COVID-19

April 18, 2024: New Living Textbook Chapter Articulates How Investigators Navigated Unexpected Challenges During Pragmatic Clinical Trials

Posted on by Karen Staman

During the course of the years-long pragmatic clinical trials supported by the NIH Pragmatic Trials Collaboratory, many unanticipated challenges have occurred, some of which have had profound effects on usual care, trial implementation, data systems, and staff. These unanticipated changes threatened the ability of the trials to address the questions they were designed to answer. A new chapter of the Living Textbook—Navigating the Unknown—describes these challenges and the responses of the study teams.

The chapter describes 3 general categories of challenges, each meriting a different response:

  1. If the challenge is a local or temporary issue (for example, a pandemic temporarily shuts down in-person care, or a partnering health system dissolves or is purchased), but the question is still relevant or important and the trial is still feasible, then a workaround may solve the problem.
  2. If the trial is no longer feasible for some reason (for example, the recruitment process is not feasible, or the intervention cannot be delivered as planned), and the question is still relevant, it is necessary to make significant changes to the protocol.
  3. If the question is no longer relevant or important (for example, new evidence or policy changes make the question no longer relevant), the trial should not continue. For this challenge, it may necessary either to stop the trial or to make fundamental changes to address a different question (since the original question is no longer relevant).

The chapter describes local or temporary challenges some of the study teams faced, such as the COVID-19 pandemic, health system mergers, and changes to the electronic health record (EHR). In these cases, the research questions were still relevant and important and the trial designs were still feasible, so workarounds were created to solve the problems.

  • Section 2: Study teams responded to staff turnover, leadership changes, and health system acquisitions and mergers.
  • Section 3: Rapid technology change created unexpected consequences, such as EHR updates causing system changes that affected intervention delivery, and sites switching EHRs systems creating complexities during the trial.
  • Section 4: COVID-19 had significant impacts on trial activities.

Section 5 of the new chapter addresses barriers that resulted from aspects of the protocol that could have impacted recruitment, retention, or implementation in a way that imperiled the ability of trials to answer the question posed by a research study. In these scenarios, researchers found it appropriate to change the protocol or research question—to pivot—in order to glean meaningful, actionable evidence.

Sections 6 and 7 describe challenges that can fall into either category 1 or 2, and investigators had to decide how to respond in real time.

  • Section 6: Clinical practice guidelines and policies changed due to new evidence from observational studies, small trials, and shifting expert opinion, and therefore, usual care changed.
  • Section 7: Quality improvement initiatives were launched to address similar problems, threatening the ability to discern differences between arms of the trial.

The NIH Pragmatic Trials Collaboratory supports pragmatic clinical trials embedded in healthcare systems to test interventions that address urgent public health problems faced by delivery systems. They involve hundreds to thousands of participants and generally include usual care as a control arm. One of the most important lessons learned through the course of these trials is that unexpected change is a given.

For more, see the section on Unanticipated Changes in the Analysis Plan chapter of the Living Textbook.

January 10, 2024: In This Friday’s PCT Grand Rounds, a Lottery for Allocating Scarce COVID-19 Resources

Posted on by Damon Seils

In this Friday's PCT Grand Rounds, Erin McCreary of the University of Pittsburgh will present "Design and Implementation of a Weighted Lottery to Equitably Allocate Scarce COVID-19 Resources."

The Grand Rounds session will be held on Friday, January 12, 2024, at 1:00 pm eastern.

McCreary is a clinical assistant professor of medicine at the University of Pittsburgh and the director of infectious diseases improvement and clinical research innovation at UPMC. She is also the president-elect of the Society of Infectious Diseases Pharmacists.

Join the online meeting.

April 12, 2023: This Week’s PCT Grand Rounds to Provide Updates on RECOVER Long COVID Initiative

Posted on by Damon Seils

Headshot of Dr. Kanecia ZimmermanIn this Friday’s PCT Grand Rounds, Kanecia Zimmerman of Duke University will present “RECOVER in Action: Status of Clinical Trial Protocols.” The Grand Rounds session will be held on Friday, April 14, 2023, at 1:00 pm eastern.

Dr. Zimmerman is an associate professor of pediatrics in the Duke University School of Medicine. The Researching COVID to Enhance Recovery (RECOVER) initiative brings together patients, caregivers, clinicians, and community leaders to conduct large-scale national research studies with the goal of understanding and improving the treatment of long COVID,

Join the online meeting.

