Study design

Grand Rounds February 13, 2026: The Making of the COMPARE-Pediatric IBD Study (Michael D. Kappelman, MD, MPH)

Posted on by Sophia Ramirez

Speaker

Michael D. Kappelman, MD, MPH
Professor, Pediatric Gastroenterology
University of North Carolina at Chapel Hill

Keywords

PCORnet; PCORI; Inflammatory Bowel Disease; Pediatrics; Common Data Model; Study Design

Key Points

  • Inflammatory Bowel Disease (IBD) is a chronic gastrointestinal condition affecting roughly 100,000 youth in the United States. It has a profound impact on nutrition, growth, physical, and psychosocial development. Anti-TNF biologics are the only FDA-approved advanced therapies for children, and approximately 30% of patients experience treatment failure within 2 years. There’s an urgent need for comparative effectiveness research that can guide treatment decisions when anti-TNF fails.
  • COMPARE-Pediatrics IBD, a PCORnet® study, includes 2 parallel multi-center, prospective cohort studies and retrospective cohort studies. The former, developed with multi-stakeholder input, will compare the effectiveness of emerging therapies in children with IBD; the latter will characterize the safety of these treatments and explore the heterogeneity of treatment effects across subgroups.
  • The study is utilizing PCORnet’s® infrastructure, including Prep-to-Research Queries and the PCORnet® Common Data Model (CDM), to inform the study design; identify administrative efficiencies; support recruitment; ease site burden; assess representativeness of the study population; and otherwise bolster their research.

Discussion Themes

Planning a PCORnet® study is a lot of work (and takes time). Start the process early and know that benefits may be on the back-end.

The study team opted not to conduct a randomized pragmatic trial because they anticipated that desperate families would be reluctant “roll the dice” with randomization and because insurance coverage for expensive off-label medications often dictates which therapy a patient can receive.

While the CDM is effective for structured data (like labs and diagnoses), Dr. Kappelman noted it cannot yet capture nuanced interpretations, such as specific MRI findings, which require more advanced AI or manual review.

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/

Grand Rounds January 17, 2025: Design for Diversity: Designing Studies for Representativeness and Generalizability (Christopher J. Lindsell, PhD)

Posted on by Sophia Ramirez

Speaker

Christopher J. Lindsell, PhD
Professor and co-Chief, Biostatistics, Duke University
Director, Data Science and Biostatistics, DCRI
Director, Biostatistics and Bioinformatics, CTSI
Editor in Chief, Journal of Clinical and Translational Science

Keywords

Study Design; Diversity; Health Disparities; Evidence Generation

Key Points

  • Health disparities are factors that contribute to preventable differences in health status and outcomes. They can be environmental, sociocultural, behavioral, and biological. These are preventable differences with adverse effects for populations.
  • When research teams don’t consider factors that change outcomes for certain populations but not others, research can contribute to a difference in health status and outcomes. A flawed evidence generation system compounds the problem.
  • One popular solution is to measure and adjust for diversity variables; however, research teams often get the variable wrong or use it incorrectly.
  • By designing for diversity, research teams can begin to address the generalizability of evidence; develop an understanding of factors that contribute to success or failure of interventions among diverse populations; and remove the evidence generation system as a contributor to health disparities.
  • Designing for diversity is an optimization problem. Historically, study designs have been optimized for the researcher; Dr. Lindsell proposed that researchers optimize for the participant.
  • Research that is optimized for the participant is rigorous and flexible; safe and practical; and complete and simple. Participants should be embedded in every part of the research process. This can be difficult – there are tradeoffs involved – but it is effective.
  • The interface between data generation and data use is crucial. Making systems that work to bring in the right information and systems that use that information appropriately are two pieces of the same puzzle.
  • Dr. Lindsell included a call to ditch the ordinary subgroup analysis, noting that groups are not binary and not all groups have meaning. He suggested a focus on interaction terms.

