January 18, 2019: Pragmatic Trials in End-stage Renal Disease (ESRD): HiLo (Myles Wolf, MD, MMSc)

Speaker

Myles Wolf, MD, MMSc
Charles Johnson, MD, Professor of Medicine
Chief, Duke Nephrology
Duke University School of Medicine

Topic

Pragmatic Trials in End-stage Renal Disease (ESRD): HiLo

Keywords

Pragmatic clinical trial; HiLo; End-stage renal disease; ESRD; Kidney disease; Hypophosphatemia; Serum phosphate; Hemodialysis; A vs B trials; Clinical equipoise; National Institute of Diabetes and Digestive and Kidney Diseases; NIDDK

Key Points

  • With high event rates and few proven therapies, patients with end-stage renal disease (ESRD) are in desperate need of clinical innovation.
  • The NIH Collaboratory’s HiLo Demonstration Project is a pragmatic, multicenter, cluster-randomized, open-label, noninferiority outcomes trial that will compare effects of two different phosphate management strategies in patients with ESRD.
  • The study hypothesizes that, compared with strict phosphate control, less stringent control will yield noninferior rates of all-cause hospitalization among patients with ESRD undergoing hemodialysis, as well as reduce the risk of all-cause mortality, enhance markers of diet and nutrition, and improve quality of life.

Discussion Themes

Dialysis clinic dieticians will have a pivotal role in implementing HiLo. They have established a rapport with patients and are among the most motivated caregivers on dialysis teams.

Individual patient-level informed consent for the HiLo trial will be via internet-linked tablets, paper forms, and educational materials including a video. Benefits of obtaining consent include promoting adherence, direct study updates and newsletters to participants, and ability to collect additional data without involving onsite study staff.

HiLo will be the first definitive clinical trial-grade evidence for opinion-based guidelines for phosphate management. Thus, results of HiLo have the potential to rapidly influence ESRD clinical practice.

Read more about the HiLo Demonstration Project in the Living Textbook.

Tags

#ESRD, #pctGR, @Collaboratory1, @DCRINews, @DukeKidney

January 11, 2019: FDA Releases Framework for Evaluating the Use of Real-World Evidence

To help fulfill the requirements of the 21st Century Cures Act by accelerating medical product development and fostering innovation and advances in medicine, FDA recently created a framework for evaluating the use of real-world evidence. The framework is intended to help evaluate trials that use real-world data for the creation of real-world evidence.

  • Real-world data: routinely collected information about a person’s health status in the electronic health record, claims, registries, and other sources, including patient-generated sources.
  • Real-world evidence: reliable, clinical information derived from real-world data about risks, benefits, and burdens of therapies.

This framework will apply to various pragmatic clinical trials embedded in health care systems and conducted as part of routine care (and will not apply to more traditional clinical trials conducted parallel to care).

Three main considerations are included in the framework:

  1. Will the real-world data be fit for use (do they reliably and adequately represent the concept)?
  2. Will the evidence generated by the trial provide adequate evidence to help answer regulatory questions?
  3. Will the conduct of the study meet FDA regulatory requirements?

January 4, 2019: TRANSFORMing Research for Patients With Heart Failure (Robert Mentz, MD, Kevin Anstrom, PhD, Eric Eisenstein, DBA, Stephen Greene, MD, Eric Velazquez, MD)

Speakers

Robert J. Mentz, MD
Associate Professor of Medicine
Duke University School of Medicine

Kevin J. Anstrom, PhD
Professor of Biostatistics and Bioinformatics
Director of Biostatistics, Duke Clinical Research Institute
Duke University School of Medicine

Eric Eisenstein, DBA
Associate Professor in Medicine
Duke University School of Medicine

Stephen J. Greene, MD
Fellow, Division of Cardiology and Duke Clinical Research Institute
Duke University School of Medicine