Grand Rounds January 6, 2023: Outpatient Treatment of COVID-19 With Metformin, Ivermectin, or Fluvoxamine: 10-Month Follow-up and Effects on Developing Long COVID (Carolyn Bramante, MD, MPH; Thomas Murray, 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
University of Minnesota School of Public Health

 

 

Keywords

COVID-19; Long COVID; COVID-OUT; Metformin; Ivermectin; Fluvoxamine

 

Key Points

  • The COVID-OUT Trial was a multi-arm remotely delivered, de-centralized Phase III clinical trial conducted at 6 institutions including 1431 patients with overweight or obesity, designed to test distinct treatment of COVID-19 with Metformin, Fluvoxamine, and Ivermectin. Arms of the trial included 6 groups: (1) metformin and fluvoxamine, (2) metformin and ivermectin, (3) metformin and placebo, (4) placebo and fluvoxamine, (5) placebo and ivermectin, (6) placebo and placebo.
  • The primary outcome was a binary, 4-part composite outcome of occurrence of severe COVID-19, defined as hypoxia, emergency department visit, hospitalization, or death. Patients were followed for 10 months after enrollment.
  • Long COVID was determined by patient-report of clinician-diagnosed Long COVID.
  • Data on Metformin plus placebo show an absolute risk reduction of 4.4% for Long COVID diagnosis at 300 days. There was a consistent direction of effect of Metformin across subgroups and no evidence of heterogeneity of treatment effect.
  • Diabetes may be a risk factor for severe COVID-19. New observational and preclinical data from patients with prediabetes and PCOS suggest there may be a dose dependent effect of metformin against SARS-CoV-2.
  • Metformin is safe, well tolerated, and familiar to providers.
  • Some limitations of the study include lack of diversity in patient population, methods of ascertainment of Long COVID that may under- or over-ascertain Long COVID, internal validity of oxygen data, and self-report of medication adherence.
  • Only 3.8% of people in the study who said they had Long COVID received treatment for Long COVID. The COVID-OUT trial data don’t suggest that Metformin will treat Long COVID in someone who already has Long COVID, but there are mechanisms that suggest it may be worth investigating.

 

Discussion Themes

– We did internally look at an unadjusted comparison of vaccinated vs unvaccinated participants, but this comparison is confounded and not the focus of this work. In the future we will do a full observational analysis predicting Long COVID using these subgroups..

– Earlier treatment versus later treatment with Metformin seems to benefit patients..

– There may be other medications in the space of diabetes that may have anti-inflammatory mechanisms that could be relevant to COVID-19 treatment. GLP-1 receptor agonists may have anti-inflammatory and immune modulatory effects. Also, DPP-4 inhibitors also have some beneficial anti-inflammatory effects. These medications are more expensive and may have a more difficult method of delivery, but could be studied to determine their effect on COVID-19.

 

LEARN MORE

Learn more about the COVID-Out trial.

Read the COVID-OUT trial results paper.

 

Tags

#pctGR, @Collaboratory1

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 October 28, 2022: The HERO (Healthcare Worker Exposure Response & Outcomes) Program: An Online Community to Support Observational Studies, Randomized Trials, and Long-Term Safety Surveillance (Emily O’Brien, PhD, FAHA; Russell Rothman, MD, MPP)

Posted on by terren.green@duke.edu

Speakers

Emily O’Brien, PhD, FAHA
Associate Professor
Duke Clinical Research Institute
Duke University School of Medicine
Department of Population Health Sciences

Russell Rothman, MD, MPP
Senior Vice President, Population and Public Health
Director, Vanderbilt Institute for Medicine and Public Health
Vanderbilt University Medical Center

 

 

Keywords

HERO Registry; HERO TOGETHER; Hydroxychloroquine; COVID-19; PCORI; PCORnet

 

Key Points

  • On March 21, 2020, in response to the COVID-19 pandemic, PCORI contacted leadership at Duke Clinical Research Institute and PCORnet and a decision was made to focus on the space of healthcare workers. The HERO Program was fully approved and began recruiting participants on April 22, 2020.
  • The HERO Registry aimed to create a diverse virtual community of healthcare workers and their families and communities, ready for future COVID-19 research.
  • The HERO Registry explored topics that mattered most to participants and found these topics changed with time. Important issues early on included COVID-19’s effects on the workplace, vaccine access and willingness, and impact on home life. Later, burnout and lack of appreciation and support became larger issues.
  • The first trial undertaken by the HERO Program, HERO-HCQ, evaluated the efficacy of hydroxychloroquine (HCQ) to prevent COVID-19 in healthcare workers. Over 1300 participants were recruited from the HERO Registry. No statistically significant benefit was found.
  • The HERO TOGETHER study leveraged the HERO Registry to estimate real-world incidence of safety events among vaccinated individuals. The most common safety events reported included non-hospitalized arthritis/arthralgia and non-hospitalized non-anaphylactic allergic reaction.

Learn more

On the HERO Program website.

