Grand Rounds Archive

Grand Rounds Ethics and Regulatory Series February 10, 2023: Informing and Consenting: What Are the Goals? (P. Pearl O’Rourke, MD; David S. Wendler, PhD, MA; Miguel Vazquez, MD; P. Michael Ho, MD, PhD)

Posted on by Elizabeth Mccamic

Speakers

Pearl O’Rourke, MD (retired)
Harvard Medical School

David S. Wendler, PhD, MA
Senior Researcher
Head, Section on Research Ethics
Department of Bioethics
NIH Clinical Center

Miguel Vazquez, MD
Professor of Internal Medicine
UT Southwestern Medical Center

Michael Ho, MD, PhD
Professor of Medicine
University of Colorado School of Medicine

 

 

Keywords

Ethics and Regulatory, Consent, Waiver of Consent, Notification

 

Key Points

  • Using informed consent addresses two of the Belmont Principles, respect for persons by informing and autonomy by allowing choice. The regulations recognize that consent is not always possible and allow for alteration, where some of the required elements of informed consent can be altered or not included, and waiver of consent, where no consent is required.
  • It is not uncommon to see waivers of consent in pragmatic clinical trials because many trials meet minimal risk criteria and involve numerous institutions and thousands of subjects. There are also concerns that obtaining consent could alter the “real-world” medical care being studied, may introduce an alteration of routine care, may introduce bias or make research impossible to conduct.
  • Informed consent is not the only way to inform. Think about methods of notification, from detailed study-specific information to a general statement that research is being conducted. There are consequences of notification, such as logistics and cost. If you are notifying, when do you offer an opt-out option and what do you do when potential subjects have questions or do not want to be in the research?
  • ICD-Pieces studied patients with chronic kidney disease (CKD), diabetes and hypertension. The intervention was to facilitate delivery of guideline-based care. The study had a waiver of informed consent. The study used a patient-information sheet to inform patients about the research, how patient data would be handled, and an option to opt-out of including their data in the study.
  • The Nudge Study is a pragmatic clinical trial seeking to improve medication adherence to patients’ already-prescribed cardiovascular medications through a series of theory-based text or voice messages that served as “nudges.” The study mailed patients an opt-out packet that included an introductory letter from the site PI, a FAQ sheet and opt-out form. If they did not opt-out within a month, we would monitor their prescription refills and send a nudge if one went unfilled for more than 7 days.
  • Participants always know some things and agree to some extent. When not getting full regulatory consent, the relevant questions are: What should they know? What should they agree (not object) to?

 

Discussion Themes

– How did the various types of notifications in the ICD-Pieces study impact opt-outs? The patient population and geography across sites was very different. The opt-outs were also very different. It was up to individuals how to deliver or make information about the study available than other sites in the study. It would be difficult for us to say a poster or letter is better.

– Whichever type of notification was used, did you tell people they could opt-out and explain how they could opt-out and give them assurance that opting-out would not impact care? For ICD-Pieces, there was a bullet that stated clearly that patients could opt-out and a phone number to opt-out. There was also a statement that said they would receive the best care from their provider. For NUDGE, there was the initial letter where patients could opt-out by sending a postcard and they could also opt-out in response to the text messages. Opt-outs were different across health systems.

 

Tags

#pctGR, @Collaboratory1

Grand Rounds February 3, 2023: Pragmatic Trials For Children With Congenital Heart Disease – Insights From The NITRIC Trial (Luregn Schlapbach, PhD, FCICM)

Posted on by Elizabeth Mccamic

Speaker

Luregn Schlapbach, PhD, FCICM
Head, Department of Intensive Care and Neonatology
University Children`s Hospital, Zurich
Zurich, Switzerland
The University of Queensland
Brisbane, Australia

 

 

Keywords

Pediatric, Pragmatic Clinical Trial, Congenital Heart Disease

 

