Study design

October 1, 2021: COVID-OUT: From Computer Modeling to a Phase III Trial of Early Outpatient Treatment for SARS-CoV-2 Infection (Carolyn Bramante, MD, MPH; Thomas Murray, PhD; Jared Huling, PhD)

Posted on by terren.green@duke.edu

Speakers

Carolyn Bramante, MD, MPH
Division of General Internal Medicine
Departments of Internal Medicine and Pediatrics
Core faculty in the Program in Health Disparities Research and the Center for Pediatric Obesity Medicine
University of Minnesota Medical School

Thomas Murray, PhD
Division of Biostatistics
Coordinating Centers for Biometric Research
School of Public Health
University of Minnesota

Jared Huling, PhD
Division of Biostatistics
School of Public Health
University of Minnesota

Topic

COVID-OUT: From Computer Modeling to a Phase III Trial of Early Outpatient Treatment for SARS-CoV-2 Infection

Keywords

COVID-OUT; Study design; Randomized controlled trial; Metformin; Parallel enrollment design; De-centralized study; Nested SMART study

Key Points

  • The COVID-OUT trial is a phase 3, double-blinded, matched placebo-controlled, factorial design study of early outpatient treatments for SARS-Co-V-2 infection.
  • Metformin has a history of antiviral properties and has been shown, pre-COVID-19, to lower inflammation in the body, inhibit mTOR action, and cytokine-reducing effects.
  • Metformin is safe, inexpensive, and widely available.
  • The COVID-OUT trial aims to test 1,124 subjects in a 6 arm study design with metformin alone, ivermectin alone, fluvoxamine alone, metformin and fluvoxamine combined, metformin and ivermectin combined, and placebo.
  • A parallel enrollment design is used with a nested SMART study prevention trial.
  • COVID-OUT uses pre-packaged pill boxes to deliver meds to participants at 7 sites in order to encourage the correct dosage for each drug.

Discussion Themes

De-centralized clinical trials take a lot of training for participating sites. You could potentially do more with a larger central site and more limited involvement of the de-centralized sites.

Randomization strategies can be challenging in de-centralized trials.

Platform factorial design with multiple agents of interest presents a challenge for statistical analysis.

 

Read more about the COVID-OUT trial.

Tags

#pctGR, @Collaboratory1

Grand Rounds October 29: Embedding Pragmatic Trials into Emergency and Critical Care

Speakers:
Matthew W. Semler, MD, MSc
Assistant Professor
Vanderbilt University Medical Center

Jonathan D. Casey, MD, MSc
Assistant Professor
Vanderbilt University Medical Center

Topic: Embedding Pragmatic Trials into Emergency and Critical Care

Date: Friday, October 29, 2021, 1:00-2:00 p.m. ET

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August 13, 2021: Got anything for this cough? Outpatient Treatment Trials in the Time of COVID (Davey Smith MD)

Posted on by terren.green@duke.edu

Speaker

Davey Smith, MD
Protocol Co-Chair ACTIV-2
Professor of Medicine, UC San Diego

Topic

Got anything for this cough? Outpatient Treatment Trials in the Time of COVID

Keywords

COVID-19 treatment; Adaptive Platform Trial; ACTIV-2 Trial; Antiviral therapy

Key Points

  • An Adaptive Platform Trial is a trial in which multiple drugs can be tested at the same time to increase efficiency and transition seamlessly from a Phase II to a Phase III trial.

  • An interim analysis determines if a drug is moved on to trial Phase III.

  • The trials adapt as researchers learn more about COVID-19 and potential treatments.

  • Monoclonal antibody therapies showed promise initially, but COVID-19 variants have lessened their efficacy.

Discussion Themes

The ACTIV-2 trial initially focused on using antivirals, specifically monoclonal antibodies, to achieve a reduced viral load as an endpoint measure.  Changes were made to this endpoint measure as it became clear that the FDA would issue an Emergency Use Authorization only for a decrease in hospitalization and death.  

To adjust to the rapidly changing COVID-19 landscape of changing therapeutics, vaccines, and variants, the ACTIV-2 team remained nimble and flexible with the ability to act quickly when presented with new situations and information.  

Read more about the Active-2 Trial.

Tags

#pctGR, @Collaboratory1, @DaveySmithMD

August 6, 2021: Early Treatment of COVID-19 with Repurposed Therapies: The TOGETHER Adaptive Platform Trial (Edward Mills, PhD, FRCP)

Posted on by terren.green@duke.edu

Speaker

Edward Mills, PhD, FRCP Professor Department of Health Research Methods, Evidence & Impact McMaster University, Canada

Topic

Early Treatment of COVID-19 with Repurposed Therapies: The TOGETHER Adaptive Platform Trial

Keywords

COVID-19 treatment; Adaptive Platform Trial; Fluvoxamine; Repurposed therapies, TOGETHER Trial

Key Points

  • The most successful clinical trials have 1 thing in common; they are all Adaptive Platform Trials with an overarching master protocol that plans for changes in the long term, such as changing the intervention.
  • Perpetual trials are key to effective adaptable trials, where the focus is to build a trial infrastructure that is not abandoned at the end of the trial, but repurposed to quickly and efficiently begin another trial.
  • The TOGETHER Trial is a randomized Adaptive Platform Trial studying repurposed therapies to treat COVID-19.
  • In the TOGETHER Trial, participants were randomized to either a placebo arm of the study, or to a repurposed therapy arm of the study.  If a particular repurposed therapy didn’t show significant benefit for COVID-19 patients, that arm of the study was discontinued and an additional repurposed therapy was introduced in a new arm of the study.
  • After many trial therapies showed little effect, Fluvoxamine, an SSRI commonly used for depression, has shown promising results when repurposed to treat COVID-19.