Eric J. Velazquez. MD, FACP, FACC, FASE, FAHA
Robert W. Berliner Professor of Medicine, Yale University
Chief, Cardiovascular Medicine, Yale New Haven Hospital
Physician-in-Chief, Heart and Vascular Center, Yale New Haven Health

Topic

TRANSFORMing Research for Patients With Heart Failure

Keywords

Pragmatic clinical trial; Heart failure; PRECIS-2; Hospitalization; TRANSFORM-HF; Clinical equipoise; Electronic health records; National Heart, Lung, and Blood Institute (NHLBI)

Key Points

  • The traditional approach to conducting clinical trials is unsustainable in many respects, including operational complexities, low enrollment rates, high costs, and failure to leverage existing resources. Incorporating pragmatic elements in the design of trials may improve efficiencies and conduct.
  • TRANSFORM-HF is a pragmatic trial evaluating torsemide versus furosemide treatment for long-term clinical outcomes among patients hospitalized for heart failure. Study randomization is 1:1, and the primary endpoint is all-cause mortality.
  • Advantages of trials with pragmatic designs include real-world effectiveness; broad patient/provider groups; reduced number and complexity of visits; streamlined data collection; potential for faster results; and results that will be more generalizable.

Discussion Themes

The clinical question involving starting a treatment (Should we start with furosemide or torsemide?) versus switching a treatment (Should we attempt to switch patients from furosemide to torsemide?) would seem to lead to different study designs.

While the peer review process for funding TRANSFORM-HF was challenging and required modifying the approach, it ultimately led to a better design.

Read more about PRECIS-2 domains along the explanatory-pragmatic continuum of a clinical trial in the Living Textbook.

Tags

#HeartFailure, #pctGR, @Collaboratory1, @robmentz, @SJGreene_md, @YaleCardiology, @ericjvelazquez

September 7, 2018: Spotlight on a New Demonstration Project: HiLo

Kidney transplantation is the preferred treatment for patients with end-stage renal disease (ESRD), but an insufficient organ supply renders dialysis the only viable treatment option for most patients. Though clinical outcomes among patients receiving dialysis have improved modestly in recent years, annual rates of hospitalization and mortality remain unacceptably high, and quality of life is poor. Poor outcomes are driven primarily by increased risk of cardiovascular disease (CVD), but interventions that improve outcomes in the general population by targeting traditional CVD risk factors have mostly failed in patients with ESRD. Current clinical practice guidelines advocate aggressive treatment of high serum phosphate to near-normal levels using dietary phosphate binders and restrictive diets. The benefits of this approach, however, are unproven, the optimal serum phosphate target remains unknown, and potential harms of aggressive treatment have not been definitively identified.

The Pragmatic Trial of Higher vs. Lower Serum Phosphate Targets in Patients Undergoing Hemodialysis (HiLo) plans to address these clinically important questions in a large, pragmatic, cluster-randomized trial that will evaluate the effects of liberalizing the serum phosphate target (“Hi”) versus maintaining aggressive phosphate control (“Lo”) for patients receiving treatment with maintenance hemodialysis.

 “The question at hand is something we grapple with on a daily basis in every dialysis facility across the country. Either answer will be important new information that will help us do a better job taking care of patients and hopefully improve their quality of life.”

HiLo is led by Myles Wolf, MD, of Duke University with support from the National Institute of Diabetes and Digestive and Kidney Diseases. Read more about HiLo.

July 23, 2018: New Report Summarizes Patient-Reported Health Data and Metadata Standards in the ADAPTABLE Trial

A new report in the Living Textbook describes results of a literature review of data standards and metadata standards for variables of interest to the ADAPTABLE trial. Based on the review, the authors recommend standards for ADAPTABLE, also known as the Aspirin Study, which is the first major randomized comparative effectiveness trial to be conducted by the National Patient-Centered Clinical Research Network (PCORnet). The trial aims to identify the optimal dose of aspirin therapy for secondary prevention in atherosclerotic cardiovascular disease.