Key Points

  • The focus of the NITRIC file was on congenital heart disease, which affects about 1 in 100 newborn children with 25 percent requiring surgery before age 2. One of the main challenges of cardiac surgery, in addition to the technical complexities, is the occurrence of low cardiac output syndrome.
  • The NITRIC Trial was a double blind, multicenter, randomized, parallel-group trial recruiting at 6 pediatric cardiac surgical centers in Australia, New Zealand, and The Netherlands. All infants and children less than 2 years of age undergoing open heart surgery on cardiopulmonary bypass were eligible for the study with exclusions for diseases that implied high severity pre-bypass.
  • The intervention was applied by perfusionists at a steady concentration from the start until the end of bypass. All other surgical staff were blinded. There was no use of nitric oxide (NO) during CPB controls. All patients could receive inhalation NO during/after surgery if considered indicated by the treatment team. There was no change in perioperative care. There was no prescription of pre-surgical, anesthetic, surgical, perfusion, and ICU management procedures.
  • The primary outcome was ventilator-free days (VFD) from start of cardiopulmonary bypass to day 28, with a number of secondary outcomes. The recruitment began in July 2017-April 2022 and 71 percent of approached parents provided consent. 1,371 patients were randomized with 1,364 in the final analysis.
  • The hypothesis was that patients with nitric oxide would recover quicker allowing for more ventilator-free days, but there was no difference between the intervention and standard of care. There was no difference in the secondary outcomes either.
  • There were a number of limitations. This was not a dose finding trial and no nitrosothiol compounds were measured; the perfusionists in the study were not blinded; we allowed open label iNO; the choice of ventilator-free days as a primary endpoint can be criticized.

 

Discussion Themes

– Can we learn the most important lessons from our trials sooner, that a particular intervention is not achieving what was hoped, with the idea that it will provide greater bandwidth of the research enterprise? Of course, you wonder is it justified to spend all of the resources for something that was negative. Our study gave us a unique power to understand what happens after newborn cardiac surgeries. The design of platform trials can build on the lessons learned from this study.

– Why didn’t you start to design the follow-on trial while you were still in the field? COVID-19 absorbed everyone in the middle of the trial. We had to concentrate a lot to even be able to finish the trial, to talk to parents and consent for the study.

Tags

#pctGR, @Collaboratory1

Grand Rounds January 27, 2023: The PREPARE II Trial: Embedding a Pragmatic Trial Into Clinical Care During an Emergency Procedure (Derek W. Russell, MD; Matthew W. Semler, MD, MSc)

Posted on by Elizabeth Mccamic

Speakers

Derek W. Russell, MD
Assistant Professor, Department of Medicine
Co-Director, Program in Medical ICU Research
Division of Pulmonary, Allergy & Critical Care Medicine
Assistant Medical Director, Birmingham Veterans Affairs Medical Center MICU
University of Alabama at Birmingham Heersink School of Medicine

Matthew W. Semler, MD, MSc
Assistant Professor of Medicine and Biomedical Informatics
Medical Director, Center for Learning Healthcare, Vanderbilt Institute for Clinical and Translational Research
Vanderbilt University Medical Center

 

 

Keywords

Pragmatic Clinical Trials

 

Key Points

  • Emergency Tracheal Intubation is a procedure that 2-5 million adults undergo, 75% of patients are comatose or delirious, and 5% of patients are in cardiac arrest. It is an important procedure and is also challenging to research. There are many choices clinicians must make for every emergency tracheal intubation for which the effect on patient outcomes is unknown. This results in arbitrary variation in clinical care.
  • The PrePARE Trial tested the initiation of a 500 mL crystalloid fluid bolus before induction in 9 U.S. ICUs. The outcome was no benefit from fluid bolus before induction at prevention of cardiovascular collapse. There was an interesting consistent pattern of subgroups of patients who were exposed earlier or more intensive positive pressure ventilation modalities, such as non-invasive ventilation, that was applied earlier in the procedure seemed to have better outcomes. This led to the PREPARE II research question: Does an IV fluid bolus prevent severe hypotension during emergency intubation?
  • PREPARE II is a multi-center, parallel-group, randomized trial conducted from February 2019-May 2021 comparing fluid bolus and no fluid bolus among critically ill adults undergoing tracheal intubation with sedation who were receiving positive pressure ventilation between induction and laryngoscopy at 11 academic ICU sites across the U.S. It was conducted with waiver of informed consent.
  • The trial had 1:1 randomization in blocks of 2, 4, & 6, stratified by site. Sites had envelopes with randomized group assignment that were kept with intubation equipment. Inside the envelop was the study group assignment and instructions to be implemented by clinical personnel for either fluid bolus or no fluid bolus.
  • There was a 1-page data collection sheet that trained site-specific observers completed with rapid feedback from research team on data quality. The data collector was not clinically taking care of the patient but familiar with the procedure and trained on data collection. The initial sample size was 750; the final sample size was 1,065.
  • The occurrence of cardiovascular collapse was 18.2% in the no fluid bolus group and the incidents was 21% in the fluid bolus group. This is an absolute risk difference of 2.8%, which is not a statistically significant difference.
  • In clinical care, patients are receiving treatments that are ineffective (or harmful). Without RCTs we cannot know which treatments are helpful and which are not. Emergency research has largely focused on a small number of conditions and neglected many common treatments, such as intubation. Embedding RCT procedures within emergency care can deliver treatments in the manner that they are delivered in clinical care, collecting data on which clinicians and patients base decisions, and it can enroll diverse and representative trial populations.