Discussion Themes

Institutions should be supporting research teams in their ability to achieve diversity; this should be a matter of course, rather than something to be achieved without support and then celebrated as a remarkable accomplishment.

Looking forward, as data infrastructure becomes increasingly robust, research teams and communities may be able to collaborate to build a more complete understanding of individuals’ health states and who may be in need of an intervention.

Toward Causal Inference in Cluster Randomized Trials: Estimands and Reflection on Current Practice

Methods: Minds the Gap Webinar Series
“Toward Causal Inference in Cluster Randomized Trials: Estimands and Reflection on Current Practice”
Fan Li, PhD; Yale School of Public Health
National Institutes of Health, Office of Disease Prevention

Cluster randomized trials (CRTs) involve randomizing groups of individuals to different interventions. While model-based methods are extensively studied for analyzing CRTs, there has been little reflection around the treatment effect estimands at the outset. In the first part of this presentation, we describe two relevant estimands that can be addressed through CRTs and point out that they can differ when the treatment effects vary according to cluster sizes. As a cautionary note, we demonstrate how choices between different analytic approaches can impact the interpretation of results by fundamentally changing the question being asked. In the second part, we revisit the linear mixed model as the most commonly used method for analyzing CRTs. The linear mixed model makes stringent assumptions, including normality, linearity, and typically a compound symmetric correlation structure, all of which may be challenging to verify. However, under certain conditions, we show that the linear mixed model consistently estimates the average causal effect under arbitrary misspecification of its working model. Under equal randomization, its model-based variance estimator, surprisingly, remains consistent under model misspecification, justifying the use of confidence intervals output by standard software. These results hold under both simple and stratified randomization, and serve as an important causal inference justification for linear mixed models. Caveats and extensions of our findings will also be mentioned.

For more information, visit https://prevention.nih.gov/education-training/methods-mind-gap/toward-causal-inference-cluster-randomized-trials-estimands-and-reflection-current-practice.

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.

 

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#pctGR, @Collaboratory1

April 11, 2022: TSOS Implements Suicide Assessment and Monitoring Method in Pragmatic Clinical Trial

Posted on by terren.green@duke.edu

The Trauma Survivors Outcomes and Support (TSOS) trial, an NIH Pragmatic Trials Collaboratory Trial, successfully implemented a large-scale suicide assessment and monitoring method in a pragmatic clinical trial focused on collaborative mental healthcare for traumatic injury survivors. Study intervention and monitoring methods are detailed in a recent publication in Psychiatry.

TSOS researchers analyzed data collected at 25 trauma centers from 635 patients experiencing posttraumatic stress disorder (PTSD) as the result of a traumatic injury. The study used a randomized stepped-wedge design and assigned 370 patients to a control group and 265 to an intervention group.

Patients in the intervention group received proactive injury care management, psychopharmacology, and psychotherapy for PTSD and depression. All patients in both groups were evaluated at 4 timepoints: baseline and 3, 6, and 12 months after injury.

Study personnel interacting with patients participated in a 1-day training workshop to learn study methods and skills for the management of acute suicidal ideation or suicidal intent. Among other measures to assess PTSD symptoms, alcohol use, and physical function, the study team administered the Patient Health Questionnaire (PHQ-9) to screen for suicidal ideation and depression.

Source: Psychiatry. 2022; Spring. doi:10.1080/00332747.2021.1991200.

Patients from both the intervention and control groups who indicated suicidal ideation on the PHQ-9 received calls, texts, and voice messages from study personnel and referral for additional care from a clinician. Study personnel reached out to 161 control and 107 intervention group patients.

The intervention group showed a small but not significant reduction in suicidal ideation compared to the control group.

Lack of a significant treatment effect may be due to the outreach and additional care received by patients in the control group. This level of additional care could be considered a minor intervention for the control group.

Future studies may learn more about treatment differences between control and intervention groups by incorporating implementation process assessments into the design of pragmatic trials.

