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?
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.
Ahmed Al-Jaishi, PhD (candidate) Health Research Methodology McMaster University
Amit Garg, MD, PhD Professor, Department of Medicine Epidemiology & Biostatistics Western University, London, Canada Senior Core Scientist, Site Director, and Program Lead ICES Western Kidney Dialysis & Transplantation Research Program, London, Canada Nephrologist, London Health Sciences Centre Victoria Hospital, London, Canada
Merrick Zwarenstein, MBBCh, MSc, PhD Professor, Department of Family Medicine Epidemiology & Biostatistics Western University, London, Canada Senior Core Scientist ICES Western Primary Care & Health Systems Research Program, London, Canada
Topic
Pragmatic and Explanatory Attitudes to RCTs: Using the PRECIS-2 Tool to Describe the Design of the MyTEMP Trial
Keywords
Pragmatic trials; PRECIS-2; Canadian Institutes of Health Research (CIHR); Study design; External validity
Key Points
Randomized controlled trial (RCT) intentions (attitudes) can be described as: pragmatic intentions provide evidence for decision-makers to choose between interventions, whereas explanatory intentions test a hypothesis about a mechanism.
Pragmatic and explanatory trials are not a dichotomy; a good trial design matches the intention of the trial.
Trials can be designed with both internal validity and external validity.
Different trial intentions, design choices, conclusions, and recommendations lead to different usefulness for decision-making.
Discussion Themes
Can you comment on the retrospective use of PRECIS-2 to dichotomize trials as pragmatic or explanatory?
What suggestions do you have to improve the labeling of trials as explanatory versus pragmatic, since both types are randomized controlled trials (RCTs)?
Read more about the PRECIS-2 tool and the CONSORT statement for pragmatic trials.
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?
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.
The NIH Collaboratory is pleased to announce that the four PRISM NIH Collaboratory Trials received approval to transition from the planning phase to the implementation phase of their studies. These embedded PCTs (ePCTs) are directly addressing the U.S. opioid crisis and exploring fundamental questions of pain management using nonpharmacologic treatments.
Congratulations to the PIs and study teams for their excellent work!
BackInAction: Pragmatic Trial of Acupuncture for Chronic Low Back Pain in Older Adults
Karen Sherman, PhD, MPHLynn DeBar, PhD, MPH
BackInAction is conducting a three-arm pragmatic trial of older adults who have chronic low back pain to evaluate acupuncture versus usual care. The study will compare a standard 12-week course of acupuncture, an enhanced course of acupuncture (12-week standard course, plus 12-week maintenance course), and usual care to assess back-related function at 26 weeks.
FM TIPS: Fibromyalgia TENS in Physical Therapy Study
Kathleen Sluka, PT, PhDLeslie Crofford, MD
The aim of FM TIPS is to demonstrate the feasibility of adding transcutaneous electrical nerve stimulation (TENS) to the treatment of patients with fibromyalgia in a real-world physical therapy setting, and to determine if adding TENS to physical therapy reduces pain, increases adherence to physical therapy, and allows patients with fibromyalgia to reach their specific functional goals with less medication use.
NOHARM: Nonpharmacologic Options in Postoperative Hospital-based and Rehabilitation Pain Management
Andrea Cheville, MDJon Tilburt, MD
NOHARM is a stepped-wedge cluster-randomized trial that is testing a sustainable system-wide strategy for perioperative pain management using nonpharmacologic options in a manner that preserves patient function, honors patient values, and maintains availability of opioids as a last resort.
OPTIMUM: Group-based Mindfulness for Patients with Chronic Low Back Pain in the Primary Care Setting
Natalia Morone, MD
OPTIMUM aims to evaluate the impact of an innovative, group-based mindfulness program for patients with chronic low back pain in a real-life clinical setting. Mindfulness is effective for the treatment of chronic low back pain, yet remains underutilized as it has not been regularly woven into the outpatient clinical setting.
The PRISM program (Pragmatic and Implementation Studies for the Management of Pain to Reduce Opioid Prescribing) is a component of the NIH’s Helping to End Addiction Long-term (HEAL) Initiative. The NIH Collaboratory serves as the PRISM Resource Coordinating Center and is supported by the National Center for Complementary and Integrative Health. Support is also provided by the NIH Common Fund through a cooperative agreement from the Office of Strategic Coordination within the Office of the NIH Director.
Gordon R. Bernard, MD CONNECTS ACC Science Unit P Professor of Medicine Executive Vice President for Research Senior Associate Dean for Clinical Science Vanderbilt University Medical Center
Sonia Thomas, DrPH CONNECTS ACC Principal Investigator Senior Research Statistician RTI International
Topic
Launching CONNECTS: Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies
Keywords
COVID-19; CONNECTS; NHLBI; Collaborative research; Data sharing; Adaptive trials; Data standardization; ACTIV; Therapeutic agent prioritization
Key Points
The Collaborating Network of Networks for Evaluating COVID-19 and Therapeutic Strategies (CONNECTS) is a research partnership coordinated by the Research Triangle Institute, Vanderbilt University Medical Center, and the National Heart, Lung, and Blood Institute (NHLBI) of the NIH.
CONNECTS aims to build on existing clinical research networks to better understand the risk of severe illness from COVID-19 and to identify therapies that will slow or halt the disease progression and speed recovery. Studies will enroll participants with health conditions that are known to increase their risk for severe complications from COVID-19.
The immediate goal is to design and implement master protocol-driven adaptive clinical trials, including outpatient, inpatient, and recovering master protocols.
CONNECTS is part of a larger ecosystem in the Department of Health and Human Services that includes the FDA, CDC, BARDA, Operation Warp Speed, and NIH. More than 34 trial networks and 1,000 sites are participating in CONNECTS.
Discussion Themes
Are the CONNECTS resources, such as the common data elements manual, draft protocols, and case report forms, publicly available?
In your effort to reach underrepresented communities, have you considered collaborating with Historically Black Colleges and Universities (HBCUs), particularly those that conduct health research?
While COVID-19 is providing you with plenty to focus on, do you see the potential for sustainability of CONNECTS beyond this pandemic?