Discussion Themes

With important breakthroughs on COVID treatments, should we wait until a study is completed, accepted by a journal, and published before disseminating the findings? 

Final results on the of Fluvoxamine trials are not yet available, but given the data thus far, there are no major concerns about the safety and tolerability of this medication.  

Read more about the TOGETHER Early Treatment of COVID Trial.

Tags

#pctGR, @Collaboratory1, @TogetherTrial

April 23, 2020: New Workshop Summary on the Design and Analysis of Pragmatic Clinical Trials

Posted on by Karen Staman

In 2019, NIH Health Care Systems Research Collaboratory held a comprehensive workshop to explore and discuss statistical issues encountered with embedded pragmatic clinical trials (ePCTs). The new Workshop Summary describes panel discussions with the principal investigators and statisticians of NIH Collaboratory Trials and the challenges and solutions encountered during the design and analysis of their trials.

The 4 panel discussions covered the following topics:

  • Measurement and Data: Outcomes, Exposures, and Subgroups Based on EHR Data
  • To Cluster or Not to Cluster?
  • Choosing a Parallel Group or Stepped-Wedge Design
  • Unique Complications

This Workshop Summary also provides lessons learned and recommends tools to help others design and analyze future ePCTs. For more on the design and analysis of pragmatic clinical trials, see the tools provided by the Biostatistics and Study Design Core and Living Textbook chapters on Experimental Designs and Randomization Schemes and Analysis Plans.

December 13, 2019: Reissuance of Funding Opportunity Announcement for HEAL Initiative/PRISM Coming January 2020

Posted on by Gina Uhlenbrauck

The National Center for Complementary and Integrative Health (NCCIH), with other NIH Institutes, Centers, and Offices, intends to reissue Funding Opportunity Announcement (FOA) HEAL Initiative: Pragmatic and Implementation Studies for the Management of Pain To Reduce Opioid Prescribing (PRISM) (UG3/UH3 Clinical Trial Optional).

This RFA solicits applications for phased cooperative research applications to conduct efficient, large-scale pragmatic or implementation trials to improve pain management and reduce the unnecessary use of opioid medications in the health care delivery setting. The re-issuance of the FOA will prioritize the following areas for pragmatic trials to integrate multimodal or multiple interventions that have demonstrated efficacy into health care systems or implement health care system changes to improve adherence to evidence-based guidelines:

  • Pain management in emergency departments, dental clinics, primary care, and hospitals
  • Chronic overlapping pain conditions
  • Pain management in individuals at risk of or with opioid use disorder
  • Pain management in those with co-occurring mental health disorders
  • Noncancer pain management in persons with medical comorbid conditions

The FOA is expected to be published in January 2020 with an expected application due date in March 2020.

The announcement is part of the NIH Heal (Helping to End Addiction Long-term) Initiative, which was created in April 2018 in an effort to speed scientific solutions for addressing the national opioid public health crisis.

 

May 17, 2019: The VITamin D and OmegA-3 TriaL (VITAL): Design and Results of a Large Pragmatic Trial (JoAnn E. Manson, MD, DrPH)

Posted on by Gina Uhlenbrauck

Speaker

JoAnn E. Manson, MD, DrPH
Chief, Division of Preventive Medicine, Brigham and Women’s Hospital
Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health
Harvard Medical School
Professor, Department of Epidemiology
Harvard T.H. Chan School of Public Health

Topic

The VITamin D and OmegA-3 TriaL (VITAL): Design and Results of a Large Pragmatic Trial

Keywords

Pragmatic clinical trial; Dietary supplements; Primary prevention; Mail-based randomized clinical trial; Cancer prevention; Cardiovascular disease prevention; vitamin D; Omega-3 fatty acids

Key Points

  • The VITAL pragmatic trial evaluated the effects of dietary supplements (vitamin D and omega-3) on reducing risk for developing cancer, heart disease, and stroke in the general population.
  • Study recruitment involved nationwide and targeted mailings, media reports, advertising, and brochures. Retention included participant newsletters, incentive gifts, and honoraria.
  • Findings included that neither omega-3s nor vitamin D significantly reduced the primary endpoints of major cardiovascular disease events or total invasive cancer. Omega-3s did reduce total myocardial infarction by 28%, with greatest reductions in those with low dietary fish intake and in African Americans.

