominated the COVID clinical trial effort, changing clinical practice with multiple results in The Lancet, New England Journal of Medicine, and the Journal of the American Medical Association. These large-scale international efforts have enrolled tens of thousands of patients and explored dozens of potential therapies for mild, moderate, and severe COVID-19. These trials are the result of a decade of theory and practice building on the experience of oncology platform trials such as I-SPY2. In addition to COVID-19 and oncology, platform trials are now used or planned in Alzheimer's disease, amyotrophic lateral sclerosis (ALS), antibiotics, psychiatry, and many other clinical areas. Conducting a large-scale platform trial is daunting. While recent platform trial review papers have hundreds of references on the theoretical design issues and research potential of these trials, there is no substitute for the actual real-world experience of implementing an adaptive platform trial, made all the more challenging within a fast-moving global pandemic. This proposed session will investigate the challenges and solutions for successfully executing a platform trial. The proposed speakers bring decades of combined expertise from executing platforms such as ISPY-2, GBM-AGILE, REMAP-CAP, TOGETHER, PRINCIPLE, ANTICOV, HEALEYALS, Precision Promise, and others. They will describe many of the challenges specific to these large global platform trials, and the infrastructure and process needs that underpin these complex trials. The session will consist of 4 speakers with integrated 20-min talks, followed by a question-and-answer period as time allows. Dr. Ed Mills will provide an overview of platform trials and their challenges in relation to simpler clinical trials. Dr. Michelle Detry will sharpen the focus on the complexities specific to trial execution and the interactions between various stakeholders, including publication plans that must account for the perpetual nature of many platform trials. Dr. Anna McGlothlin will then discuss the specific requirements and role of the committee performing the actual interim analyses, and, finally, Dr. Hong Yu will discuss these challenges in the context of the HEALEY-ALS platform trial. All speakers will include examples from their rich realworld experience in implementing complex adaptive platform trials. Speakers (in proposed order) Ed Mills, Cytel COVID-19 has exemplified the utility of platform trials for making clinical and public health decisions in a timely manner. The most useful trials that emerged during the pandemic have been from platform trials. However, with the enthusiasm for platform trials comes the concern that trials should be implemented using methods that many groups are unfamiliar with, such as advanced statistical approaches and implementation of quick changes to the protocols. Challenges exist in interactions with funders, partners managing data sets, and clinical users. This session will use real-world experiences of platform trials in the pandemic to exemplify the utility and challenges of this new approach to clinical evaluation. This talk is for any audience with an interest in clinical trials and will address strategies to promote the use of platform trials while also highlighting the concerns about the quick adoption of this method. Michelle Detry, Berry Consultants Adaptive platform trial designs include interim analyses for pre-specified adaptations, sharing of control arm information, and a perpetual design where investigational agents enter and leave the trial at different time points. This talk will discuss the infrastructure considerations for a perpetual platform trial, ongoing statistical support from both blinded and unblinded statistical teams, setting clear communication channels and firewalls between blinded and unblinded teams, and the role of Data and Safety Monitoring Committee (DSMC) and their interaction with the independent Statistical Analysis Committe that implements the protocol-specified interim analyses. In addition, ongoing platform trials face unique challenges in determining ''who knows what, when.'' Dr. Detry will discuss planning for public releases of results, and data sharing in situations where an investigational arm may complete their trial arm participation, but the control arm data will still be used for ongoing investigational arms. Anna McGlothlin, Berry Consultants A Statistical Analysis Committee (SAC) is a team of unblinded statisticians tasked with performing the interim analyses for an adaptive trial. The unblinded SAC must have expertise in the statistical methodology being utilized and in the complexities of adaptive designs. This talk will describe the role of the SAC during the preparation and conduct of a platform trial. Responsibilities of the SAC include performing analyses in accordance with the pre-specified design, monitoring each analysis to ensure that the adaptive algorithm is performing as intended, building semi-automated reproducible reports to facilitate quick turnaround of interim results, and partnering with the Data and Safety Monitoring Board (DSMB) to aid in the interpretation of interim results. In addition, platform trials may have the unique aspect that arms may complete their final read out while other arms continue in the trial. In some cases, the fully unblinded SAC may be the only group that has complete access to the necessary data to perform the final analysis for an arm while other arms continue. Hong Yu, Massachusetts General Hospital A complex adaptive platform trial requires complex infrastructure, and many of the challenges are not revealed when conceiving or planning the trial, but only in the face of actual implementation. In this talk, we will discuss real-world experiences in developing infrastructure for adaptive platform trials, particularly the HEALEY-ALS platform. The specific challenges to be investigated are the required personnel to implement a platform, the system architecture required to support a perpetual trial design beyond the initial set of therapies, and the monitoring and management plans required to maintain robust data throughout multiple interim analyses and periodic reporting of results. Platform trials must be nimble to fulfill their goal of efficiently exploring multiple therapies as quickly as possible. These infrastructure solutions allow the trial to adapt to changing arms, maintain data quality as well as trial integrity, and support multiple sets of results and publications throughout the trial's duration.

