Grand Rounds Archive

Grand Rounds April 21, 2023: Personalised Cooler Dialysate for Patients Receiving Maintenance Haemodialysis (MyTEMP): A Pragmatic, Cluster-randomised Trial (Amit Garg, MD, MA, FRCPC, FACP, PhD; Stephanie N. Dixon, PhD MSc)

Posted on by Elizabeth Mccamic

Speakers

Amit Garg, MD, MA (Education) FRCPC, FACP, PhD
Associate Dean, Clinical Research, Schulich School of Medicine and Dentistry
Lead, Institute for Clinical Evaluative Sciences Kidney, Dialysis and Transplantation Provincial Program
Director, Institute for Clinical Evaluative Sciences (ICES) Western Facility
Nephrologist, London Health Sciences Centre
Professor, Medicine, Epidemiology & Biostatistics, Western University

Stephanie N. Dixon, PhD MSc
Staff Scientist, Institute for Clinical Evaluative Sciences Kidney, Dialysis and Transplantation Research Program
Biostatistician, London Health Sciences Centre

 

Keywords

MyTEMP, Pragmatic Clinical Trials, Ethics, Biostatistics

 

Key Points

  • For each hemodialysis treatment clinicians typically set the temperature of dialysate on the machine to 36.5 or 37.0 degrees Celsius. The reasoning for this temperature is unclear, though it likely represents what was considered the average body temperature of most patients.
  • In a recent international survey of more than 270 centers, nearly half now use a cooler temperature dialysate in patient care of less than or equal to 36.0 degrees C. This change in practice is based on data that suggests the at cooler (vs. standard) temperature dialysate is beneficial. However, in two recent systematic reviews the overall quality of evidence for dialysate cooling was deemed low with a high risk of bias.
  • The MyTEMP trial is a pragmatic, cluster randomized controlled trial in Ontario, Canada, to determine if adopting a default center-wide policy of personalized cooler dialysate is superior to a standard temperature dialysate of 36.5 degrees C.
  • MyTEMP was innovative and pragmatic, implemented as part of a learning healthcare system, with covariate constrained randomization, registry-based, and embedded in routine care delivered by more than 2,000 nurses at 84 centers.
  • During the 4-year study period, about 8,000 patients were randomized for the personalized cooler dialysate and about 7,400 were randomized for the standard temperature dialysate. The mean temperature for the standard group was 36.4 degrees C, and the mean temperature for cooler group was 35.8 degrees C.
  • The primary composite outcome was cardiovascular mortality or hospital admission with MI, stroke, or heart failure. There is a high risk of these events in the hemodialysis population with a cumulative instance at 30% at 4 years. There was no appreciable difference in the estimate for the cooler temperature group. Additionally, the cooler temperature group reported a higher likelihood of discomfort.
  • The lack of cardiovascular benefit and higher likelihood of patient discomfort provides no justification to adopt cooler dialysate as a center-wide policy vs. use of 36.5 degrees. After MyTEMP, centers in Ontario stopped adopting colder temperature dialysate as a center-wide policy, and patients felt less discomfort during hemodialysis care.
  • Cluster randomized trials of hemodialysis center-wide policies raise complex ethical issues. Many patients who receive hemodialysis are vulnerable. A patient or their nephrologist could decide to opt-out of the randomly allocated center-wide default policy but could not opt out of the symptom data but not de-identified health records. The REB approved the MyTEMP request to use an altered patient consent process because the research was deemed of minimal risk to patients.
  • MyTEMP worked with patients and caregivers to develop the trial, and Kidney Patient and Family Advisory Councils guided the choice of additional outcomes. Participants were debriefed on the trial results.

Learn more

Read about the MyTEMP trial in The Lancet.

Read about the MyTEMP statistical analysis plan.

Discussion Themes

–We run into situations where we are talking to stakeholders and thinking about criteria for waiver of consent and it’s just not right. Where the risks and benefits are equal, but I wouldn’t want to be randomly assigned. There is a natural assertion of autonomy. Did some of these questions of autonomy vs. risk come up? I think it is very complex, and it is not black and white. You need to identify the principles before the process. In terms of the dialysis component, in routine care we get consent when we start treatment but there are many things in the background. As a clinician when I am providing care, I’m not discussing these concerns; we are talking about other things. Am I delivering great medicine when I’m not sure what to do here when there is practice variability?