Discussion Themes

– The HERO Registry survey collected a large broad range of information. Participant feedback revealed that shorter more targeted surveys focusing on the most high-value information may have been less burdensome for participants..

– The creative multi-faceted approach to recruitment that includes diverse stakeholder engagement could be successful in creating research registries for other important health issues. .

Tags

#pctGR, @Collaboratory1

Grand Rounds July 8, 2022: Results From the COVID-OUT Trial, A Phase-3 Trial of Outpatient Treatment for Covid-19 Using Metformin, Ivermectin, and Fluvoxamine (Carolyn Bramante, MD, MPH; Thomas Murray, PhD; Jared Huling, PhD)

Posted on by Elizabeth Mccamic

Speakers

Carolyn Bramante, MD, MPH
Assistant Professor, General Internal Medicine and Pediatrics
Core Faculty, Center for Pediatric Obesity Medicine
Core Faculty, Program for Health Disparities Research
University of Minnesota Medical School

Thomas Murray, PhD
Assistant Professor of Biostatistics
Division of Biostatistics
University of Minnesota School of Public Health

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

 

 

Keywords

COVID-19, COVID-OUT

 

Key Points

  • The COVID-OUT Trial is a remotely delivered, Phase 3, de-centralized clinical trial at 6 participating institutions to see if Ivermectin, Metformin or Fluvoxamine would prevent severe COVID-19. The primary outcome was a 4-part composite: hypoxemia on a home oxygen monitor, ED visit, hospitalization or death due to COVID-19.
  • The dosing for the drugs during the trial was Ivermectin 390 (470mcg/kg/day x 3 days), Metformin titration to 1,500mg/day over 7 days, and Fluvoxamine 50mg.
  • Trial participants were adults ages 30-85, who tested positive for SARS-CoV-2 within 3 days, with fewer than 7 days of symptoms, no known prior infection with SARS-CoV-2, no severe kidney, liver, or heart failure. Patients with diabetes or prediabetes were not excluded (except for those on insulin or sulfonylurea); pregnant patients were not excluded for the Metformin arm; the trial restricted participants to people who were overweight or obese to enrich the population for having a high risk of outcomes and for anti-inflammatory hypotheses around Metformin.
  • Initially, the randomization of the trial was 1:1 Metformin or Placebo. When Ivermectin and Fluvoxamine were added enrollment was even across 6 arms (except for pregnant participants). When the DSMB recommended stopping Fluvoxamine, the trial reduced to 4 arms.
  • The primary outcome of the trial was negative. Some aspects were a success, particularly delivery of study medication nation-wide within 1 day of consent. None of the medications appeared to have any effects on symptoms. A pre-specified secondary analysis of the primary outcome indicates a substantial reduction in ED visits, hospitalizations, and death from COVID-19 with Metformin.

Discussion Themes

-How did the trial handle recruitment? It was a huge challenge. We started only looking within the participating health system and sites. We used Google Ads and partnerships with some testing clinics. We worked together between the sites when there were issues with bandwidth at one of the sites, the main site would call those participants. We also kept equal focus on follow-up.

Learn more about COVID-OUT.

Tags

#pctGR, @Collaboratory1

Grand Rounds July 29, 2022: Effect of Early Treatment With Single-Dose Pegylated Interferon Lambda Among Patients With COVID-19: Results From The TOGETHER Trial (Edward Mills, PhD, FRCP; Jeffrey S. Glenn, MD, PhD)

Posted on by Elizabeth Mccamic

Speaker

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

Jeffrey S. Glenn, MD, PhD
Joseph D. Grant Professor and Professor of Microbiology and Immunology
Stanford University

 

 

Keywords

TOGETHER, COVID-19, Peginterferon Lambda

 

Key Points

  • TOGETHER is a randomized adaptive platform trial that was initiated in June 2020 to investigate the efficacy of repurposed treatments for COVID-19 disease among high-risk adult outpatients. TOGETHER has been through 14 interventions within the trial and has four active arms.
  • For the overall trial, anyone over the age of 18 with a known risk factor for disease progression is eligible; they have to present at an outpatient care setting with an acute clinical condition consistent with COVID-19 and have a positive rapid test in the clinic. The consent process is in-person, which was challenging in the beginning days of the trial.
  • The arm evaluating Peginterferon Lambda is a multicenter, investigator sponsored, randomized placebo-controlled Phase 3 study in Brazil with 12 sites and Canada (5 sites). It is a single injection of peginterferon lambda verses placebo, patients were randomized within 7 days of symptom onset and positive SARS-CoV-2 test. The trial has enrolled 1,900 high-risk non-hospitalized and 84% of patients were vaccinated to some extent, from July 2021-Feb 2022. The primary endpoint is either reduction in COVID-19-related hospitalizations or emergency hospital visits through day 28 and hospitalization or death.
  • The primary outcome had a relative risk reduction of 51% when given 7 days or less of symptoms before treatment; when the trial looked at early treated patients (less than 3 days of symptoms before treatment) the treatment effect when up to 57% risk reduction. 43% risk reduction for hospitalization (65% reduction when treated early). Hospitalization or death due to COVID-19 was 41% if treated within 7 days and 65% if treated within 3 days of symptoms. It was a big treatment effect observed in a predominantly vaccinated population.
  • When compared to other drug trials for COVID-19, there was a 61% reduction for the primary outcome and 54% reduction in hospitalization and death for unvaccinated populations. In the same population, if treated early there was a 65% reduction for the primary outcome and hospitalization or death due to COVID-19. The unvaccinated and early treatment population saw a 89% risk reduction, which is very similar to what was identified in the Paxlovid trial.