The efficacy of medicinal products based on plasma immunoglobulins and monoclonal antibodies for the treatment and prevention of COVID-19

The development of the COVID-19 pandemic initiated the search for effective drugs for the treatment and prevention of infection. Of particular importance for the fight against the pandemic is the timing of the introduction of drugs into clinical practice. Therefore, countries with developed healthcare systems (EU, USA, Russian Federation, etc.), issue conditional marketing authorizations of drugs for treatment and prevention of COVID-19, based on regulatory requirements for the circulation of medicines in emergency situations. The approval is issued on the basis of limited clinical data, with the condition that the full evaluation of safety and effectiveness will be carried out after the issuance of the authorization in the post-registration period. The COVID-19 pandemic has revolutionized the design and time frame of clinical trials, including phase I, II, and III adaptive trials, which has led to the approval of biologics for the treatment and prevention of COVID-19 in record time in most advanced pharmaceutical countries. At the same time, regulatory/healthcare authorities or international organizations constantly monitor the safety and effectiveness of used drugs and, if necessary, make adjustments (changes to the indications for use, dosage change, drug discontinuation etc.). Since the beginning of the pandemic, in fact, in conditions where the use of medicines was allowed based on very limited data, studies have begun to substantiate the safety and effectiveness of the use of immunoglobulin preparations and monoclonal antibodies for the treatment and prevention of COVID-19. As new data became available, changes were made regarding the indications for use, doses, and other characteristics of preparations of immunoglobulins and monoclonal antibodies for the treatment and prevention of COVID-19. The review presents a critical analysis of the results of evaluation the safety and effectiveness of the use of immunoglobulin preparations and monoclonal antibodies in a pandemic. Copyright © 2022 Meditsina Publishers. All rights reserved.

ANTICOV: Initiating a platform adaptive trial for COVID outpatients in Africa

Introduction/ Background: Early evidence on mortality and ICU intervention rates for SARS-CoV-2 patients, and modelling of COVID in Africa, prompted calls for treatment to prevent progression of mild/moderate COVID. WHO's SOLIDARITY trial aimed to prevent death in hospitalized patients and others looked at prevention, but no trials assessed treatment for mild/moderate cases. Methods: The challenge was to rapidly launch a large and flexible study. A consortium of African research institutions already part of the COVID response and additional technical partners developed a Target- Product-Profile and a clinical protocol to allow percountry adaptation while maintaining key common features. ANTICOV is an adaptive platform trial in 13 African countries, testing two treatment arms (700 max./arm), nitazoxanide/inhaled ciclesonide and ASAQ/ivermectin, in patients with mild/moderate SARS-CoV-2 infection and symptoms up to 7 days before randomisation. ANTICOV has submitted an amendment to test fluoxetine/inhaled budesonide. Ancillary studies are conducted in a subset of countries. Results: This unique, diverse, 26-partner consortium was established rapidly. The protocol was ready for submission by mid-June 2020, and funding was quickly granted, thanks to clear needs and the experience of consortium members. 9 of 13 countries have started recruitment. Despite support from AVAREF, approval processes per country took longer than hoped, and approved drug importation was also a bottleneck. Changes in diagnostic referral impacted recruitment, so active screening was established in some countries. An interim analysis was conducted after 300 patients were randomized with no treatment interruption resulting;the next is planned after 750 patients are randomized. Impact: ANTICOV is driven by a unique research alliance to respond to region/context-specific treatment and pandemic control, unlike much of global research to date. In a context of emerging variants and inequitable vaccine access, effective therapeutics to prevent disease progression globally but prioritized only by the African region until recently. Conclusion: ANTICOV was set up collaboratively, bringing experience and know-how from diverse African and European leaders to find treatment adapted to the needs of low-resource settings. It was rapidly developed and financially supported. Results will be shared quickly. Future pandemic preparedness will require similarly established networks and expedited funding.