Tags

#pctGR, @Collaboratory1

Grand Rounds April 14, 2023: RECOVER in Action – Status of Clinical Trial Protocols (Kanecia Zimmerman, PhD, MD, MPH)

Posted on by Elizabeth Mccamic

Speaker

Kanecia Zimmerman, MD, PhD, MPH
Associate Professor of Pediatrics
Duke Clinical Research Institute
Duke University School of Medicine

 

Keywords

COVID-19, RECOVER, Clinical Trials

 

Key Points

  • Long COVID is a set of multiple conditions with diverse clinical manifestations that can affect every major organ/tissue system, reflecting varied potential underlying and co-existing causes.
  • There are many hypothesized causes that may co-exist in the same patient, such as persistent virus or antigens, reactivation of other viruses, uncontrolled immune responses, damage to a wide range of organs and tissues, and injury to blood vessels and abnormal blood clotting. This broad set of clinical conditions and varied underlying causes underscore the need for testing a broad portfolio of therapeutic agents.
  • RECOVER is a patient-centered, integrated, adaptive research network. The goals of RECOVER is to understand how people are recovering from COVID and changes in our bodies over time; define risk factors, number of people getting Long COVID, and if there are specific different Long COVID types; study how Long COVID progresses over time and how that may relate to other illnesses; and identify possible treatments to help with Long COVID symptoms.
  • RECOVER has used cohort data to identify major symptom clusters and develop 5 platform protocols that will investigator priority symptom clusters and their causes; test known and novel interventions across domains; and evaluate treatments to improve Long COVID symptoms.
  • The 5 platform protocols are integrated rather than siloed, disparate studies to achieve efficiencies, allow researchers to rapidly assess targeted therapeutics and pivot as needed to new treatment arms, maximize knowledge gained from patient participation, and to enable cross-trial analysis and accelerated knowledge acquisition.
  • The 5 trials, RECOVER-VITAL, RECOVER-AUTONOMIC, RECOVER-SLEEP, RECOVER-NEURO, and RECOVER-ENERGIZE, will enroll about 2,600 total participants, and each trial will include between 25-100 sites. The first trial will begin enrolling in July 2023.

Learn more

Visit https://recovercovid.org

Discussion Themes

– What experts are being convened for the different trials? It’s all over the place. We have people with experience with post-viral symptoms, treating ME/CFS, general COVID knowledge, biomarker experience, clinical trials, patient-reported outcomes, and more.

– As people think about the health measures and outcomes, can you describe the process for how to understand and select those types of measures? It was such an iterative process to get to where we are. People with experience to prior disease that might be similar is where we started. Can we use measures that have been used previously for those populations and if we can how do we tweak them to make sure they are valid within this population? Prior information, data and experience and then adapt it for patients with PASC.

-While the pandemic is transitioning from pandemic to endemic state, do you see any signs that PASC will go away? No, there are no signs PASC is going away. It seems the most severely affected people came from the early waves of COVID. Over time the epidemiology has changed some for those people with PASC, but there are still people who are still symptomatic and want answers.

Tags

#pctGR, @Collaboratory1

Grand Rounds April 7, 2023: A Nudge Towards Cardiovascular Health: Incorporating Insights From Behavioral Science to Improve Cardiovascular Care Delivery (Srinath Adusumalli, MD, MSHP, MBMI, FACC)

Posted on by Hannah Webster

Speaker

Srinath Adusumalli, MD, MSHP, MBMI, FACC
Adjunct Assistant Professor of Medicine, Perelman School of Medicine
Adjunct Professor of Healthcare Management, The Wharton School
Affiliated Faculty, Center for Health Incentives and Behavioral Economics
Staff Cardiologist, Hospital of the University of Pennsylvania and Philadelphia VAMC University of Pennsylvania
Senior Medical Director, Enterprise

Keywords

Pragmatic trials, cardiovascular medicine, cardiovascular care delivery, behavioral science, electronic health records, implementation science

