May 16, 2019: NIH Collaboratory Investigators Author Recommendations for Responding to Guideline or Policy Changes That Affect Ongoing Pragmatic Trials

A new perspective article by NIH Collaboratory investigators describes the unique, unexpected challenges researchers face when clinical practice guidelines and policies change during the conduct of a pragmatic clinical trial (PCT). The article was published online this week in Clinical Trials.

The NIH Collaboratory Demonstration Projects are PCTs that test interventions to address urgent public health problems. They involve hundreds to thousands of participants and generally include usual care as a control arm. During the course of these years-long trials, clinical practice guidelines and policies changed due to new evidence from observational studies, small trials, and shifting expert opinion. Such changes can have profound effects on usual care and, therefore, threaten the ability of the PCTs to address the questions they were designed to answer. Investigators must strike a balance between the primary ethical obligation to protect patients by adhering to new best-practice guidelines and policy and the secondary, yet crucial, obligation to develop high-quality evidence to improve care.

“PCTs are an important means of producing high-quality evidence needed to better inform clinical practice. However, when guidelines or reimbursement policies change during the conduct of a PCT, the ethical obligation to gather information to develop evidence-based practices may conflict with the primary ethical obligation to participants.” — Curtis et al, Clinical Trials, 2019

Based on their aggregate experience with the NIH Collaboratory, the authors provide broad recommendations and strategies for overcoming these challenges, including protecting the well-being of patients; involving stakeholders, health system leaders, and the entity charged with data and safety monitoring; and actively monitoring changes and site-level responses to them. If changes to the standard of care are merited, investigators should provide equal opportunity and support for the recommended changes. Finally, during the design phase, investigators should communicate with the entities charged with creating guidelines to see what is needed and to anticipate possible future changes.

“The ability to appropriately address the tension between modifications to clinical guidelines and the need to generate quality evidence to support those guidelines is a crucial consideration for the fulfilment of a learning health system.” — Curtis et al, Clinical Trials, 2019

April 19, 2019: Trauma Survivors Outcomes & Support (TSOS) Pragmatic Trial: Revisiting Effectiveness & Implementation Aims (Doug Zatzick, MD)

Speaker

Doug Zatzick, MD
Professor of Psychiatry
Harborview Medical Center
University of Washington School of Medicine

Topic

Trauma Survivors Outcomes & Support (TSOS) Pragmatic Trial: Revisiting Effectiveness & Implementation Aims

Keywords

Trauma outcomes; Demonstration Project; Hybrid study design; Implementation science; Pragmatic clinical trial; Cluster randomization; Stepped-wedge design; Posttraumatic stress disorder; PRECIS-2; Mental health intervention

Key Points

  • The TSOS Demonstration Project is a cluster-randomized, stepped-wedge trial conducted at 25 U.S. trauma centers. The intervention involves an electronic health record PTSD screen and a baseline PTSD and comorbidity assessment. TSOS is turned on at each site across 4 “waves.”
  • During the course of this hybrid effectiveness-implementation trial, two domains on PRECIS-2 (Pragmatic-Explanatory Continuum Indicator Summary) were scored as more pragmatic and one domain as more explanatory than at the outset of the study.
  • The study team developed a methodology for assessing TSOS implementation aims. Called RAPICE (Rapid Assessment Procedure Informed Clinical Ethnography), the method yielded findings around recurrent intervention and research staff turnover across sites; observations that some patients do not engage in the intervention; and ways to inform a priori secondary hypotheses that suggest per-protocol modifications to the original intention-to-treat analyses.
  • TSOS will present results at the 2020 summit of the American College of Surgeons with the potential to integrate findings into the College’s regulatory and verification processes.

Discussion Themes

Regarding the need to collect outcome data, there may be an important distinction between two aspects of “pragmatic.” That is, while collecting outcome data makes a trial more expensive (one aspect of pragmatic), it doesn’t necessarily affect relevance or generalizability (another, more important, aspect of pragmatic).

Might there be studies which, by design, are not aiming to be on the outer [more pragmatic] spokes of the PRECIS-2 wheel?

Read more about the TSOS Demonstration Project.

Tags

#pctGR, @Collaboratory1, @PRECIS_2

April 22, 2019: TiME Trial Confirms Feasibility of Embedding Large Pragmatic Trials in Clinical Care

Laura Dember

The primary results of the Time to Reduce Mortality in End-Stage Renal Disease (TiME) trial, an NIH Collaboratory Demonstration Project, were published online this month in the Journal of the American Society of Nephrology. The study confirmed the feasibility of embedding a large pragmatic clinical trial in clinical care delivery.

Although maintenance hemodialysis has long been a staple of care for patients with end-stage renal disease, there are limited data from clinical trials to inform optimal approaches, including the optimal duration of hemodialysis sessions. The TiME trial investigators, in partnership with 2 large dialysis provider organizations, evaluated the effects of a longer hemodialysis session duration on mortality and hospitalization rate among more than 7000 patients receiving care in 266 dialysis facilities.

