study design

November 19, 2021: Exploring Approaches in Using Digital and Mobile Health in Patient-oriented Research: Pearls and Pitfalls (Anish K. Agarwal MD, MPH MS)

Posted on by terren.green@duke.edu

Speaker

Anish K. Agarwal MD, MPH MS
Assistant Professor of Emergency Medicine
Clinical Innovation Manager, Penn Medicine Center for Health Care Innovation
University of Pennsylvania, Perelman School of Medicine

Topic

Exploring Approaches in Using Digital and Mobile Health in Patient-oriented Research: Pearls and Pitfalls

Keywords

Mobile health; Digital health; Patient-oriented research; Study design

Key Points

  • Digital and mobile health is a rapidly evolving field that integrates with the electronic health records in both low and high tech ways.
  • Dr. Agarwal conducted a randomized control trial of overweight veterans who had daily access to a smartphone or tablet. These participants were sent a wearable device to collect step count data.
  • An important consideration for studies using mobile health technology is participant access to a smart or mobile device. 85% of Americans have access to a Smartphone where 97% have access to a mobile device that can receive texts. 20% use a smartwatch.
  • Mobile methods are just tools to support overall study design.
  • Dr. Agrawal conducted a study on post-operative opioid prescribing and use. Data was gathered from participants via text messaging systems.
  • Simple text messages that are more conversational in nature are received better by the participant. Links in text messages should be limited. It’s important for participants to understand the privacy and security of their communications and data. Nudge a participant with a text at the right time to avoid being overbearing.

Discussion Themes

Let patients know that SMS is not secure, and frame questions to avoid patients sending HIPAA covered data via text.

A good relationship with your institutions Privacy and Safety office is fundamental to navigating IRB regulations for research with digital and mobile devices.

 

Read more about Dr. Agarwal’s studies using mobile health devices: Effect of Gamification With and Without Financial Incentives to Increase Physical Activity Among Veterans Classified as Having Obesity or Overweight: A Randomized Clinical Trial and Patient-Reported Opioid Consumption and Pain Intensity After Common Orthopedic and Urologic Surgical Procedures With Use of an Automated Text Messaging System.

 

Tags

#pctGR, @Collaboratory1

October 29, 2021: Embedding Pragmatic Trials into Emergency and Critical Care (Matthew W. Semler, MD, MSc; Jonathan D. Casey, MD, MSc)

Posted on by terren.green@duke.edu

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

Keywords

Pragmatic clinical trials; Study design; Comparative effectiveness trials; Treatment effect; SMART trial; PreVent trial; Exception from Informed Consent (EFIC)

Key Points

  • Emergency medical clinicians are faced with common decisions in everyday practice with little to no data from randomized clinical trials to help inform their decisions.
  • Four barriers to comparative effectiveness trials in a critical care setting are a brief therapeutic window, patients with multiple co-morbidities, the inability of the patient to consent to research, and analyzing average treatment effect rather than individual treatment effect.
  • The PreVent Trial studied the use of bag-mask ventilation to prevent hypoxemia for patients who had been administered anesthesia in preparation for intubation.
  • Efficient, pragmatic trial procedures that don’t delay treatment enable comparative effectiveness randomized clinical trials to be conducted effectively.
  • After 50 years of debate about bag-mask ventilation during this interval period, the PreVent Trial found that bag-mask ventilation cut the rate of hypoxemia by 50% without affecting aspiration.
  • The SMART Trial was a cluster-randomized, multiple-crossover trial of fluid management that studied patient outcomes when Balanced Crystalloids were used versus Saline solution.
  • The large sample size of over 15,000 patients provided the SMART trial with the power to detect that a balanced crystalloid fluid prevented Major Adverse Kidney Events in 1% of patients compared to Saline solution. /li>
  • Exception from Informed Consent (EFIC), implemented in 1996 allows trials in emergency situations of the condition is life-threatening, existing treatments are unproven or unsatisfactory, and research involves no more than minimal risk.
  • Analyzing Individual Treatment Effects will allow clinical providers to tailor their decisions to their individual patient.

Discussion Themes

Clinical equipoise poses a challenge for comparative effectiveness trials.

Key to getting buy-in from clinician stakeholders is explaining the importance of the research to the patient.

 

Read more about PreVent trial and the SMART trial.