Because the ADAPTABLE trial relies on patients to report key information at baseline and throughout follow-up, it represents a unique opportunity to develop, pilot, and evaluate methods to validate and integrate patient-reported information with data obtained from electronic health records (EHRs). In 2016, the National Institutes of Health implemented a project with the goal of using the ADAPTABLE study to develop methods to (1) assess the quality of patient-reported data and (2) integrate the data with existing EHR data. It is hoped that this project will inform future efforts to synthesize potentially inconsistent data from patient-reported and EHR sources and identify opportunities to streamline data.

Download the report.

June 4, 2018: New Article Explores Misleading Use of the Label “Pragmatic” for Some Randomized Clinical Trials

A recent study published in BMC Medicine found that many randomized controlled trials (RCTs) self-labeled as “pragmatic” were actually explanatory in nature, in that they assessed investigational medicines compared with placebo to test efficacy before licensing. Of the RCTs studied, one-third were pre-licensing, single-center, or placebo-controlled trials and thus not appropriately described as pragmatic.

Appropriately describing the design and characteristics of a pragmatic trial helps readers understand the trial’s relevance for real-world practice. The authors explain that RCTs suitably termed pragmatic compare the effectiveness of 2 available medicines or interventions prescribed in routine clinical care. The purpose of such pragmatic RCTs is to provide real-world evidence for which interventions should be recommended or prioritized.

The authors recommend that investigators use a standard tool, such as the CONSORT Pragmatic Trials extension or the PRECIS-2 tool, to prospectively evaluate the pragmatic characteristics of their RCTs. Use of these tools can also assist funders, ethics committees, and journal editors in determining whether an RCT has been accurately labeled as pragmatic.

The BMC Medicine article cites NIH Collaboratory publications by Ali et al. and Johnson et al., as well as the Living Textbook, in its discussion of pragmatic RCTs and the tools available to assess their relevance for real-world practice.

“Submissions of RCTs to funders, research ethics committees, and peer-reviewed journals should include a PRECIS-2 tool assessment done by the trial investigators. Clarity and accuracy on the extent to which an RCT is pragmatic will help [to] understand how much it is relevant to real-world practice.” (Dal-Ré et al. 2018)

October 11, 2017: New grant awarded to Dr. Jeffrey Jarvik and his team of investigators to promote pragmatic musculoskeletal clinical research

Congratulations to Dr. Jeffrey Jarvik and his colleagues at the University of Washington for their recent grant award to establish the Core Center for Clinical Research (CCCR). The initiative will promote pragmatic, multi-institutional clinical research on musculoskeletal conditions, such as the diagnosis and treatment of back pain. The new center—the UW Center for Clinical Learning, Effectiveness And Research (CLEAR)—will investigate the effectiveness of interventions such as imagining tests, physical therapy, opioids, spine injections, and spine surgery, as well as approaches for implementation.  The National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) are funding the 5-year, $3.7 million initiative, which will include pragmatic and comparative effectiveness trials and Core groups, including:

  • The Methodology Core, led by Patrick J. Heagerty PhD, Chair of the Department of Biostatistics, and Sean Mooney PhD, Professor of Biomedical Informatics and Chief Research Information Officer
  • The Resource Core, led by Janna Friedly MD, Associate Professor of Rehabilitation Medicine, and Danielle Lavallee PharmD PhD, Research Associate Professor of Surgery

Dr. Jarvik is a Professor of Radiology at University of Washington and the Principal Investigator the Collaboratory Demonstration Project, the Lumbar Imaging with Reporting of Epidemiology (LIRE) trial.

 

September 19, 2017: The NIH Health Care Systems Research Collaboratory Turns Five!

Five years ago this September marks the birth of the NIH Health Care Systems Collaboratory, an NIH Common Fund project designed to build national infrastructure for conducting pragmatic clinical trials (PCTs). At the heart of the NIH Collaboratory is an ongoing series of Demonstration Projects that embed innovative pragmatic clinical research within the “real-world” conditions of working healthcare systems.