Key Points

  • A nudge is a subtle change in design that is intended to impact human behavior. They are intended to remind, guide, or motivate a decision, and they should be transparent. Dr. Srinath Adusumalli described a nudge as something that helps make the right choice an easier choice.
  • Nudges and other behavioral interventions are prevalent in industries like business and entertainment, but there is an opportunity for nudges in medicine and health care delivery.
  • Launched in 2016, the Penn Medicine Nudge Unit is the world’s first behavioral design team embedded within a health system. It works to improve health care value and outcomes, advance the science of designing interventions to change behavior and evaluate and disseminate the impact of interventions. The team then worked to incorporate an implementation science lens for designing interventions for scale to the health system.
  • The health behavior is supported by a technology backbone, including the Penn Medicine EHR and other systems that bring insight and nudge within workflows. The context and stakeholder input have been key in developing and implementing nudges.
  • Useful nudge principles are limitations of information provisions, inertia or status quo bias, choice overload, loss aversion or framing, social ranking and the limits of willpower.
  • Implementing the nudge tool within the Penn Medicine revealed several positive impacts, including referral rates increasing significantly via the implementation of a default pathway.
  • The PRESCRIBE trial revealed the value of active choice as well as peer decision-making to prompt decision-making.
  • The randomized controlled trial Effect of Nudges to Clinicians, Patients or Both to Increase Statin Prescribing published in JAMA found that the clinician nudge and the combined nudge interventions significantly increased the proportion patients prescribed a statin compared with usual care but the patient nudge had no impact.
  • Key considerations for developing and implementing a nudge include the right information and guidelines, the right individual to receive the nudge, the right intervention format, the best channel for the nudge and the best time in a provider’s workflow to receive the nudge.
  • Key learnings from the studies highlighted included the need for more transparency as to the reason for a nudge, limiting the number of choices in CDS intervention, passive CDS is often ineffective and it is critical to provide the path for the individual to immediately act.
  • New frontiers in nudging include integrating nudges and behavioral science with applied machine learning, phenotyping patient and clinician behavior to more precisely target single or combination nudges, the simplification and automation of downstream actions, and the alignment of incentive and behaviors across health care actors, including systems and payers.

Discussion Themes

– In the last few years, there has been great reception to the value of behavioral science and implementation science in the field of cardiology. There is opportunity for more evidence to be developed and to implement lessons that have been learned.

– Behavioral science tools, such as these EHR-integrated nudges, must be modified to fit within different settings and EHR systems, but they often provide a strong foundation for other contexts. Customizing existing tools to different systems can save significant time and resources in developing behavioral health tools.

Tags

#pctGR, @Collaboratory1

Grand Rounds March 31, 2023: Efficacy and Safety of a Quadruple Ultra-low-dose Treatment for Hypertension (QUARTET USA): Results From A Randomized Controlled Trial (Jody D. Ciolino, PhD)

Posted on by Elizabeth Mccamic

Speaker

Jody D. Ciolino, PhD
Associate Professor
Director, Master of Science in Biostatistics
Department of Preventive Medicine – Biostatistics
Biostatistics Collaboration Center (BCC) / Northwestern University Data Analysis and Coordinating Center (NUDACC)
Northwestern University Feinberg School of Medicine

Keywords

QUARTET, hypertension, RCT, biostatistics

Key Points

  • Elevated blood pressure (>130/80) is leading cause of preventable morbidity and mortality globally. In the U.S. nearly half of adults have hypertension and prevalence rates are rising. While most Americans are aware of their hypertension and while most who are aware receive treatment (75%), less than half (47%) are controlled using a goal blood pressure of <130/<80 mmHg.
  • The typical plan for treatment includes repeated clinic visits with repeated dose titrations of multiple individual drugs, which is challenging for both patients and providers. Maximizing doses of individual drugs leads to greater risk of side effects.
  • QUARTET sought to investigate whether initiating treatment with ultra-low-dose quadruple-combination therapy (LDQT) will lower office blood pressure more effectively, and with fewer side effects, compared to initiating standard dose monotherapy in patients with hypertension.
  • QUARTET hypothesized that a combination pill comprising 4 types of blood pressure lowering medications, each at one-quarter standard doses, will lower office blood pressure more effectively than initiating patients with standard dose monotherapy in patients with hypertension.
  • Study participants came from ACCESS Community Health Network. Participants were adult, Spanish and English speakers with blood pressure withing range for Stage 1 hypertension as defined in the protocol; eventually this changed to automated blood pressure readings in clinic.
  • The primary outcome was automated office systolic blood pressure (SBP) at 12 weeks and analyses will compare this change across arms for primary outcome analyses, adjusting for baseline. Secondary outcomes included automated office diastolic blood pressure (DBP) at 6 and 12 weeks; proportion of patients with hypertension control at 6 and 12 weeks; proportion of patients requiring step-up treatment; proportion of patients with adverse event-free hypertension control; medication adherence; and health-related quality of life (PROMIS Global Health).
  • QUARTET planned for a total of 365 participants randomized 1:1 with a 20% dropout rate by the 12-week follow up time point. The study launched a second site in February 2020, right before the pandemic and political unrest. In August 2020, the study launched third site. All sites were in Chicago.
  • QUARTET found that initiating a four-drug quarter-dose combination blood pressure lowering therapy was associated with a ~4.8/4.9mmHg greater reduction in mean change in BP from baseline to 12 weeks compared with standard-dose ARB monotherapy in patients with mild to moderate hypertension.
  • Differences in SBP were not statistically significant, which may be due to limited power related to the sample size. Adverse events were more common in the intervention arm, but the rates of discontinuation were higher in the comparator arm. No SAEs were deemed related to the study drug.
  • New approaches are needed to achieve lower BP targets, especially for patients and communities with a high burden of hypertension and hypertension-related diseases.