Tags

#pctGR, @Collaboratory1

October 22, 2021: The STAMP Trial: Increasing Engagement in Advance Care Planning and Lessons Learned from Partnering with Community Ambulatory Practices (Terri R. Fried, MD)

Posted on by terren.green@duke.edu

Speaker

Terri R. Fried, MD
Section Chief, Geriatrics
Professor of Medicine
Yale School of Medicine
Attending Physician
VA Connecticut Healthcare System

Topic

The STAMP Trial: Increasing Engagement in Advance Care Planning and Lessons Learned from Partnering with Community Ambulatory Practices

Keywords

STAMP Trial; Advance Care Planning; ACP; Patient engagement; Cluster randomized trial

Key Points

  • The STAMP (Sharing and Talking about My Preferences) Trial is a cluster randomized controlled trial aimed at increasing engagement in Advanced Care Planning (ACP).
  • The STAMP Trial first aimed to re-conceptualize advance care planning (ACP) to achieve the ultimate goal of enabling the patient or surrogate to make decisions in a future moment rather than making decisions in advance. In this way, ACP is a flexible act of communication that allows for in-the-moment advice of a patients care providers about the nuances of a particular clinical situation.
  • ACP is a Health Behavior that involves stages of change. The STAMP Trial uses a 10 minute survey to assess how ready a patient is to start the ACP communication process.
  • Patients are given ACP materials based on their stage of readiness as assessed by the survey.
  • Results showed a small increase in ACP planning for groups randomized to the study interventions, but that small increase applied over large numbers of patients could have a significant impact on the number of people participating in ACP.

Discussion Themes

Cluster randomized trial design is complex unless you are working with an intervention that is implemented in a whole health care system rather than individual patients.

Determining a denominator in a cluster randomized trial at the patient level was very difficult.

 

Read more about Dr. Fried’s work on the STAMP Trial.

Tags

#pctGR, @Collaboratory1

October 15, 2021: The Impact of Community Masking on COVID-19: A Cluster-Randomized Trial in Bangladesh (Jason Abaluck, PhD)

Posted on by terren.green@duke.edu

Speaker

Jason Abaluck, PhD
Professor of Economics
Yale School of Management

Topic

The Impact of Community Masking on COVID-19: A Cluster-Randomized Trial in Bangladesh

Keywords

COVID-19; Cluster-randomized trial; Masking; Community spread; NORM model

Key Points

  • Dr. Abaluck’s cluster-randomized trial on the impact of community masking in ~350,000 adults in 600 villages of Bangledesh aimed to answer 2 questions: What strategies or interventions will increase mask-wearing? and What is the impact of mask wearing intervention on COVID-10?
  • There are two major differences between the existing randomized trials of mask wearing for flu and the impact of community masking in Bangladesh trial. The first issue is the existing trials were randomized individually not by communities so you cannot evaluate weather masks act as source control. The second issue with the existing trials is the discrepancy between the number of people who attest to wearing a mask and the number who actually wore a mask.
  • The impact of community masking in Bangladesh trial used the NORM model to increase mask wearing. The NORM model distributes masks at No-cost, Offers information about why mask wearing is important, Reinforces mask wearing by having mask promoters give free masks and information in public places, and Modeling by trusted community leaders wearing masks and endorsing mask wearing.
  • The NORM model more than tripled mask usage(13% usage increased to 42%), increased physical distancing, and had a sustained impact that lasted at least 10 weeks.
  • Communities where the NORM model was employed saw a 9% reduction in symptomatic COVID-19 infections.
  • Mask wearing showed a greater reduction in COVID-19 among the elderly.

Discussion Themes

The NORM model would have different efficacy rates in different cultures and communities.

You can get some people to wear a mask by just distributing the masks in public places and asking them to wear them.

Masks are not an all-or-nothing protection. Masks have a dose-reduction effect and that dose-reduction translates into a transmission effect.

 

Read more about the Dr. Abaluck’s work on masking and COVID-19 in the recently published Discussion Paper.

Tags

#pctGR, @Collaboratory1, @Jabaluck

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

August 30, 2021: New Living Textbook Materials on Designing a Trial to Match Its Intention

Posted on by Gina Uhlenbrauck

The Living Textbook has recently published materials that explore how randomized trials can be designed to promote both internal and external validity. The new contributions, from Drs. Merrick Zwarenstein, Ahmed Al-Jaishi, and Amit Garg, explain that consideration of the trial’s intention, whether pragmatic or explanatory, is the key to designing a trial that successfully answers its primary research question. While there is a contrast between pragmatic and explanatory intentions, there is not a dichotomy. Instead, trials will vary across the spectrum of design decisions leaning toward choices that match the trial’s purpose. The PRECIS-2 tool can help investigators design their trial to align with its intention. The authors illustrate these points in a new Living Textbook section, PRECIS-2 Case Study, which contrasts the design decisions made for two trials in a renal dialysis setting.

“The purpose should be decided before embarking on designing a trial, and each element of the trial design should be aligned to the chosen purpose.”­– Zwarenstein et al. 2021

Read more at:

August 26, 2021: Li Receives PCORI Award to Study Methods for Cluster Randomized Trials

Posted on by Damon Seils
Headshot of Dr. Fan Li
Dr. Fan Li

Dr. Fan Li, a longtime member of the NIH Collaboratory’s Biostatistics and Study Design Core, has received approval for a $1 million grant award from the Patient-Centered Outcomes Research Institute (PCORI) to develop methods and software for designing cluster randomized trials. Li is an assistant professor of biostatistics in the Yale School of Public Health.