In addition to supporting these Demonstration Projects, the NIH Collaboratory also works to advance PCT methodologies and ensure that knowledge and lessons learned are disseminated as widely as possible. With a series of Core Working Groups dedicated to exploring different facets of trial design and conduct, the NIH Collaboratory has already made significant contributions to the knowledge base in the PCT arena. In addition, its Distributed Research Network allows rich electronic data resources to be efficiently queried by investigators while ensuring the security of confidential information.

As the NIH Collaboratory celebrates its fifth birthday, it is also preparing to embark upon a new phase of efforts. With the award of grant funding for an additional 5 years this September and the unveiling of the redesigned and expanded Living Textbook, the NIH Collaboratory offers a growing array of resources and knowledge that will equip health systems to engage in sustainable pragmatic clinical research on a national scale.

For more, see Duke Clinical Research Institute’s article on the Collaboratory’s first 5 years.

Recent Collaboratory Publications on Research Ethics


The American Journal of Bioethics has recently published three articles authored by members of the Regulatory/Ethics core group describing various questions related to research on medical practices:

  • Is shared decision making an appropriate analytic frame for research on medical practices (Sugarman 2015) discusses the role of shared decision making (SDM) in research on medical practices. The author cautions that “while SDM is in many ways similar to informed consent, there are some important differences, especially in the research setting.” This publication is freely accessible through PubMed Central.
  • Patients’ views concerning research on medical practices: implications for consent (Weinfurt et al. 2015) describes the results of focus group sessions that elicited a range of patients’ views and opinions about different types of research on usual medical practices. The authors state that “our data suggest that effective policy and guidance will involve balancing different patients’ interests and potentially different sets of interests for different types of research studies on usual medical practices.”
  • Ethics of research in usual care settings: data on point (Sugarman 2016) introduces a special five-article supplement in the American Journal of Bioethics, stating that the “growing empirical ethics literature regarding research in usual care settings provides data to inform conceptual and policy debates regarding this research and suggests areas that require further study.”

These publications were supported by a bioethics supplement awarded to the Regulatory/Ethics Core group by the NIH’s Office of the Director.


STOP CRC Trial: Analytic Challenges and Pragmatic Solutions


Investigators from the STOP CRC pragmatic trial, an NIH Collaboratory Demonstration Project, have recently published an article in the journal eGEMs describing solutions to issues that arose in the trial’s implementation phase. STOP CRC tests a program to improve colorectal cancer screening rates in a collaborative network of Federally Qualified Health Centers by mailing fecal immunochemical testing (FIT) kits to screen-eligible patients at clinics in the intervention arm. Clinics in the control arm provided opportunistic colorectal-cancer screening to patients at clinic visits in Year 1 and implemented the intervention in Year 2. In this cluster-randomized trial, clinics are the unit of analysis, rather than individual patients, with the primary outcome being the proportion of screen-eligible patients at each clinic who complete a FIT.

The team dealt with various challenges that threatened the validity of their primary analysis, one of which related to potential contamination of the primary outcome due to the timing of the intervention rollout: for control participants, the Year 2 intervention actively overlapped with the Year 1 control measurements. The other challenge was due to a lack of synchronization between the measurement and accrual windows. To deal with these issues, the team had to slightly modify the study design in addition to developing a few sensitivity analyses to better estimate the true impact of the intervention.

“While the nature of the challenges we encountered are not unique to pragmatic trials, we believe they are likely to be more common in such trials due to both the types of designs commonly used in such studies and the challenges of implementing system-based interventions within freestanding health clinics.” (Vollmer et al. eGEMs 2015)

The Publish EDM Forum Community publishes eGEMs (generating evidence & methods to improve patient outcomes) and provides free and open access to this methods case study. Readers can access the article here.