Learn More
Read more about QUARTET in the Journal of the American Heart Association.

Discussion Themes

-Did automated office blood pressure include 5-minute rest? If so, how did it differ from “research grade” BP measurement? Automated office blood pressure was according to how they measured blood pressure in the clinic with an automated cuff. Before the study started, there was some training with the research nurses on taking blood pressure from participants and there was a 5-minute rest, though I am not sure how that was adhered to. The research grade blood pressure was meant to be unattended, automated (taken 3 times), and there was an average of the 2.

Tags

#pctGR, @Collaboratory1

Grand Rounds March 24, 2023: From Observational Studies to Pragmatic Clinical Trials: (Almost) A Decade of Research in PCORnet® (Erin Holve, PhD, MPH, MPP; Russell Rothman, MD, MPP; Schuyler Jones, MD; Neha Pagidipati, MD, MPH)

Posted on by Elizabeth Mccamic

Speakers

Erin Holve, PhD, MPH, MPP
Chief Research Infrastructure Officer,
Patient-Centered Outcomes Research Institute (PCORI)

Russell Rothman. MD, MPP
Director Institute for Medicine and Public Health and Senior Vice President, Population and Public Health, Vanderbilt University Medical Center

Schuyler Jones, MD
Associate Professor, Duke Clinical Research Institute and Population Health Sciences,
Duke University School of Medicine

Neha Pagidipati, MD, MPH
Associate Professor, Duke Clinical Research Institute
Duke University School of Medicine

 

Keywords

Pragmatic Clinical Trials, PCORI, PCORnet®

 

Key Points

  • The Patient-Centered Outcomes Research Institute (PCORI) funds studies designed to help people make better informed healthcare decisions. It is an independent, nonprofit, research institute and leading funder of patient-centered comparative clinical effectiveness research (CER).
  • PCORnet®. is funded by PCORI and was launched almost 10 years ago. It has grown to be a major force for supporting pragmatic research, both real-world evidence research and supporting observational research and pragmatic clinical trials.
  • PCORnet®. has 8 clinical research networks across the country. Patients and caregivers are integrated into all phases of PCORnet®.-enabled research. Data are drawn from millions of EHRs with growing links to patient-reported and payor data. PCORnet®.connects you to thousands of clinicians and researchers who can support your effort.
  • Every PCORnet®. project has very robust approaches to engaging patients across the continuum of the research from the identification of research questions to the planning phase to the implementation phase to the analysis phase and out to the dissemination of results.
  • Many different types of observational studies are possible with PCORnet®. across all therapeutic areas. It is one of the only data resources with granular clinical data, lab data, and very large sample sizes. We have significantly improved the process of working with sites to collect and refine the data over time. PCORnet®. sites and PIs are really interested in collaborative academic partnerships.
  • As the network was launched and the first trial, ADAPTABLE, was getting started, we came to the conclusion that we needed large, generalizable studies that were efficient. How could we harness the data that are already being produced, have patient partnership, and results that matter?
  • Lessons learned from 3 PCORnet®.trials: We have to work smarter, not harder. We need scalability and team work. We have to continue to make strides to improve our clinical trial infrastructure and how we do studies.

Learn more

PCORnet Front Door

Discussion Themes

– Is there anything about what PCORnet®. has achieved that wasn’t imagined and, with a look to the future, what are the most important next steps to take to fully realize PCORnet’s potential? We did achieve a lot of the things we talked about in the first year, many of which we did not think were achievable. There are still some discussions now about where we might go with the common data model and if there are efficiencies in supporting more than one data model. For now, PCORnet®.has worked well for supporting the types of projects we want to support. We have tried to build engagement that helps us work with the CRNs and health systems to engage a broad array of stakeholders for each project we are doing.