Learn more

Read more in JAMA: Effect of Fluid Bolus Administration on Cardiovascular Collapse Among Critically Ill Patients Undergoing Tracheal Intubation.

Discussion Themes

– Was there information to the patients so they knew that they were part of the trial? After enrollment, there is an IRB-approved document that includes information on the trial, the investigators, and contact information that patients receive.

– How did you navigate the IRB process? This trial used a mixed approach. Many of the sites used a single IRB but some chose to approve the IRB locally. At Vanderbilt, we did not have any contact internally with the IRB. We had to develop an ethical framework for this for our institution. We provided a lot of data that show treatments are available at all sites and there is already variability by clinicians.

Tags

#pctGR, @Collaboratory1

Grand Rounds January 20, 2023: Collaborative Pragmatic Trials in Action: EVOLVE-MI (Mikhail Kosiborod, MD)

Posted on by Elizabeth Mccamic

Speakers

Mikhail Kosiborod, MD
Vice President of Research
Saint Luke’s Health System
Professor of Medicine
University of Missouri-Kansas City

 

 

Keywords

Pragmatic Clinical Trials

 

Key Points

  • EVOLVE-MI is testing an important clinical hypothesis that aggressive LDL lowering for patients with atherosclerotic cardiovascular disease immediately after an acute coronary syndrome can actually improve patient outcomes. There is little question about the utility of LDL lowering as a means of cardiovascular risk reduction. This study is looking at a particular subpopulation, where there is a lack of outcomes data.
  • EVOLVE-MI is a pragmatic, effectiveness outcome trial of Evolocumab dosed within 10 days of a myocardial infarction (MI). Participants within 10 days of index MI will either receive Evolocumab (140mg Q2W) every two weeks plus routine clinical care or standard of care. The primary endpoint is a composite of total events including first and recurrent MI, ischemic stroke, any arterial revascularization, and death from any cause.
  • This is a collaborative study with Academic-Industry Partnership with oversight by an Academic Executive Committee. EVOLVE-MI has trial innovation through its Academic Research Organizations (AROs), who are also enrolling and understand challenges firsthand.
  • Patient recruitment is through a network of sites in different geographic locations managed by a collaboration of AROs. EVOLVE-MI is enrolling 4,000 patients in 3 countries. Study participants are managed within health systems in-line with local standard of care. EVOLVE-MI has trial design and infrastructure innovations, including automated data collection and leveraging Swedish registries.
  • EVOLVE-MI has several innovations in protocol development, including streamlined inclusion/exclusion criteria, minimal procedures and ability to screen/randomize in the same day, a simplified schedule of events, and streamlined safety.
  • So far EVOLVE-MI’s early experience in the trial has been that nearly every site enrolled a patient within days of activation. The recruitment rate is higher than what you would expect in a normal ACS trial.

 

Discussion Themes

– Is the trial being done under an IND or is it under label? The treatment is on-label because anyone with an acute coronary has at risk cardiovascular disease so technically it is on-label. Can it be done under an IND. In general, what we’ve done in the past for PCTs like this is that they could be done under an IND.

– The randomization unit is at the patient level, and they do sign an informed consent. Patients are approached by the study team at the hospital and receive their initial treatment in the hospital or standard of care with data collection.

– Could you talk a little bit more about hybrid data collection? In a traditional trial you would have study staff identify outcome events and they would enter them in a data capture form. In our study the staff could add the events, but for example in Sweden, where the data has been shown to be better detailed in the national registry, the folks in the Swedish trials is randomized and the follow up data is collected in the national registry.

