adaptive platform trial

Grand Rounds September 19, 2025: Hurdles for the Delivery of Clinical Trials: Insights From the REMAP-CAP Trial in Europe (Denise van Hout, MD, PhD)

Posted on by terren.green@duke.edu

Speaker

Denise van Hout, MD, PhD
Postdoctoral Researcher
Julius Center for Health Sciences and Primary Care
University Medical Center Utrecht, the Netherlands

Keywords

Adaptive platform trial, Regulatory efficiency, REMAP-CAP, Study design, Study startup.

Key Points

  • Randomised Embedded Multifactorial Adaptive Platform trial for Community-Acquired Pneumonia (REMAP-CAP) began in 2016 as a data driven analysis of ethical, administrative, and logistical and ethical (EARL) delays in clinical trials studying respiratory infections. The goal was embedded trials that are flexible, efficient, and agile to provide clinicians with high-quality evidence to make the best treatment decisions.
  • REMAP-CAP is a global multifactorial adaptive platform trial with a master protocol that can investigate multiple interventions in different treatment domains for a single disease.
  • Over 8000 patients in REMAP-CAP were randomized to 44 interventions in 16 different treatment domains between January 2019 and June 2023. Patients could be randomized to more than 1 domain resulting in 15656 randomizations. Enrollment increased during the COVID-19 pandemic.
  • Dr. van Hout believes that to improve clinical trials, we should treat the challenges as a scientific problem and solve them with the same rigor.
  • Regulatory requirements and informed consent regulations differed among sites causing confusion for the researchers about what documents should be submitted with the contract and protocol in each country. Drug labeling requirements in some countries also slowed protocol approval. EARL processes also slowed trial initiation and patient enrollment.
  • It was clear that overall enrollment in the UK outpaced the other 257 sites worldwide. The UK had a shorter period of time to a fully signed study contract and protocol approval compared with sites in other countries (5 days in the UK compared with 183 days in non-UK countries). This quicker time to signed contract was accomplished by either accepting the contract as-is or rejecting the contract – without negotiating small details. The UK was also 3 months faster than non-UK countries at enrolling the first patient after study approval (1 month vs 4 months, respectively) leading to more enrollment and more research questions answered.
  • In January of 2022 the EU centralized regulatory submission to a single portal (CTIS) to ease and speed the process of starting a new trial.

Discussion Themes

Adaptive platform trials were uncommon before the COVID-19 pandemic, but their value became clear during the pandemic. After the pandemic, REMAP-CAP focuses on different treatment domains for pneumonia. Maintaining the infrastructure for an adaptive platform trial is difficult if there is not a clear need such as there was during the COVID-19 pandemic.

Centralizing approval for trials under one government body could speed the approval process for studies. During times of high need, prioritizing one or two good trials over a lot of smaller trials can also help speed the process.

 

Learn more about REMAP-CAP at https://www.remapcap.eu/

January 4, 2023: This Week’s COVID-19 Grand Rounds Will Share Long COVID Outcome Data From the COVID-OUT Trial

Posted on by Damon Seils

Headshots of Dr. Carolyn Bramante and Dr. Thomas MurrayIn this Friday’s COVID-19 Grand Rounds, Dr. Carolyn Bramante and Dr. Thomas Murray of the University of Minnesota will present “Outpatient Treatment of COVID-19 With Metformin, Ivermectin, or Fluvoxamine: 10-Month Follow-up and Effects on Developing Long COVID.”

The Grand Rounds session will be held on Friday, January 6, at 1:00 pm eastern. Join the online meeting.

The NIH Pragmatic Trials Collaboratory Coordinating Center is using its popular Grand Rounds platform to share late-breaking research and promote resources in support of clinical researchers affected by the COVID-19 public health emergency. For previous COVID-19 Grand Rounds, and more news and resources related to the COVID-19 public health emergency, see the COVID-19 Resources page.

Grand Rounds August 5, 2022: Economic Evaluation of Platform Trial Designs (Jay JH Park, PhD, MSc)

Posted on by Elizabeth Mccamic

Speaker

Jay JH Park, PhD, MSc
Assistant Professor
Department of Health Research Methods, Evidence and Impact
Faculty of Health Sciences
McMaster University

 

 

Keywords

Platform Trial, Study Design, Pragmatic Clinical Trials

 