The RELIEHF registry & clinical trial design (Relieving Increasing Oedema due to Heart Failure)

Background: Water retention leading to worsening congestion is a common reason for heart failure (HF) hospitalisation. Increases in aldosterone, due to increased secretion (driven by angiotensin and hyperkalaemia) and reduced degradation (due to hepatic dysfunction), contribute to congestion. Mineralocorticoid receptor antagonists (MRA) reduce morbidity and mortality in advanced HF. However, use of MRA is often limited by hyperkalaemia, renal dysfunction and hypotension. Hyperkalaemia can be corrected by potassium binding agents. Methods: An open-label, randomised, multi-centre (up to 100 UK sites) trial investigating the use of a potassium binding agent, patiromer, to facilitate higher doses of MRA for HF with worsening congestion requiring treatment with ≥80mg/day of furosemide (or equivalent). Patients are first entered on an unconsented screening-log (approved by the UK Health Research Authority) and then asked to consent to a registry (no exclusion criteria). If they agree, and are eligible (systolic blood pressure ≥90mmHg, eGFR ≥30mL/min/1.73 m2, no other terminal disease, no active infection or myocardial ischaemia), they are invited to participate in a randomised trial. Patients who consent for the trial enter a run-in phase of ≤35 days, when they receive ≤100mg/day of spironolactone. If serum potassium rises to >5.0mmol/L, the patient is randomised either to receive an MRA at guideline recommended doses or to have spironolactone increased ≤200mg/day, using patiromer to manage hyperkalaemia, providing eGFR remains ≥30mL/min and the patient does not become hypotensive. The primary outcome of the first phase of the trial (n = 400) is severity of congestion at 60-days but patients will be followed The RELIEHF Registry & Randomised Trial long-term for morbidity and mortality. An adaptive trial design allows recruitment to be increased up to 2.000 patients. Results: The conduct of the trial has been disrupted by COVID. As of January 2022, from 10 sites, >300 patients (40% women;median age 76 (65-83) years have been screened, >100 (37% women;median age 72 (62-80) years) have consented for the registry and >25 for the randomised trial. Of patients screened, about 50% were asked for registry-consent, of whom one third refused. The main reason for not asking was that the care-team considered it inappropriate due to patient frailty and/or cognitive dysfunction. Most patients who consented for the registry agreed, in principle, to participate in a randomised trial. Most patients have tolerated 100mg of spironolactone during the run-in period. Conclusions: For a high proportion of patients admitted to hospital with worsening HF, research staff do not deem it appropriate to approach them to ask for research consent. Most patients with HF who were asked to participate in research were willing to do so and to participate in a randomised trial, although a substantial proportion were not eligible for this trial. Of those who were, the majority tolerated spironolactone at a dose of 100mg/day.

Subcutaneous Sarilumab for the Treatment of Hospitalized patients with Moderate to Severe COVID19 Disease: A Pragmatic, Embedded, Multi-Center Randomized Clinical Trial

Background. The aim of this pragmatic, embedded adaptive trial was to measure the effectiveness of subcutaneous sarilumab in addition to an evolving standard of care for clinical management of inpatients with moderate to severe COVID-19 disease (NCT04359901). The study is also a real-world demonstration of the realization of a prospective learning healthcare system. Methods. Two-arm, randomized, open-label controlled 5-center trial comparing standard care alone to standard care (SOC), which evolved over time, with addition of subcutaneous sarilumab (200 mg or 400 mg anti-IL6R) among hospitalized patients with moderate to severe COVID-19 not requiring mechanical ventilation. The primary outcome was 14-day incidence of intubation or death. The trial used a randomized play-the-winner design and was fully embedded within the EHR system, including the adaptive randomization process. Results. Among 417 patients screened, 162 were eligible based on chart review, 53 consented, and 50 were evaluated for the primary endpoint of intubation or death ( >30% of eligible patients enrolled) (Figure 1). After the second interim review, the unblinded Data Monitoring Committee recommended that the study be stopped due to concern for safety: a high probability that rates of intubation or death were higher with addition of sarilumab to SOC (92.6%), and a very low probability (3.4%) that sarilumab would be found to be superior. Conclusion. This randomized trial of patients hospitalized with COVID-19 and requiring supplemental oxygen but not mechanical ventilation found no evidence of benefit from subcutaneous sarilumab in addition to an evolving standard-of-care. The numbers of patients and events were too low to allow independent conclusions to be drawn, but this study contributes valuable information about the role of subcutaneous IL-6 inhibition in the treatment of patients hospitalized with COVID-19. The major innovation of this trial was the advancement of embedded, point-of-care clinical trials for FDA-approved drugs;this represents a realization of the learning healthcare system. Methods developed and piloted during the conduct of this trial can be used in future investigations to speed the advancement of clinical science.