Tags

#pctGR, @Collaboratory1

Grand Rounds Ethics and Regulatory Series January 13, 2023: Ethical Considerations When Vulnerable Populations are Subjects in Pragmatic Trials (Emily A. Largent, JD, PhD, RN)

Posted on by Elizabeth Mccamic

Speakers

Emily A. Largent, JD, PhD, RN
Emanuel & Robert Hart Assistant Professor of Medical Ethics and Health Policy
Department of Medical Ethics and Health Policy
University of Pennsylvania Perelman School of Medicine

 

 

Keywords

Ethics, Vulnerable Populations

 

Key Points

  • Vulnerability guidelines and regulations often refer to groups such as pregnant people, children, and prisoners. But this might obscure heterogeneity within groups, intersecting sources of vulnerability, and other vulnerable participants, such as people with dementia.
  • One definition of vulnerability is “an identifiably increased likelihood of incurring additional or greater wrongs,” as a result of research participation. We need to ask how might researchers wrong participants, and one way to think about this is how might researchers fail to discharge duties to them?
  • The Belmont Report lays out three principals of duties researchers have: respect for persons, beneficence, and justice. What is entailed by each of these duties? Respect for persons involves seeking voluntary informed consent or, if participants lack capacity, seek permission from a surrogate, and respect privacy. Beneficence involves minimizing risks, and ensuring they stand in reasonable relation to potential benefits. Justice involves ensuring the burdens and benefits of research are fairly distributed.
  • In a review of studies, researchers identified the ways participants in a particular study might be wronged and identified corresponding protections, such as conducting a capacity assessment if we are worried about participants having an inadequate understanding in informed consent. Going through this process helps researchers see where vulnerabilities might arise and how to address them.
  • The issue of informed consent comes up often with vulnerable populations that have dementia. Researchers seeking to enroll people living with dementia need a plan for assessing participants’ capacity to consent to research participation. When prospective participants lack capacity, researchers should identify a surrogate to give permission for enrollment and still find ways of involving the person with diminished capacity in research-related decision-making. Caregivers may also need to be enrolled and give their own consent as they may be more involved as the participant’s cognitive impairment worsens.
  • Many pragmatic clinical trials are conducted with waivers of informed consent, but when vulnerable populations are subjects in research, there may still be additional important considerations, such as outreach, identifying caregivers through the medical record, and being certain a diagnosis of dimension has already been disclosed to the patient.
  • It is ethically acceptable and imperative to enroll vulnerable subjects in research, but when they are enrolled it is important that we think about their vulnerability in systematic ways so that we know not only what they are vulnerable to but how we can protect them. Issues of consent and considerations for waivers of consent are particularly important for this population.

Learn more

Ethical Challenges in Conducting Research Using a Waiver of Informed Consent with People Living with Dementia.

Discussion Themes

- You noted that the criteria of waivers and alterations gets left out. How do you think about the fact that people are uncomfortable with waivers and that notification may turn people off? Any time we are not notifying because we might upset people is a sign we need to think more carefully how we are going to approach it. When you use a waiver, you need to go in and explain why a waiver is being used and why there was no meaningful way to opt out. Hopefully you can share what has been learned.

- Sometimes consenting in a “good moment” feels stressful because they may forget that they consented. You need to have a plan in place for assessing capacity and ability to consent. Take time to check in with the participant and caregiver to make sure they are on board and assess their continued willingness to participate.

-What if a patient has capacity to consent but their surrogate disagrees? That’s difficult. Take the individual’s consent as word; however, if they are dependent on the surrogate for transportation, etc., it can be a barrier.

Tags

#pctGR, @Collaboratory1

Grand Rounds January 6, 2023: Outpatient Treatment of COVID-19 With Metformin, Ivermectin, or Fluvoxamine: 10-Month Follow-up and Effects on Developing Long COVID (Carolyn Bramante, MD, MPH; Thomas Murray, PhD)

Posted on by terren.green@duke.edu

Speakers

Carolyn Bramante, MD, MPH
Division of General Internal Medicine
Departments of Internal Medicine and Pediatrics
Core faculty in the Program in Health Disparities Research and the Center for Pediatric Obesity Medicine
University of Minnesota Medical School

Thomas Murray, PhD
Division of Biostatistics
Coordinating Centers for Biometric Research
University of Minnesota School of Public Health

 

 

Keywords

COVID-19; Long COVID; COVID-OUT; Metformin; Ivermectin; Fluvoxamine

 