Discussion Themes

VITAL’s hybrid design—remote or mail-based intervention plus serial in-clinic visits in a sample—has advantages in promoting quality and cost-efficiency.

Next steps for VITAL include continued follow-up for 5 years; genetic studies; and fostering new ancillary studies through nationwide collaborations.  

Visit the VITAL study website and read more about the results of VITAL (Manson et al., New Engl J Med, 2019)

Tags

#dietarysupplements, #pctGR, @Collaboratory1

April 5, 2019: The ENGAGES Pragmatic Trial and the Power of Negative Thinking (Michael S. Avidan, MBBCh)

Posted on by Gina Uhlenbrauck

Speaker

Michael S. Avidan, MBBCh
Dr. Seymour and Rose T. Brown Professor of Anesthesiology
Chief, Division of Clinical and Translational Research
School of Medicine, Department of Anesthesiology
Washington University in St. Louis

Topic

The ENGAGES Pragmatic Trial and the Power of Negative Thinking

Keywords

Pragmatic clinical trial; Surgery; Electroencephalography; EEG-guided anesthesia; Postoperative delirium; Older patients; Patient-centered outcomes; ENGAGES

Key Points

  • The ENGAGES pragmatic trial evaluated whether electroencephalogram-guided anesthetic administration decreases postoperative delirium incidence in older patients undergoing major surgery.
  • Delirium is a disturbance in consciousness or change in cognition for a short period of time as a consequence of a medical illness. 25% to 50% of older adults experience delirium after major surgery, and the number is even higher for ICU patients.
  • The ENGAGES trial found that, among older adults undergoing major surgery, EEG-guided anesthetic administration, compared with usual care, did not decrease the incidence of postoperative delirium.

Discussion Themes

Aside from the intensity of patient follow-up and the expertise needed to deliver the EEG-guided protocol, the ENGAGES study fulfilled the criteria for a pragmatic clinical trial as shown in PRECIS-2 ratings.

Clinicians participating in ENGAGES were not researchers but carried out the intervention on the ground. They understood the appeal of it and found it easy to implement.

With respect to study findings, instead of referring to “negative” or “null” findings, why not say, “this is what we found and these are interesting findings.”

Learn more about the results of the ENGAGES trial in JAMA (Feb 2019).

Tags

#delirium, #pctGR, @Collaboratory1, @WUSTL_med

March 1, 2019: Approaches to Patient Follow-Up for Clinical Trials: What’s the Right Choice for Your Study? (Keith Marsolo, PhD)

Posted on by Gina Uhlenbrauck

Speaker

Keith Marsolo, PhD
Department of Population Health Sciences
Duke Clinical Research Institute
Duke University School of Medicine

Topic

Approaches to Patient Follow-Up for Clinical Trials: What’s the Right Choice for Your Study?

Keywords

Pragmatic clinical trial; Real-world data; Distributed research network; Electronic health records; EHR; Health data sources; Data standardization; Common data model; Fast Healthcare Interoperability Resources (FHIR); Application programming interface (API)

Key Points

  • Different sites have different capabilities and levels of sophistication around data. Clinical trial investigators should think from the beginning about the questions they want to answer and how much data is needed.
  • From different sources, such as the EHR, claims, or participant, data can be procured and provided in different ways, either by the patient, staff or clinician, or through IT and data experts.
  • PCTs with many sites may require a “patchwork quilt” of approaches for patient follow-up depending on the needs of the trial. Clinician-generated reports, direct from patients, and solutions involving application programming interfaces (APIs) are all good options for data exchange.

Discussion Themes

How do we think through the options for getting patient data where some sites may not be in the distributed research network or use a common data model?

Fast Healthcare Interoperability Resources (FHIR) is a draft standard describing data formats and elements and an application programming interface (API) for exchanging electronic health records. The FHIR interface requests data as an object, and for each defined domain it specifies allowable values and variables and predefines the information that you get out of the system.

Until data are collected/generated using the same standards/formats as the API, there will still be a need to understand the EHR-to-interface mapping.

For more information on using health data in embedded pragmatic clinical trials, visit the NIH Collaboratory’s EHR Core webpage.

Tags

#CommonDataModel, #RealWorldData, #FHIR, #pctGR, @Collaboratory1

January 22, 2019: New Self-Paced ePCT Training Course Available

Posted on by Gina Uhlenbrauck

The NIH Collaboratory is pleased to announce the availability of a new self-paced, 10-module introductory course on how to design, conduct, and disseminate embedded PCTs (ePCTs). This course presents condensed material from the inaugural ePCT Training Workshop held in 2018 and provides users with important things to know and do when designing an ePCT, along with helpful links to additional learning resources within the Living Textbook.

Also available in the Living Textbook are links to videocast workshops hosted by the NIH on a range of ePCT topics including:

  • Embedded PCTs of therapeutic A versus B interventions
  • Unique opportunities for disseminating, implementing, and sustaining evidence-based practices into clinical care
  • Ethical and regulatory issues of PCTs

For these and other ePCT resources, visit the Training Resources webpage.