– Where do you see the opportunities or steps to fulfill PCORnet’s potential? PCORnet®. works. There were a lot of components to how the network works. It is really phenomenal with how far it has come. Are there ways it can work more smoothly, take advantage of technology, have more consumer information that can facilitate these efforts? Those are the areas we are looking at moving forward. Where do we take the research activities that best use the infrastructure and move them forward?

Tags

#pctGR, @Collaboratory1

Grand Rounds March 17, 2023: Remote Symptom Monitoring with Electronic Patient-Reported Outcomes (ePROs) in Oncology (Ethan Basch, MD, MSc)

Posted on by Elizabeth Mccamic

Speaker

Ethan Basch, MD, MSc
Richard M. Goldberg Distinguished Professor and Chief of Oncology
Physician-in-Chief, North Carolina Cancer Hospital
Director, Cancer Outcomes Research Program
University of North Carolina

 

Keywords

Patient-reported outcomes, Oncology, Clinical Trials

 

Key Points

  • Symptoms are common in cancer care. They interfere with physical function and daily activities, lead to avoidable ER/hospital visits and readmissions, and preclude treatment. Symptom management is a cornerstone of quality care, but do we adequately detect and manage symptoms?
  • In the standard approach to symptom monitoring, the clinical team may not be aware of a patient’s symptoms, so when the symptoms become worse the care team has to be reactive. In a model for systematic symptom monitoring, a patient might report symptoms electronically in real-time via e-reports or e-alerts so the care team can respond proactively and have data to review at the next visit.
  • Clinicians think they know how patients are doing already and do not need self-reported data; however in a study that compared patient-reported and clinician-reported symptoms, there was a substantial gap between the symptoms that were reported by patients and symptoms that were not reported by clinicians. There is an opportunity to do better through navigation, portals, and patient-reported outcomes to bridge the gap.
  • We conducted a large single-center “STAR” Study to find out if the gap between patient and clinician reported symptoms makes an impact on clinical outcomes. There were 766 patients enrolled in the study with a median follow up of 7 years. Quality of life (QOL) was assessed at 6 months. Compared to standard care, 31% more patients in the self-reporting arm experienced QOL benefits; 7% fewer patients in self-reporting arm visited the ER with durable effects throughout the study; and median survival was 5.2 months longer among patients in the self-reporting arm. There was a 5-year absolute survival benefit of 8%.
  • Proactive monitoring prompts clinicians to act early before symptoms worsen and cause downstream complications. Symptom control enables patients to stay more functional, which is known to be associated with better survival. Symptom monitoring enables control of chemotherapy side effects, enabling more intensive and longer duration of cancer treatment.
  • The PRO-TECT Cancer Symptom Study was a cluster randomized trial at 52 U.S. community oncology practices across 25 states. At each practice up to 50 patients with metastatic cancer, receiving systemic therapy, not on a therapeutic trial, were randomized to an intervention arm with digital monitoring or a control arm with usual care. The intervention arm had to complete weekly PRO survey items from NCI PRO-CTCAE (pain, nausea, vomiting, constipation, diarrhea, dyspnea, insomnia, depression, oral intake).
  • In this study adherence with week ePROs was 91.5%. When patients didn’t report, they received a phone call to make sure they were OK. In the PRO arm there was a statistically significant improved physical function score, the study found significant benefits for the PRO arm for symptoms, and significant benefits on health-related quality of life.
  • Patient self-reporting improves symptom monitoring and outcomes in routine cancer care and clinical research by expanding our understanding of the patient experience and engaging patients. From a health services research perspective, it demonstrates how hard it is to change a simple process, even if it makes a lot of intuitive sense.

Learn more

Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

Discussion Themes

– How have clinician views changed in terms of patient-reported symptoms verses clinician understanding of symptoms? The culture has fundamentally changed. The research in this area has grown over time. 10 years ago or even 5 years ago many clinicians had not heard about patient-reported outcomes. Now almost any physician has heard of patient-reported outcomes. Technology has advanced during this time, and there are all kinds of ways for patients to communicate with providers. Regulatory authorities have become interested in PROs and it is thought of as a fundamental part of drug development. I have seen a remarkable change in views on patient-reported outcomes.

– How do we take all of these ePRO options and choose something that is right for a trial? It depends on the goals of the study. When you have more than one choice for the symptom domain or you run the risk of duplication how do you choose? FDA and other regulatory authorities want to think about symptoms separately from adverse events. You will want a dedicated tool for adverse events.