The TiME trial was discontinued early (median follow-up, 1.1 years) because there was an insufficient difference in mean hemodialysis session duration between the intervention group and the usual care group. The investigators observed no reduction in mortality or hospitalization rate in either group.

Despite ending early, the trial met important objectives for informing the implementation of large pragmatic clinical trials embedded in health care systems. In a large multicenter study with no onsite research personnel, the investigators quickly and efficiently enrolled a large number of participants using an opt-out consent approach. The study data were obtained entirely from the electronic health and administrative records of the partnering dialysis provider organizations and were generated from routine clinical care delivery.

“The TiME trial provides an important foundation for future pragmatic trials in dialysis as well as in other settings,” said Dr. Laura M. Dember of the University of Pennsylvania Perelman School of Medicine, the principal investigator of the TiME trial.

The TiME trial was supported within the NIH Collaboratory by a cooperative agreement from the National Institute of Diabetes and Digestive and Kidney Diseases and received logistical and technical support from the NIH Collaboratory Coordinating Center. Download a study snapshot about the TiME trial, and learn more about the NIH Collaboratory Demonstration Projects.

April 15, 2019: Registration Now Open for Workshop on the Design & Analysis of Embedded Pragmatic Clinical Trials (ePCT)

The NIH Health Care Systems Research Collaboratory is hosting a one-day workshop on the Design & Analysis of Embedded Pragmatic Clinical Trials (ePCTs) on May 2, 2019, in the Lister Hill Auditorium on the NIH Campus.

The workshop will include a series of moderated discussions that focus on issues of measuring trial outcomes from available data sources, potential randomization strategies, specific ePCT design considerations, and unique challenges associated with ePCTs. Panel discussions will utilize case examples from the Collaboratory repertoire and beyond to illustrate how clinical investigators and biostatisticians work to address research questions posed by specific trials.

The Workshop Website provides information on meeting logistics, agenda, and registration. There is also an option to attend the workshop remotely via the NIH Videoconference Center, and those details are also available at the Workshop Website.

March 29, 2019: ICD-Pieces: Lessons Learned in an Ongoing Trial (Miguel Vazquez, MD, George (Holt) Oliver, MD, PhD)

Speakers

Miguel A. Vazquez, MD
Professor of Medicine
Clinical Chief Nephrology Division
UT Southwestern Medical Center

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

Topic

ICD-Pieces: Lessons Learned in an Ongoing Trial

Keywords

Multiple chronic conditions; Chronic kidney disease; Hypertension; Diabetes; Pieces™; Electronic health record; Parkland Center for Clinical Innovation; Primary care; U.S. Department of Veterans Affairs

Key Points

  • Improving Chronic Disease Management with Pieces™ (ICD-Pieces) is an NIH Collaboratory Demonstration Project that is implementing a novel technology platform (Pieces) to enable the use of electronic health record data in the management of chronic kidney disease, diabetes, and hypertension within primary care practices.
  • The aim of the study is to reduce hospitalizations, emergency department visits, readmissions, and cardiovascular events and deaths for patients with multiple chronic conditions.
  • ICD-Pieces is employing centralized clinical decision support across 4 large, diverse healthcare systems in addition to the use of Practice Facilitators within primary care.

Discussion Themes

In embedded pragmatic clinical trials conducted in real-world settings, it is important to anticipate changes over the course of the study, which could involve changes at every level, from staff turnover to changes in national policies or standards.

As one of the largest healthcare providers in the world for patients with chronic kidney disease, the VA has been an effective healthcare system partner in the ICD-Pieces trial.

When partnering with healthcare systems, it is important to align goals and plan together, minimize disruption, anticipate and adapt to changes, and create a sustainable foundation for future studies.

Learn more about ICD-Pieces on their website.

Tags

#pctGR, @Collaboratory1

March 13, 2019: PROVEN Publishes Study of Nursing Home Characteristics Associated With Implementation of an Advance Care Planning Video Intervention

The Collaboratory Demonstration Project Pragmatic Trial of Video Education in Nursing Homes (PROVEN) is testing the effectiveness of a novel advance care planning (ACP) video education program in 360 nursing homes within 2 large nursing home healthcare systems. The investigators of PROVEN recently published a study that examines the characteristics of nursing homes associated with implementation of the video. They found that lower quality nursing homes (rated 1 star) had lower offer rates than higher quality nursing homes, suggesting that ongoing support might be necessary in these settings, as well as engagement with a local champion.

ACP is a process by which individuals define their future goals and preferences for medical treatment at the end of life and discuss these goals with their family and healthcare providers. ACP is especially important for nursing home residents, who often receive unnecessary care and experience burdensome transitions at the end of life. The ACP intervention in PROVEN is delivered by an onsite champion at the facility—usually a social worker with structured training in how and when to offer and show the ACP videos to residents and families.

 “These results have implications for future pragmatic trials in the NH [nursing home] setting because ongoing engagement between research and NH staff appears crucial for successful integration of interventions into routine clinical practice. Future research is needed to understand how to best engage NHs in implementation and encourage communication between NHs to share pragmatic strategies for improving clinical practice without the support of research staff.”