TSOS was supported within the NIH Collaboratory by a cooperative agreement from the National Institute of Mental Health and by the NIH Common Fund through a cooperative agreement from the Office of Strategic Coordination within the Office of the NIH Director. Learn more about the NIH Collaboratory Trials.

April 1, 2022: ICD-Pieces: Improving Care for CKD, Diabetes and Hypertension in Health Systems (Miguel A. Vazquez, MD; George (Holt) Oliver, MD, PhD)

Posted on by terren.green@duke.edu

Speaker

Miguel A. Vazquez, MD
Professor of Medicine
University of Texas Southwestern Medical Center
Dallas, TX

George (Holt) Oliver, MD, PhD
Vice President Clinical Informatics
Parkland Center for Clinical Innovation
Dallas, TX

Keywords

ICD-Pieces; Chronic kidney disease (CKD); EHR data collection; Diabetes; Hypertension

Key Points

  • ICD-Pieces focuses on the chronic conditions of Diabetes, Hypertension, and CKD. These conditions are common, under-recognized, and can have serious complications.
  • PIECES is an information technology software developed to help facilitate primary care practices provide comprehensive evidence-based care for patients with these chronic conditions.
  • Researchers enrolled 11,000 patients with CKD in the study. The interventions included controlling blood pressure with medication, avoiding hypoglycemia, use of statins, and avoidance of NSAIDs.
  • Interventions were determined to be feasible. Outcomes for study populations are to be determined with further analysis of the data.

Discussion Themes

Pragmatic trials are often practical laboratories for implementation science.

An inherent challenge of collecting data from the EHR record is delay. It may help to have part of the study team embedded in the clinical trial for the data collection aspect, or possibly to collect the data at the time of intervention rather than waiting.

 

Read more about ICD-Pieces.

 

 Tags

#pctGR, @Collaboratory1

March 25, 2022: A Telehealth-Delivered Pragmatic Trial of Mindfulness for Persons with Chronic Low Back Pain (Natalia Morone, MD, MS)

Posted on by terren.green@duke.edu

Speaker

Natalia E. Morone, MD, MS
Associate Professor of Medicine
Boston University/Boston Medical Center

Keywords

Chronic pain; Mindfulness; Stress Reduction; Low back pain; OPTIMUM; The Pain, Enjoyment of Life and General Activity (PEG) Scale; HEAL Initiative

Key Points

  • Chronic back pain is very common across all racial and ethnic groups. Doctors treat chronic back pain with non-pharmacologic methods before resorting to pharmacologic treatments.
  • Optimizing Pain Treatment in Medical Settings Using Mindfulness (OPTIMUM) is a randomized study of mindfulness for low back pain operating in 3 health settings: Boston Medical Center; UPMC, Pittsburgh, PA; and University of North Carolina, Chapel Hill in partnership with Piedmont Health Services.
  • Participation in the OPTIMUM study requires 8 weekly 90 minute group-based sessions of mindfulness meditation training delivered in primary care through a telehealth medical visit with follow up assessments at 6 and 12 months.
  • Four methods of mindfulness meditation are taught: Walking meditation, body scan, breath focused meditation, and mindful stretching.
  • The OPTIMUM study uses the PEG scale as the main outcome measure at the 6 and 12 month follow up assessments.
  • Group tele-health visits provide a variety of benefits for patients including more time with a clinician, better medication adherence, and more patient satisfaction.

Discussion Themes

Primary care usually consists of 1 provider and 1 patient, but family medicine evolved to see patients in a group. This group setting model may have unexpected benefits.

OPTIMUM is part of the PRISM project and is collecting data on participant use of opioids along with all PRISM projects.

Recruiting minority participants has been a priority in the OPTIMUM trial. Targeting recruitment advertisements to zip codes where more minorities live makes a difference in recruiting a diverse population.

 

Read more about the OPTIMUM trial.