Tags

#pctGR, @Collaboratory1

Grand Rounds March 10, 2023: Estimands in Cluster-Randomized Trials: Choosing Analyses that Answer the Right Question (Brennan Kahan, PhD)

Posted on by Hannah Webster

Speaker

Brennan Kahan, PhD
MRC Clinical Trials Unit
University College London (UCL)

 

Keywords

Cluster-Randomized Trial, Estimands, Cluster-Average Treatment Effect, Participant-Average Cluster Size

 

Key Points

  • The TRIGGER trial inspired statistician Brennan Kahan to ask in the questions, “But what if we’d chosen a different analysis? “and “How much would standard errors really change?”
  • An estimand is a precise description of the treatment effect that a researcher aims to estimate from the trial. This concept is especially important in the context of cluster-randomized trials, but it is important to determine if the estimand will reflect participant-average treatment effect versus a cluster-average treatment effect or a marginal versus cluster-specific. The difference relates to how data is weighed.
  • Two estimands will differ when there is informative cluster size in a trial. Informative cluster size refers to situations in which outcomes or treatment effects differ in large clusters versus smaller clusters. An example of this is when patients experience better outcomes in a large hospital compared to a small hospital when given the same medication.
  • Which estimand (participant-average or cluster-average) to use depends on the study question. Participant-average treatment effect will demonstrate the population-effect when going from one intervention to another. A cluster-average treatment effect better enables the evaluation of an intervention or treatment’s impact directly on clusters.
  • Mixed-effects models or Generalized Estimating Equations (GEE) are the most common analysis methods for clustered randomized trials, but when informative cluster size is present, both are bias. To avoid this bias, Independence Estimating Equations (IEEs) and cluster-level summaries can be used to estimate either cluster- or participant-average effects.
  • The occurrence of informative cluster size has never formally been evaluated to the presenter’s knowledge. Statisticians working on pragmatic trials should consider estimand and tailor analysis around the chosen estimand.

Learn more

Many of the concepts described in the Grand Rounds presentation are outlined the article published in the International Journal of Epidemiology: Estimands in cluster-randomized trials: choosing analyses that answer the right question

Discussion Themes

– The summary measure scale is very important in determining the best estimand for a specific cluster-randomized trial.

– Equal cluster size does not necessarily mean that estimand is irrelevant because of differences in sample size. Reweighting may be necessary, and there may be additional assumptions.

– It’s difficult to determine definitively if there is informative cluster size, but it would be interesting to evaluate in pilot data clusters.

– Stratification would not be a solution to solve the issue of informative cluster size in analysis.

Tags

#pctGR, @Collaboratory1

Grand Rounds March 3, 2023: Adoption, Implementation and Sustainment of Family-focused Prevention in Health Care Systems: How Do We Get There? (Margaret Kuklinski, PhD; Stacy Sterling, DrPH, MSW)

Posted on by Elizabeth Mccamic

Speakers

Margaret Kuklinski, PhD
Endowed Associate Professor of Prevention in Social Work
Director, Social Development Research Group
Acting Director, Center for Communities That Care
School of Social Work, University of Washington

Stacy Sterling, DrPH, MSW
Kaiser Permanente Division of Research
Co-Director, Center for Addiction and Mental Health Research
Associate Adjunct Professor, UCSF Department of Psychiatry and Behavioral Sciences
Associate Professor, Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine

Keywords

Pragmatic Clinical Trial, GGC4H, Prevention

Key Points

  • Guiding Good Choices for Health Study (GGC4H) is about the Guiding Good Choices (GGC) intervention, a group-based program for parents and caregivers of younger adolescents (ages 9-14). The intervention has been shown in two previously study trials to better family and adolescent health outcomes.
  • GGC4H chose a parent-focused prevention and health promotion because stronger bonds with family results in better health and educational outcomes, and they are cost effective. Across 5 sessions, GGC4H offers strategies for promoting health and wellbeing, such as setting healthy and clear guidelines, positive discipline, dealing with anger constructively, resisting negative influences (with adolescents) and strengthening bonds and building life skills.
  • GGC4H is a 5-year, longitudinal cluster-randomized trial that took place in pediatric primary care. The study randomized 75 pediatricians and recruited 1,975 adolescents in 2 cohorts that were gender balanced, racially and ethnically diverse. The study offered GGC to all caregivers in the intervention arm, using 2 modalities, virtual groups and digital self-guided.
  • GG4CH conducted 4 studies asking 1) Do caregivers want virtual parenting support? 2) Can virtual GGC be delivered with fidelity? 3) Is virtual GGC satisfying to parents and 4) What do health care system leaders say? The study found that virtual parenting support coincided with the COVID-19 and helped families deal with the impact of the pandemic; GGC was delivered with high fidelity across cohorts, sessions, and sites; parents were satisfied with virtual GGC, with parents valuing the flexibility, connection and community.
  • GG4CH identified strengths of the intervention and barriers through interviews with health care system leaders. Resources are a perennial challenge, pediatric well visits are full of competing priorities, and return of investment takes time to unfold. The most effective levers to move toward widespread adoption are systems level support normalizing prevention; national guidelines and performance measures; cost-effectiveness evidence; and a groundswell of interest from parents and clinicians.