– Loomer et al. Journal of the American Medical Directors Association

March 6, 2018: Results of the Active Bathing to Eliminate (ABATE) Infection Trial Published in The Lancet

The Active Bathing to Eliminate (ABATE) Infection trial compared routine bathing to decolonization with universal chlorhexidine and targeted nasal mupirocin in non-critical-care units. Similar interventions have been found to reduce multidrug-resistant pathogens and bloodstream infections in intensive care units (ICUs), and this was the first large-scale trial in non-critical-care units. The primary outcome was methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococcus (VRE) clinical cultures attributed to participating units.

“We found that universal decolonization did not reduce infection in the overall population, but in post-hoc analyses of patients with medical devices the regimen was associated with significant reductions in all-cause bloodstream infections and MRSA or VRE clinical cultures.” —Huang et al. The Lancet 2019

The ABATE Infection trial was a large-scale pragmatic trial involving approximately189,000 patients in the baseline period and 340,000 patients in the intervention period across 194 non-critical-care units in 53 hospitals. The trial was one of the first NIH Collaboratory Demonstration Projects, and in keeping with the Collaboratory’s mission, the investigators have helped expand the knowledge base about the design, conduct, and dissemination of pragmatic clinical trials.

February 21, 2019: Living Textbook Offers New Content on Design and Analysis of Pragmatic Clinical Trials

Members of the NIH Collaboratory’s Biostatistics and Study Design Core contributed 3 new sections to the Living Textbook exploring issues in the design and analysis of pragmatic clinical trials. The new sections offer insights into emerging issues in embedded pragmatic clinical trials and lessons learned from the NIH Collaboratory’s first round of Demonstration Projects.

  • The Designing to Avoid Identification Bias section addresses a type of selection bias that can occur in pragmatic clinical trials that use information from electronic health records to determine study population eligibility and in which the study intervention influences who undergoes screening or receives a diagnosis in clinical care.
  • The Alternative Cluster Randomized Designs section describes alternative design choices for cluster randomized trials and their implications for statistical power and sample size calculations. Modified cluster randomized designs, such as cluster randomization with crossover, may reduce the sample size required for a pragmatic clinical trial and may be particularly feasible in trials embedded in healthcare systems with electronic health records.
  • Case Study: STOP CRC Trial explores challenges in design and analysis that were faced in the Strategies and Opportunities to Stop Colorectal Cancer in Priority Populations (STOP CRC) trial, one of the NIH Collaboratory Demonstration Projects. The case study illustrates how the study team dealt with pragmatic issues during the planning and conduct of the trial.

In addition to contributing content to the Living Textbook, the Biostatistics and Study Design Core works with the NIH Collaboratory Demonstration Projects to address challenges in their statistical plans and study designs during the planning phase and to develop guidance and technical documents related to study design and biostatistical issues relevant to pragmatic clinical trials.

February 1, 2019: Promoting Effective Advance Care Planning Communication in the Elderly: The ACP-PEACE Trial (James Tulsky, MD, Angelo Volandes, MD, MPH)

Speakers

James Tulsky, MD
Chair, Department of Psychosocial Oncology and Palliative Care
Dana-Farber Cancer Institute
Professor of Medicine, Harvard Medical School
Chief, Division of Palliative Medicine
Brigham and Women’s Hospital

Angelo Volandes, MD, MPH
Associate Professor of Medicine
Massachusetts General Hospital
Harvard Medical School

Topic

Promoting Effective Advance Care Planning Communication in the Elderly: The ACP-PEACE Trial

Keywords

Pragmatic clinical trial; Advance care planning; ACP PEACE; Dana-Farber Cancer Institute; National Institute on Aging; Palliative care; Video declarations; Goal-concordant care; Patient preferences

Key Points

  • Many people with serious illness die without receiving goal-concordant care, and patients over the age of 65 with cancer experience this disproportionately. Helping patients engage in advance care planning (ACP) can empower them to express and record their goals so that their care can be aligned with their preferences.
  • The ACP PEACE Demonstration Project is a pragmatic, stepped-wedge, randomized trial of a comprehensive ACP program in oncology clinics at 3 health systems. It will involve a combination of 2 evidence-based programs:
    • VitalTalk teaches clinicians important communication skills in having empathic conversations with seriously ill patients.
    • ACP Decisions uses videos to promote planning and decision-making by patients and families.
  • The ACP PEACE study will monitor long-term outcomes to evaluate whether patients received the care they planned for and wanted.

Discussion Themes

The last element of the ACP PEACE trial is a video declaration (ViDec), recorded by a subset of patients. In recording the ViDec, patients are prompted by questions assessing their confidence with their decision, satisfaction, decisional regret, and patient-provider experience.

The ACP PEACE study team has a scaling strategy in place if the intervention proves effective. Implementing the intervention as standard of care will involve a culture shift from what is currently expected in health systems.

Read more about the ACP PEACE Demonstration Project in the Living Textbook.

Tags

#AdvanceCarePlanning, #pctGR, @Collaboratory1 @VitalTalk, @ACPDecisions

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