 

 Tags

#pctGR, @Collaboratory1

March 11, 2022: Understanding a Patient’s Daily Experience Through Mobile Devices and Wearables: Lessons Learned From the 8,000 Patient MIPACT Study and Implementation in a National Pragmatic Trial (Sachin Kheterpal, MD, MBA; Jessica Golbus, MD; Nicole Pescatore, MPH)

Posted on by terren.green@duke.edu

Speakers

Sachin Kheterpal, MD, MBA
Professor of Anesthesiology
Associate Dean for Research IT
PI for MIPACT and Co-PI for THRIVE University of Michigan

Jessica Golbus, MD
Clinical Instructor, Cardiovascular Medicine
Co-I for MIPACT
University of Michigan

Nicole Eyrich, MPH
MIPACT Clinical Research Project Manager University of Michigan

Keywords

MIPACT; Patient-reported outcomes; Virtual recruitment; Cohort Identification Toolkit; VALENTINE study; THRIVE study; Wearable data research; Propofol

Key Points

  • The MIPACT study combined patient reported outcome data with electronic health record data and data collected from wearable devices.
  • The MIPACT study followed over 7,000 participants for 3 years. Both in-person and virtual recruitment had similar success rates. Participant diversity was a priority during recruitment.
  • The VALENTINE Study was a prospective randomized controlled study using mobile wearable devices to enhance cardiac rehabilitation.
  • Older participants in the VALENTINE study were receptive and capable of using wearable technology to assist data collection for the study.
  • THRIVE is pragmatic clinical trial studying Propofol anesthesia in 22 states and 2 countries.

Discussion Themes

Economic barriers to participation may be present when using wearable device technology as an inclusion criteria for a study. There are various methods to reduce these barriers, such as providing participants with the wearable device and a minimal data plan.

There may be limits to the types of participant reported outcomes that can be collected remotely. Ideally, participants will decide what data researchers will have access to.

Read more about MIPACT, VALENTINE, and THRIVE study.  Read results from MIPACT and VALENTINE.

 

 Tags

#pctGR, @Collaboratory1

February 25, 2022: The Next Generation of Patient-Centered Trials – No Site Visits, Home-delivery of Meds and Patient-reported Outcomes – The CHIEF-HF Trial (John Spertus, MD, MPH, FACC, FAHA)

Posted on by terren.green@duke.edu

Speaker

John Spertus, MD, MPH, FACC, FAHA
Daniel Lauer/Missouri Endowed Chair and Professor
University of Missouri – Kansas City
Clinical Director of Outcomes Research
Saint Luke’s Mid America Heart Institute

Keywords

Heart failure; Canagliflozin; INVOKANA; Kansas City Cardiomyopathy Questionnaire (KCCQ); tele-health; tele-trials

Key Points

  • The CHIEF-HF trial (Canagliflozin: Impact on Health Status, Quality of Life and Functional Status in Heart Failure) was a double blind randomized clinical trial of the medication Canagliflozin for heart failure.
  • CHIEF-HF was designed to learn if patients have fewer symptoms after 3 months of treatment with Canagliflozin.
  • CHIEF-HF used a novel trial design that involved no site-visits and electronic monitoring of patient engagement. The follow up rate for this study was over 97%.
  • The Total Symptom Score on the KC Cardiomyopathy Questionnaire was the key outcome measure in the CHIEF-HF Trial.
  • Heart failure patients treated with Canagliflozin experienced a statistically significant improvements in symptoms.
  • Sites in the study chose recruitment methods that worked best for them. More personalized recruitment strategies were most successful.
  • Difficulties of electronic trials include the technology limitations of the participants, and electronic consent concerns from regulatory agencies. Positives of electronic trials are high enrollment and completion rates.

Discussion Themes

How do technology heavy studies enroll diverse and underserved populations who may not have access to smartphones and wearable technology?

Virtual studies such as this that enrolled at 6 to 8 times the rate on a traditional trial can save quite a bit of money on overhead expenses.

 

Read more about the CHIEF-HF trial.

 

Tags

#pctGR, @Collaboratory1