Want to know more about the goals and challenges of the NIH Collaboratory’s PRISM NIH Collaboratory Trials? New downloadable handouts summarize the study aims, implementation lessons, and recent presentations from these innovative embedded pragmatic clinical trials (ePCTS).
The 2-page study snapshots are accessible from each NIH Collaboratory Trial page and the links below:
BackInAction: Pragmatic Trial of Acupuncture for Chronic Low Back Pain in Older Adults
FM TIPS: Fibromyalgia TENS in Physical Therapy Study
OPTIMUM: Group-based Mindfulness for Patients with Chronic Low Back Pain in the Primary Care Setting
NOHARM: Nonpharmacologic Options in Postoperative Hospital-based and Rehabilitation Pain Management
Matthew Shun-Shin, BMBCh, PhD Imperial College London
Topic
The SAMSON Trial: An N-of-1 Trial of Statin, Placebo, and No Treatment to Assess Patient Symptoms
Keywords
Statins; SAMSON; N-of-1 study design; Side effects; Placebo; Nocebo effect
Key Points
Studies have shown that more than half of patients abandon statin medications completely within 2 years. Yet, placebo-controlled trials do not show excess withdrawals in the statin arm.
The SAMSON trial was a double-blind, three-group, N-of-1 trial in which participants were randomized to receive 12 one-month medication bottles in a computer-generated sequence. Four bottles contained statin tablets, 4 contained placebo tablets, and 4 were empty. The aim was to determine, for an individual participant, to what extent their symptoms were associated with the statin. Participants used a smartphone to rate the severity of their symptoms every day.
After 1 year, personalized study results were shared with each participant (n=60). Six months later, the study team evaluated whether participants were able to restart a statin.
Discussion Themes
The most important message from the SAMSON trial is that side effects from statin tablets are very real, but they are mainly caused by the act of taking the tablets, not the statin contained within them.
Because this N-of-1 design incorporated a period with no medication, participants could see as clearly as the study team the powerful magnitude of the “nocebo effect.” This resulted in half the participants successfully restarting statins.
Read more about the SAMSON trial in a letter from study investigators in the New England Journal of Medicine and an interview in Medscape.
Karen P. Alexander, MD Professor of Medicine/Cardiology Duke University School of Medicine
W. Schuyler Jones, MD Associate Professor of Medicine/Cardiology Duke University School of Medicine
Topic
PREVENTABLE: Starting a Pragmatic Trial in a Pandemic
Keywords
Heart disease; Dementia; Cholesterol; Statins; Pragmatic trial; National Heart, Lung, and Blood Institute; National Institute on Aging; Mild cognitive impairment
Key Points
More than half of older adults (age 75+) in the United States have cognitive impairment or frailty or both.
PREVENTABLE is one of the largest research studies in older adults. The purpose is to learn if taking a statin could help older adults live well for longer by preventing dementia, functional decline, or heart disease.
The study medication (statin) is mailed directly to participants’ homes. Study sites are part of the research infrastructure within PCORnet and Veterans Affairs (VA).
Pragmatic aspects of the trial include the study question: Do statins work in practice for outcomes that matter most to older adults? Also, enrollment is telehealth-enabled, and consent is electronic (e-Consent).
Discussion Themes
How did the study team work with IT to make the EHR system changes (eg, tools and workflow) needed to conduct the research?
Are older participants able to interact well with the technology used in the trial?
Are there special considerations embedded within the study to encourage the retention of study participants?
Tariq Ahmad, MD, MPH Director, Advanced Heart Failure Program Yale School of Medicine and Yale New Haven Health
Topic
The Yale New Haven Health System as an Evidence Generation Ecosystem for Heart Failure
Keywords
Heart failure; Best practice alerts; Electronic health records; Risk prediction; Guideline-directed medical therapy; REVEAL-HF
Key Points
The REVEAL-HF study is a pragmatic randomized controlled trial testing an electronic alert system that informs clinicians about the 1-year predicted mortality for their patients with heart failure using validated data from the EHR.
It is important to use guideline-directed medical therapy for patients with heart failure. The hypothesis of the trial is that providing prognostic information for a patient with heart failure will lead to improved use of therapies and appropriate referral to subspecialties.
Discussion Themes
How did you get health system leadership and all of the clinicians, IT folks, and others to buy in to implementing your trial?
How can we make risk information valuable and actionable to healthcare providers?
Clinicians bring something to the table that an algorithm does not. It will be interesting to see how clinician behavior is affected by using the prediction models and interacting with the data.
Daniel Edmonston, MD Medical Instructor Duke University School of Medicine
Topic
Drug Development in Kidney Disease: Proceedings from a Multi-Stakeholder Panel
Keywords
Chronic kidney disease (CKD); Dialysis; Evidence-based medicine; Electronic health records; Think Tank
Key Points
Only 5 percent of treatment recommendations for kidney disease reach a Grade A level of evidence.
In 2019, the DCRI convened a panel to address the urgent need for evidence-based treatments for kidney disease. “Accelerating Drug Development for Chronic Kidney Disease and End-Stage Renal Disease” included stakeholders from regulatory agencies, kidney societies, patient advocacy organizations, academia, and industry.
Key discussions explored the uses of interconnected data and site research networks, pragmatic and adaptive trial designs, robust surrogate endpoints, real-world data, and methods to improve the generalizability of trial results and uptake of approved drugs for kidney-related diseases.
Discussion Themes
Since there is more than one therapeutic agent showing promise for CKD, how should evidence be generated to understand the right combination of agents?
Could the principles laid out in the FDA Patient Focused Drug Development guidance be applied in these trials to ensure the patient perspective is included?