 

Discussion Themes

-How do you most effectively move this toward adoption? There is a growing appreciation for integrated behavior health and the crisis that our adolescents are facing. Health system leaders are aware that and there is an interest in addressing social determinates of health and adverse childhood experiences. Taking advantage of the momentum in terms of screening programs and other programs that will address these factors, hopefully health system leaders will see Guiding Good Choices as a way to help?

-What was the biggest surprise coming out of these studies to you? I don’t know that it is a surprise as much as a heartening thing but to see in the parent quotes the affirmation of wanting bonding and be willing to give their time and to talk about the value of that, it is affirming of a program like GGC. I was surprised and pleased by how well the virtual adaption went. It was a huge amount of work during the scary time of the beginning of COVID.

Tags

#pctGR, @Collaboratory1

Grand Rounds February 24, 2023: S2302 Pragmatica-Lung: New Directions for Decreasing Burden and Increasing Inclusion in NCTN Clinical Trials (Konstantin Dragnev, MD; Karen Reckamp, MD, MS)

Posted on by Elizabeth Mccamic

Speakers

Konstantin Dragnev, MD
Professor of Medicine, Hematology/Oncology
Irene Heinz Given Professor in Pharmacology
Associate Director for Clinical ResearchPrincipal Investigator – Dartmouth Lead Academic Participating Site for NCTN
Dartmouth Cancer Center
Dartmouth Health

Karen Reckamp, MD, MS
Director, Division of Medical Oncology
Associate Director, Clinical Research
Clinical Professor, Department of Medicine
Cedars-Sinai Cancer

 

Keywords

Pragmatic Clinical Trial, Lung Cancer

 

Key Points

  • S2302 is an ongoing Phase III pragmatic clinical trial designed to reduce the burden of clinical trial participation and to promote the inclusion of all participants with non-small cell lung cancer (NSCLC).
  • S1800A was a Phase II randomized study of ramucirumab plus pembrolizumab versus standard of care for NSCLC patients previously treated with immunotherapy performed within the Lung-MAP platform. Overall survival was significantly improved with a hazard ratio of 0.69, median OS of 14.5 and 11.6 months, for pembrolizumab and ramucirumab vs. standard of care, respectively. The aim of S2302 is to validate the improvement in overall survival in S1800A.
  • Patients are eligible to participate in the S2302 if they are at least 18 years old with Stage IV or recurrent non-small cell lung cancer, need for prior treatment with one line of immunotherapy and a platinum based combination performance status between 0 and 2 and determination by the treating investigator that it is safe for the participant to receive either the investigational combination or standard of care.
  • For the standard of care arm, treatment is determined by the treating investigator and participant, with the recommendation that the choice of drug is based on NCCN guidelines and dosing administration based on the participant’s previous therapy and disease.
  • For the investigational ramucirumab plus pembrolizumab arm, the drugs are administered per FDA package insert and institutional standard in a 21-day cycle under one of the criteria for removal is met. Ramucirumab will be administered prior to pembrolizumab; participants will receive 35 cycles of pembrolizumab, and maintenance ramucirumab may continue for participants past 35 cycles until reaching discontinuation criteria.
  • Criteria for removal from treatment include progression of disease based on investigator assessment; unacceptable toxicity; and participants may withdraw from the protocol treatment at any time for any reason.
  • To reduce the burden on sites, the study has simplified data reporting by reducing time points data, reducing the number of forms that need to be submitted, and reducing the number of data elements within a form. The study does not include tissue specimen collection, image submission, or patient-reported outcome instruments. The informed consent document has been simplified and is shorter than the usual NCTN template informed consent document.