The study, entitled “New Methods for Planning Cluster Randomized Trials to Detect Treatment Effect Heterogeneity,” will contribute new methods, guidance, and user-friendly software for planning parallel and stepped-wedge cluster randomized trials to enable confirmatory “heterogeneity of treatment effect” (HTE) analyses with sufficient statistical power.

HTE occurs when there is systematic variation in treatment effect across predefined patient or provider subgroups that can arise due to diverse practices, varying responses to treatment, or differing vulnerability to certain diseases, among other reasons. While understanding of HTE has been a recognized goal in individually randomized trials, methods for planning cluster randomized trials with HTE analyses are limited. This PCORI-funded study will expand the current cluster randomized design toolbox to accommodate confirmatory HTE analysis and meet a growing interest in better understanding how patient- and provider-level characteristics moderate the impact of new care innovations in pragmatic trials.

The award has been approved pending completion of a business and programmatic review by PCORI staff and issuance of a formal award contract.

Joining Li on the research team are coinvestigators Dr. Patrick Heagerty of the University of Washington, Dr. Rui Wang of Harvard Medical School and the Harvard Pilgrim Health Care Institute, and Dr. Denise Esserman of the Yale School of Public Health. Heagerty and Wang are members of the NIH Collaboratory’s Biostatistics and Study Design Core. The team will work closely with other NIH Collaboratory colleagues and stakeholders, including Dr. Adrian Hernandez of Duke University, Dr. Jerry Jarvik of the University of Washington, and Dr. Richard Platt of Harvard Medical School and the Harvard Pilgrim Health Care Institute.

August 19, 2021: Biostatistics Core Helps Projects ‘Roll With the Punches’ of the Pandemic

Posted on by Damon Seils

Leaders of the NIH Collaboratory’s Biostatistics and Study Design Core Working Group spoke in a recent interview about the impacts of the COVID-19 pandemic on the NIH Collaboratory Trials, including the 2 newest projects, BeatPain Utah and GRACE.

“BeatPain Utah and GRACE are fascinating studies, as all our NIH Collaboratory Trials are, and are giving us lots of food for thought at the Biostatistics Core,” said Dr. Liz Turner, associate professor of biostatistics and bioinformatics at Duke University and a cochair of the Core. View the full video.

The 2 studies “have been pretty well positioned to roll with some of the distancing required or the lack of in-person visits,” said Dr. Patrick Heagerty, professor of biostatistics at the University of Washington and the other cochair of the Core. “The BeatPain project had a remote delivery from the beginning, so I think the impact of COVID was not as dramatic as it’s been for other projects. But GRACE, where acupuncture is part of it, they have to figure out what are the elements of the research protocol they can do remotely but still need to get folks in person to do that acupuncture,” Heagerty said.

“There really have been some considerable challenges for several of the other NIH Collaboratory Trials,” said Turner. “Good examples of these challenges are those faced by 2 stepped-wedge cluster randomized trials, ACP PEACE and PRIM-ER. …They had to really restructure the design and respond very quickly to what was happening in practice out in the field. Interestingly, on the flip side, the disruptions last spring in 2020 did provide opportunities to address other research questions and perhaps generate other interesting evidence,” Turner said.

(Learn more about the ACP PEACE study’s COVID-19 supplement: “Can a Primary Care Telehealth Intervention Change the Paradigm for Advance Care Planning?”)

Heagerty and Turner also described ongoing projects of the Core to support pragmatic research, including guidance on longitudinal analysis in randomized trials, considerations for studies with multiple outcomes, and handing of studies with variable cluster sizes. Learn more about the Biostatistics and Study Design Core.

 

Screen shot of interview with Patrick Heagerty and Liz Turner

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

July 8, 2021: New Living Textbook Section on Intervention Functions and Forms

Posted on by Gina Uhlenbrauck

Readers are invited to visit a recent addition to the chapter Monitoring Intervention Fidelity and Adaptations in the Living Textbook. The new content offers considerations for study teams who are preparing to track the fidelity of an embedded—and potentially complex—clinical intervention. Considerations include identifying which features of the intervention (i.e., functions) are so essential to its effectiveness that modifying them could negatively affect the study’s outcomes and impact. Equally important is knowing which elements (i.e., forms) can be adapted to accommodate contextual factors or local needs without affecting fidelity. The section provides an introduction and link to methodology standards for complex interventions recently developed by the Patient-Centered Outcomes Research Institute (PCORI).

“Functions of a complex intervention represent a purpose or goal, while forms are the tools or processes used to achieve a function. Identifying forms and functions allows adapted complex interventions to retain a level of standardization and integrity in design.” (Hill et al. 2020)