What are your thoughts on whether to focus on enrolling early CKD patients—some of whom will not progress—or patients later in the course of disease, when disease modification may be more challenging?
Read more about the Think Tank in a special report in the American Journal of Kidney Disease.
The CODA (Comparing Outcomes of Drugs and Appendectomy) Collaborative involved 25 sites across 14 states. The Co-PIs included surgeons and emergency medicine physicians.
The CODA pragmatic trial aimed to inform the health decision for appendicitis treatment by asking two research questions:
Are antibiotics as effective as appendectomy for appendicitis?
Which patients are most likely to have a successful outcome with antibiotics?
Instead of appendectomy, the intervention group received antibiotics intravenously for 24 hours followed by pills for a total of 10 days. The primary outcome in the trial was 30-day health status, as assessed with the European Quality of Life-5 Dimensions questionnaire.
The patients who received antibiotics cared about outcomes such as “Am I going to feel better,” followed by “Is it safe,” and “Will I return to work sooner?”
Discussion Themes
Antibiotics for appendicitis can be a good choice for some but not all. Decision-makers must weigh patient characteristics, preferences, and circumstances.
Can you comment on the relative “disappearance” of appendicitis during the COVID-19 pandemic?
Based on your results, how would you counsel a patient (or parent) in the emergency department with a diagnosis of appendicitis?
Will there eventually be a biomarker that’s predictive for appendectomy?
These virtual randomized controlled trials evaluated hydroxychloroquine as a post-exposure prophylaxis, pre-emptive early treatment, and pre-exposure prophylaxis for COVID-19.
The trial of post-exposure prophylaxis employed patient-reported outcomes around COVID-19 symptoms and severity as well as side effects of hydroxychloroquine.
Enrollment and screening of eligible participants was automated through a REDCap survey.
Discussion Themes
Being a virtual trial, were there concerns about practicing medicine “across state lines?”
There has been a mix of science and politics over the course of the COVID-19 pandemic. Because your trial had substantial media coverage, how did the publicity affect enrollment?
Many big strategy questions can be studied virtually. What changes do you see for trials during future pandemics?
Patrick O’Connor, MD, MA, MPH Senior Clinical Investigator HealthPartners Institute
JoAnn Sperl-Hillen, MD Senior Clinical Investigator HealthPartners Institute
Topic
Outpatient Clinical Decision Support – An Evidence-Based Implementation Framework
Keywords
Clinical decision support; Electronic health record (EHR); Automated tools; Web applications; Clinical informatics
Key Points
A well-designed clinical decision support (CDS) system should fire only when there is a potential large benefit, such as a cardiovascular benefit for patients with a reversible risk. The CDS trigger should be patient-centric, and the system should save clinician time and improve the quality of care.
The CDS in question was designed for use in cardiovascular (CV) disease to:
Identify and target individuals with the greatest potential for a CV benefit and prioritize CV risk factors based on potential benefit.
Danny Benjamin, MD, PhD Kiser-Arena Distinguished Professor of Pediatrics, Duke University Chair, Pediatric Trials Network Deputy Director, Duke Clinical Research Institute
Kanecia O. Zimmerman, MD, MPH Associate Professor of Pediatrics Co-chair, ABC Science Collaborative Duke University School of Medicine
Topic
Back to School, It’s More Than Just a Trip to Target This Year: The ABC Science Collaborative
Keywords
COVID-19; ABC Science Collaborative; Public school administration; Health disparities; Infection mitigation; Risk-benefit ratio; Community engagement
Key Points
The ABC Science Collaborative is a program that pairs scientists and physicians with school and community leaders to help understand the most current and relevant information about COVID-19. The program uses a data-driven approach to help school leaders make informed decisions about returning to school, using data from their own communities, with the goal of keeping teachers, children, and their local communities healthy and safe.
School boards, superintendents, principals, staff, and families are essential stakeholders in the ABC Science Collaborative.
Science shows that bringing kids back to school can be a success—if done the right way, including adherence to mask-wearing, hand hygiene, and physical distancing. Leadership support and implementing a coordinated, detailed plan are crucial to a successful approach.
Discussion Themes
The real power of the ABC Science Collaborative is the partnership between the researchers and stakeholders and their commitment to study the outcomes—and learn—together.
With scarce school resources, it’s better to maximize what has been shown to work in an interior environment, such as boosting adherence to masking and hand hygiene.
It could be said that “an ounce of data on COVID-19 provides more than an ounce of prevention.”
High serum phosphate is a ubiquitous complication in end-stage renal disease (ESRD), a serious illness that affects ~500,000 people in the United States. However, evidence is lacking for the best approach to reducing high phosphate that benefits survival in patients.
The hemodialysis setting is ideal for conducting a pragmatic trial because of an accessible study population, frequent clinical encounters, granular and uniform data collection via electronic health record (EHR), and the many unanswered questions about major aspects of dialysis care.
Pragmatic features of HiLo include:
Real-world setting
Cluster randomization
Broad entry criteria
Electronic informed consent
No traditional on-site study staff
Remote site monitoring
Outcomes based on EHR with no adjudication
Discussion Themes
The HiLo Ambassadors, a patient advisory group, have contributed to HiLo study materials including the protocol, informed consent form, eConsent script, informational videos, FAQs, flyer, and website content. They are providing strategies to help patients successfully participate and stay in the trial.
Dieticians are critical to the success of HiLo as they directly interact with dialysis patients and are among the most motivated caregivers on dialysis teams.
The onset of the COVID-19 pandemic came after the first week of HiLo site activation, causing a pause of trial activities and enrollment at the dialysis facilities.
What will success look like for the HiLo trial? A clear, proven answer to the question of higher versus lower target.