 

Discussion Themes

– What does a study champion mean in the context of this study? One network is the lead, but the trial will be available in all four U.S. networks. We have found that having an involved investigator in each network improves engagement. We are working on inclusion and making sure all of our trials have buy in across the group.

– What was the rationale for the choice of study treatments (i.e., verses other immunotherapeutic agents)? There is a strong mechanistic rationale. They are both approved and used widely in lung cancer, and combining two existing agents is logistically and clinically simpler. We got both Merck and Lily to work together in the Phase II trial, then the data from that trial that showed survival benefit led to the Phase III study. It’s been a collaboration across multiple groups and entities and the fact that a lot of people decided to work together.

–Are there any concerns that the pragmatic nature could reduce the chance of showing a benefit? When we started working on this the discussions with NCI and FDA were about stripping away eligibility, we realized the population would be less controlled than previous studies. We kept coming back to the one thing we want to know, which is the overall survival. We have a higher threshold than most because we know that these patients will be a little more variable and robust

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#pctGR, @Collaboratory1

Grand Rounds February 17, 2023: The Heartline Trial: A New Paradigm in Conducting Virtual Clinical Trials (C. Michael Gibson, MS, MD)

Posted on by Elizabeth Mccamic

Speaker

Michael Gibson
Professor of Medicine Harvard
Interventional Cardiologist BI Lahey
CEO & President of the non-Profit Baim Institute for Clinical Research & PERFUSE Study Group

 

 

Keywords

Pragmatic Clinical Trial, Heartline Trial

 

Key Points

  • The Heartline Trial is one of the world’s first randomized virtual trials. It will demonstrate that we can do trials at less cost than a normal trial (about 1% of a normal study). The question is can we pivot from very expensive trials to test cardiovascular drugs to at least a hybrid model that takes the best of what we have learned so far from the Heartline Trial?
  • The Heartline Trial has moved to a new form of information sharing, one that is open source, innovates from without, knowledge flows to and from all via the internet, people can share information, retaining credit for it but sharing it freely. The new way is more collaborative and global. The biggest change is that the patient now has a seat at the table. Providers must now earn the trust of relatively informed and knowledgeable patients through a two-way conversation.
  • The Heartline Trial is a randomized trial of up to 28,000 patients to test whether the new Apple watch (with built-in single lead EKG) can detect new onset atrial fibrillation in participants age 65 and older.
  • Patients were enrolled via an app in this virtual trial. Patients were followed-up online by apps for Patient Reported Outcomes and claims database. The consent form is electronic and approved by a central IRB.
  • Heartline is using direct to patient recruitment and includes real world patients with a broad range of modifiable risk and limited exclusion criteria. The study is enrolling people where they are using social media, such as Facebook ads, twitter influencers, tv ads, interviews with print/electronic news outlets, national tv (an appearance on “The Talk” to discuss the study), targeted advertising, physicians, electronic health records.
  • In this new trial model, we don’t have to track down missing information unless the patient leaves the country. We are empowering the patient and family, who have access to their data. The family can be notified if the patient goes into Afib. There also is no need for an independent clinical event committee to adjudicate events. In the new model we are using ICD-10 codes, not specific to the trial, to find events and lead to lower specificity, more events. In Heartline, patients will be reimbursed for effort to complete patient reported outcomes and interacting with the app.
  • Digital health is upon us, and we want to make sure that technology works for healthcare and that healthcare should not work for technology. Digital health should complement nurses and physicians by putting patients back at the center of trials

 

Discussion Themes

– One of the things you noted is how sticky the app was and the excellent completion rates of the data. To what extent were you observing the methods for providing value to the patients through the app actually changing the observed function? The engagement with the original Apple health study was not good, about 30-40%. In Heartline, the older population engaged much more than I thought they would, 90% engagement initially and fell after a few months to 80-85%. It was achieved because it wasn’t just them answering questions. There was news pushed out about general health. They liked being kept up to date about general medicine and this provided value to them. We asked why are you participating and engaging with the app? They wanted to give back and help others learn something. It’s so important to maintain patients trust and credibility to them.

– There are systems in place to ensure equipment used in clinics are reliable. How do you account for the lack of oversight in the remote setting? What kind of trials would this be suitable for? If you are doing biomarker work, patients will have to go to a brick and mortar for that. But for outcomes and others you can do virtually. I think you’ll probably end up with a hybrid model. Consent is one that should be done virtually.

Tags

#pctGR, @Collaboratory1