Key Points

  • Adaptive trial design is an overarching terminology for trials that use accumulating data in a formal way. In this design, we come up with how we are going to look at the data, how we plan to react to the data, with one or more rounds of internal evaluations or interim reviews where we make the adaptations to the trial design, if the data says we should. The most common types of adaptive trial design are sequential design and response adaptive randomization.
  • Platform trial design refers to trials that are designed with the flexibility to add new intervention. They use a series of documents called “master protocols” that outline trial plans and standard operating procedures for evaluation of multiple interventions. You can conduct platform trials using adaptive trial designs or fixed sample trial designs.
  • To evaluate these trial methods, we did an economic evaluation to determine what are the costs and time requirements conducting a single platform trial versus multiple independent trials? We administered a survey to international experts with publication record on platform trials and master protocols using purposive sampling. The response rate was low (10%). Participants were asked how long it takes and cost for trail set up, conduct, and analysis for a two-arm multi-trial and in addition for a platform trial how long it takes what it costs to add a new intervention.
  • The main outputs were the set-up cost and time, comparing the single study set-up and the total set-up cost and time across different trials and scenarios, and the total cost and time (set-up, conduct, and analysis). We compared a single platform trial to a single 2-arm trial and found it takes considerably less time and cost in setting up a single trial for conventional trials. The findings were similar for cost. There was not much difference in cost between a platform trial and multi-arm trial; setting up a single platform does appear to save money. The single platform trial requires less time measured by total persons.
  • The key takeaway from the simulation is that the platform trial has larger set-up requirements, but it can save money and time in the long run. The platform trial model is not easy but not impossible; as we saw during the COVID-19 pandemic, it can be an effective way to discover important therapies and research in a fast and effective manner.

Discussion Themes

-Did the total cost include both coordinating center costs and site-level costs? We did not get into the site-level costs.

-These platform trials are almost a public good so that there is a sustainable model for the infrastructure so it continues to grow and evolve and no one bears the full cost. Does academic environment create some disincentives as well? Who becomes the PI is an important question because their institution gets the overhead. I’m not sure what the right answer is. There’s lots of red tape in the academic world. It’s an example of the kind of barriers there are to innovative approaches. How can we chip away at the barriers? At the individual level there is interest and commitment, and we see the value in this but there are barriers that do get in the way. Calling them out is step one.

Read the full study.

 

Tags

#pctGR, @Collaboratory1

August 3, 2022: Economic Evaluation of Platform Trial Designs Featured in This Week’s PCT Grand Rounds

Posted on by Damon Seils

Head shot of Dr. Jay JH ParkIn this Friday’s PCT Grand Rounds, Dr. Jay JH Park of McMaster University will present “Economic Evaluation of Platform Trial Designs.” The Grand Rounds session will be held on Friday, August 5, 2022, at 1:00 pm eastern.

Dr. Park is director of the Platform Trials Initiative in the Canadian Critical Care Trials Group and an assistant professor in the Department of Health Research Methods, Evidence, and Impact at McMaster University.

Join the online meeting.

March 18, 2022: Early Treatment of COVID-19: The TOGETHER Adaptive Platform Trial (Edward Mills, PhD, FRCP; Craig Rayner, PharmD)

Posted on by terren.green@duke.edu

Speakers

Edward Mills PhD, FRCP
Professor, McMaster University

Craig R Rayner FRCP Edin PharmD MBA
Certara Distinguished Scientist
Adjunct Associate Professor, Monash University

Keywords

COVID-19; Ivermectin; TOGETHER trial; Patient engagement; Adaptive platform trial

Key Points

  • The TOGETHER trial is a randomized adaptive platform trial investigating 11 different treatments for COVID-19 including Ivermectin.
  • Initial in vitro experiments of Ivermectin in April of 2020 showed promising results, but many of those original papers were later retracted.
  • The TOGETHER trial used PBPK modelling to determine trial dose regimen. The trial started with 1 dose and later moved to 3 doses.
  • The primary outcome of the TOGETHER trial was emergency room visits due to COVID-19 or hospitalization due to the progression of COVID-19.
  • No evidence was found of treatment effect for ivermectin compared to placebo, but a small treatment effect cannot be ruled out. It may have an effect for a subgroup of patients.

Discussion Themes

A low confidence interval could signal that the trial was stopped too early.

Building trust within the community is key to the success of a trial. Recruitment is difficult if the patients don’t trust the trial or researchers.

Read more about the TOGETHER trial.

 

 Tags

#pctGR, @Collaboratory1

March 16, 2022: Ivermectin Results From the TOGETHER Trial Will Be Shared in COVID-19 Grand Rounds

Posted on by Damon Seils
Headshots of Dr. Edward Mills and Dr. Craig Rayner
Dr. Edward Mills and Dr. Craig Rayner

In this Friday’s COVID-19 Grand Rounds session, Dr. Edward Mills of McMaster University and Dr. Craig Rayner of Monash University will present “Better Data on Ivermectin Is Finally Here: Results from the TOGETHER Trial.”

The Grand Rounds session will be held on Friday, March 18, at 1:00 pm eastern. Join the online meeting.

The NIH Pragmatic Trials Collaboratory Coordinating Center is using its popular Grand Rounds platform to share late-breaking research and promote resources in support of clinical researchers affected by the COVID-19 public health emergency.

For previous COVID-19 Grand Rounds, and more news and resources related to the COVID-19 public health emergency, see the COVID-19 Resources page.