Discussion Themes

-Were any concerns raised on ethics of keeping a placebo arm in this population? For the countries we are working in this has not been an issue because of the drugs that were available during the time of the study.

-Immunosuppressed patients might be a subgroup that would particularly benefit from this type of treatment.

Learn more about TOGETHER.

 

Tags

#pctGR, @Collaboratory1

Grand Rounds July 22, 2022: ACTIV-6: 1-Year Later and Trial Results for Ivermectin-400 and Inhaled Fluticasone (Susanna Naggie, MD, MHS)

Posted on by Elizabeth Mccamic

Speaker

Susanna Naggie, MD, MHS
Professor of Medicine
Vice Dean for Clinical Research
Duke University School of Medicine

 

 

Keywords

ACTIV, ACTIV-6, COVID-19, Ivermectin, Inhaled Fluticasone

 

Key Points

  • The key clinical questions of the ACTIV-6 study are: how to help someone feel better faster with newly diagnosed mild-moderate COVID-19 and how to prevent hospitalizations or death in someone with newly diagnosed mild-moderate COVID-19?
  • ACTIV-6 is testing medication doses approved by the FDA for other purposes, i.e., repurposed drugs. It is a decentralized, fully remote trial, and data are largely patient reported. Participants test positive for COVID-19 with a FDA-authorized test, register from home, are randomized remotely, receive study medication through the central pharmacy, and follow instruction until their clinical symptoms improve. All of the surveys are completed online. The measured outcomes for ACTIV-6 are days of benefit and time to recovery/hospitalization and death.
  • ACTIV-6 is actively recruiting across 93 sites with 5,034 randomized. Results have been shared for the Ivermectin-400 and Fluticasone arms. The study has closed the Fluvoxamine-50 and Ivermectin-600 arms.
  • There were no differences observed in the relief of mild-to-moderate COVID-19 symptoms between patients taking Ivermectin-400 and the placebo. There were no safety concerns or differences in hospitalization or death.
  • There is no evidence that Fluticasone Furoate decreased time spent unwell. There is no observed symptomatic or clinical benefit of this medication of this dose or duration. There is no improvement for time to recover or reduction in hospitalizations. There was some evidence of increased acute care needs (urgent care, emergency room visit) in the fluticasone furoate arm. No safety concerns were identified.

Discussion Themes

–Before anyone was enrolled, which arm did you think would enroll the fastest? Given the history with other repurposed drugs, I was concerned people would not want to take Ivermectin. This was one of the reasons we gave people options about which drugs they were willing to take. It turned out that Ivermectin turned out to be a good recruitment tool.

-What were some early lessons learned in terms of how to reach people given the hybrid nature of the study? The sites had a very clear role, and the training was really important. There was a lot of outreach to sites and they embraced the remote trial. One thing that has been a struggle is the diversity in the population and the equity in access to trials. We did not see as much diversity in this decentralized trial.

-Were there concerns about having patients not associated with a site? For ACTIV-6, if we had not had a call center we would not have gotten the word out as much and participation would not have been as robust.

Learn more about ACTIV-6.

Tags

#pctGR, @Collaboratory1

July 27, 2022: COVID-19 Grand Rounds to Feature Interferon Therapy Results From TOGETHER Trial

Posted on by Damon Seils

Head shots of Dr. Edward Mills and Dr. Jeffrey GlennIn this Friday’s COVID-19 Grand Rounds, Dr. Edward Mills of McMaster University and Dr. Jeffrey Glenn of Stanford University will present “Effect of Early Treatment With Single-Dose Pegylated Interferon Lambda Among Patients With COVID-19: Results From The TOGETHER Trial.”

The TOGETHER trial is a randomized adaptive platform trial investigating several treatments for COVID-19.

The Grand Rounds session will be held on Friday, July 29, 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.