Bayesian modeling in COVID-19-disease modeling, therapeutics, and vaccines

COVID-19 efforts have dominated the headlines in 2020. These efforts have involved efforts across the medical and statistical spectrum, from modeling of the pandemic to the development of therapeutics to the testing of possible vaccines. Novel methodologies have been utilized, such as platform trials, Bayesian modeling of pandemic uncertainty, and Bayesian adaptive trials to facilitate timely vaccine delivery. In this session, we will present four real examples of Bayesian methods across this range of activities. These include the official modeling of the epidemic within Los Angeles County by the leader of the team, both design and execution of platforms trials within the COVID-19 pandemic, and the Bayesian Pfizer vaccine trial. All speakers confirmed. Roger Lewis is the leader of the COVID-19 epidemic modeling team for Los Angeles County, California, advising government officials on the progress of the epidemic and projecting future developments. He will discuss the Bayesian SEIR modeling performed for Los Angeles, including capturing uncertainty in the predictions and real-world issues in data collection and adjusting modeling in the presence of evolving medical care and government policies. Ben Saville will discuss therapeutic adaptive platform trials like PRINCIPLE and REMAP-CAP (focus on PRINCIPLE). Both trials are ongoing adaptive platform trials investigating multiple therapies for COVID- 19. PRINCIPLE is a UK national priority trial and is focused on ambulatory participants with suspected COVID-19 and a higher risk of morbidity (e.g. .50 years age with comorbidities). The trial is open-label and has co-primary endpoints of subject-reported time to recovery and hospitalization. REMAP-CAP includes both open-label and blinded interventions focused on hospitalized patients in the intensive care unit across eight countries. The primary endpoint is the number of organ support-free days, and includes multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Both trials use innovative Bayesian modeling that account for potential drift over time, with frequent interim analyses allowing early decisions of futility or superiority. Response-adaptive randomization is used to increase allocation to interventions with better observed outcomes, which can increase statistical power for finding effective therapies and result in better participant outcomes. Mark Fitzgerald will present some of the challenges of execution for the statistical analysis committee for a trial that is rapidly adapting to an ongoing pandemic, with a focus on REMAP-CAP. REMAP-CAP is an adaptive platform trial that explores the efficacy of interventions across a range of treatment domains, including the combinations across domains, that utilizes a novel endpoint: organ-support free days. The international effort combines data from five continents, evaluates thousands of treatment combinations, and rapidly evolves to accommodate information from external sources. The statistical analysis committee faces unique challenges in adjusting to rapid changes when combining data from disparate sources, updating models and reports to incorporate new design features, and producing results for public disclosure for closed domains or interventions, all while ensuring proper communication and maintaining trial integrity. Satrajit Roychoudhury will discuss the design of the Pfizer Bayesian adaptive vaccine trial. This trial incorporates multiple interim analyses, each based on achieving a sufficiently high Bayesian posterior probability of vaccine efficacy. The trial also incorporates early stopping for futility based on Bayesian predictive probabilities. In November 2020, the trial is currently ongoing. Additional information may be publicly available at the time of SCT 2021 that may be discussed, but this will depend on future events at time of submission.

CIRCULATE-Japan: Circulating tumor DNA-guided adaptive platform trials to refine adjuvant therapy for colorectal cancer.

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE-Japan including three clinical trials. The GALAXY study is a prospectively conducted large-scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high-risk stage II or low-risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double-blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor-positive status in the GALAXY study. Therefore, CIRCULATE-Japan encompasses both "de-escalation" and "escalation" trials for ctDNA-negative and -positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA-guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management.

Anti-Thrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC): Study design and methodology for an international, adaptive Bayesian randomized controlled trial.

BACKGROUND: Mortality from COVID-19 is high among hospitalized patients and effective therapeutics are lacking. Hypercoagulability, thrombosis and hyperinflammation occur in COVID-19 and may contribute to severe complications. Therapeutic anticoagulation may improve clinical outcomes through anti-thrombotic, anti-inflammatory and anti-viral mechanisms. Our primary objective is to evaluate whether therapeutic-dose anticoagulation with low-molecular-weight heparin or unfractionated heparin prevents mechanical ventilation and/or death in patients hospitalized with COVID-19 compared to usual care. METHODS: An international, open-label, adaptive randomized controlled trial. Using a Bayesian framework, the trial will declare results as soon as pre-specified posterior probabilities for superiority, futility, or harm are reached. The trial uses response-adaptive randomization to maximize the probability that patients will receive the more beneficial treatment approach, as treatment effect information accumulates within the trial. By leveraging a common data safety monitoring board and pooling data with a second similar international Bayesian adaptive trial (REMAP-COVID anticoagulation domain), treatment efficacy and safety will be evaluated as efficiently as possible. The primary outcome is an ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation or death. CONCLUSION: Using an adaptive trial design, the Anti-Thrombotic Therapy To Ameliorate Complications of COVID-19 trial will establish whether therapeutic anticoagulation can reduce mortality and/or avoid the need for mechanical ventilation in patients hospitalized with COVID-19. Leveraging existing networks to recruit sites will increase enrollment and mitigate enrollment risk in sites with declining COVID-19 cases.