August 3, 2021: COVID-19 Grand Rounds Continues With the TOGETHER Early Treatment Trial

Posted on by Damon Seils
Headshot of Edward Mills
Dr. Edward Mills

In this Friday’s COVID-19 Grand Rounds session, Dr. Edward Mills of McMaster University will present “The TOGETHER Early Treatment of COVID Trial: Building Platform Trial Infrastructure for Infectious Diseases.”

The Grand Rounds session will be held on Friday, August 6, at 1:00 pm eastern. Join the online meeting.

The NIH Collaboratory Coordinating Center is using its popular Grand Rounds platform to share late-breaking research and promote resources in support of clinical researchers affected by the COVID-19 public health emergency.

For previous COVID-19 Grand Rounds, and more news and resources related to the COVID-19 public health emergency, see the COVID-19 Resources page.

June 3, 2021: Town Hall Will Introduce ACTIV-6 Study to Potential Sites and Investigators

Posted on by Damon Seils

Leaders of the ACTIV-6 study, featured recently during NIH Collaboratory Grand Rounds, will hold a town hall Wednesday, June 9, to share information about the study with interested stakeholders, including sites and investigators that may want to participate. The leadership team will describe the rationale for ACTIV-6, share an overview of the platform and objectives, and provide information about how to join and contribute to the study.

Contact DCRI-ACTIV6@dm.duke.edu if you would to receive a calendar invitation the event. The town hall will be recorded for those who are unable to attend.

ACTIV-6, part of the NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program, is a platform trial that will test whether several already approved medications can be repurposed for treating symptoms of mild to moderate COVID-19 in nonhospitalized patients.

View the April 30 Grand Rounds webinar.

May 21, 2021: The PRINCIPLE Adaptive Platform Trial for Community Treatment of COVID-19: Innovation in Trial Design and Delivery (Chris Butler, MD; Ben Saville, PhD)

Posted on by Damon Seils

Speakers

Chris Butler, MD
Nuffield Department of Primary Care Health Sciences
University of Oxford

Ben Saville, PhD
Berry Consultants

Topic

The PRINCIPLE Adaptive Platform Trial for Community Treatment of COVID-19: Innovation in Trial Design and Delivery

Keywords

COVID-19; Adaptive platform trial; PRINCIPLE; Master protocols; Direct-to-participant trial; Repurposed drugs

Key Points

  • Adaptive platform trials focus on a specific disease, asking: What is the best treatment for a unique patient with this disease? Such trials involve making adaptations to accruing data and conducting frequent interim analyses. Multiple interventions can be evaluated at the same time, and study arms can be staggered.

  • An adaptive platform is well suited to studying COVID-19 interventions. The PRINCIPLE trial aims to evaluate whether repurposed drugs can make a difference with early intervention for patients with COVID-19 symptoms. It is a nationwide (UK) clinical study from the University of Oxford to find treatments for recovery at home.

  • Adaptive platform trials have the potential to evaluate treatments quickly (to determine early superiority or futility) and the flexibility to add or remove treatments during the ongoing study. The use of “response adaptive randomization” allocates more patients to interventions having better outcomes.

  • Because most people with COVID-19 are managed in the community, community treatments may have the widest reach and impact. PRINCIPLE takes “research to the patient,” with online consent, study materials that are sent directly to patients, and patient self-sampling. Participation in the trial is not limited to where people receive healthcare.

Discussion Themes

The “inverse research participation law” (proposed by Julian Tudor Hart) posits that access to research is often inversely proportional to a participant’s potential contribution and to where the research findings should be most applicable.

A pragmatic trial should ensure that the comparator group is as close to usual care as possible. So while the trial design does not allow an understanding of the mechanisms behind any observed effect, it is the best design to find out what would happen if the treatment were used in the real world.

The PRINCIPLE study team was able to do intensive remote monitoring of patients online, by telephone, trial partner, or using routinely collected data.

Read more about PRINCIPLE and adaptive platform trials.

Tags

#pctGR, @Collaboratory1

May 18, 2021: COVID-19 Grand Rounds Continues Friday With the PRINCIPLE Adaptive Platform Trial

Posted on by Damon Seils

Photographs of Dr. Chris Butler (left) and Dr. Ben Saville (right)
Dr. Chris Butler (left) and Dr. Ben Saville (right)

In this Friday’s COVID-19 Grand Rounds session, Dr. Chris Butler of Oxford University and Dr. Ben Saville of Berry Consultants will present “The PRINCIPLE Adaptive Platform Trial for Community Treatment of COVID-19: Innovation in Trial Design and Delivery.” The Grand Rounds session will be held on Friday, May 21, at 1:00 pm eastern. Join the online meeting.

The NIH Collaboratory Coordinating Center is using its popular Grand Rounds platform to share late-breaking research and promote resources in support of clinical researchers affected by the COVID-19 public health emergency.

For previous COVID-19 Grand Rounds, and more news and resources related to the COVID-19 public health emergency, see the COVID-19 Resources page.