Key Points

  • The COVID-OUT Trial was a multi-arm remotely delivered, de-centralized Phase III clinical trial conducted at 6 institutions including 1431 patients with overweight or obesity, designed to test distinct treatment of COVID-19 with Metformin, Fluvoxamine, and Ivermectin. Arms of the trial included 6 groups: (1) metformin and fluvoxamine, (2) metformin and ivermectin, (3) metformin and placebo, (4) placebo and fluvoxamine, (5) placebo and ivermectin, (6) placebo and placebo.
  • The primary outcome was a binary, 4-part composite outcome of occurrence of severe COVID-19, defined as hypoxia, emergency department visit, hospitalization, or death. Patients were followed for 10 months after enrollment.
  • Long COVID was determined by patient-report of clinician-diagnosed Long COVID.
  • Data on Metformin plus placebo show an absolute risk reduction of 4.4% for Long COVID diagnosis at 300 days. There was a consistent direction of effect of Metformin across subgroups and no evidence of heterogeneity of treatment effect.
  • Diabetes may be a risk factor for severe COVID-19. New observational and preclinical data from patients with prediabetes and PCOS suggest there may be a dose dependent effect of metformin against SARS-CoV-2.
  • Metformin is safe, well tolerated, and familiar to providers.
  • Some limitations of the study include lack of diversity in patient population, methods of ascertainment of Long COVID that may under- or over-ascertain Long COVID, internal validity of oxygen data, and self-report of medication adherence.
  • Only 3.8% of people in the study who said they had Long COVID received treatment for Long COVID. The COVID-OUT trial data don’t suggest that Metformin will treat Long COVID in someone who already has Long COVID, but there are mechanisms that suggest it may be worth investigating.

 

Discussion Themes

– We did internally look at an unadjusted comparison of vaccinated vs unvaccinated participants, but this comparison is confounded and not the focus of this work. In the future we will do a full observational analysis predicting Long COVID using these subgroups..

– Earlier treatment versus later treatment with Metformin seems to benefit patients..

– There may be other medications in the space of diabetes that may have anti-inflammatory mechanisms that could be relevant to COVID-19 treatment. GLP-1 receptor agonists may have anti-inflammatory and immune modulatory effects. Also, DPP-4 inhibitors also have some beneficial anti-inflammatory effects. These medications are more expensive and may have a more difficult method of delivery, but could be studied to determine their effect on COVID-19.

 

LEARN MORE

Learn more about the COVID-Out trial.

Read the COVID-OUT trial results paper.

 

Tags

#pctGR, @Collaboratory1

Grand Rounds December 16, 2022: The Use of EHR-Agnostic Clinical Decision Support to Prevent Thromboembolism in Hospitalized Medically Ill Patients (Alex C. Spyropoulos, MD, FACP, FCCP, FRCPC; Jeffrey Solomon, BFA)

Posted on by Elizabeth Mccamic

Speakers

Alex C. Spyropoulos, MD, FACP, FCCP, FRCPC
Professor of Medicine – The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
Professor – Institute of Health System Science – The Feinstein Institutes for Medical Research
System Director – Anticoagulation and Clinical Thrombosis Services
Northwell Health at Lenox Hill Hospital

Jeffrey Solomon, BFA
Senior Director, Usability Lab
Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY

 

 

Keywords

Pragmatic Clinical Trials, Cluster Randomized Trial, EHR solutions

 

Key Points

  • The majority of hospital-acquired Venous Thromboembolism (VTE) occurs in non-surgical medical inpatients, but Thromboprophylaxis for medically ill patients during and after hospital stays is underutilized. Electronic alerts incorporating VTE risk models could increase appropriate use of Thromboprophylaxis and reduce symptoms of VTE.
  • The study team’s health informatics group developed a novel clinical decision support (CDS) tool, called IMPROVE-DD VTE CDS, which can be integrated into different electronic health record (EHR) systems. The effectiveness of the intervention was then evaluated through a cluster randomized trial at four academic tertiary hospitals from December 21, 2020 to January 21, 2022.
  • This trial tested the hypothesis that the use of a platform-agnostic, EHR-embedded VTE risk model with integrated CDS would 1) increase rates of appropriate Thromboprophylaxis, and subsequently 2) reduce thromboembolism, compared to usual medical care in hospitalized, medically-ill patients.
  • The study team developed the tool using high-quality evidence from randomized trials related to risk factors for subpopulations and guideline recommendations. The solution’s interface was developed using workflow analysis, multiple iterations of the tool and usability testing.
  • The trial is the first to show that a universal EHR-integrated CDS tool using a validated VTE risk model (IMPROVE-DD) had a high adoption rate (77%), significantly increased rates of in-hospital appropriate Thromboprophylaxis and significantly reduced major Thromboembolic events without an increase in major bleeding at 30 days post-discharge compared to usual medical care. Thirty-day mortality was higher in the intervention hospital group.
  • The study team spoke about the tension that often exists between solutions that are tightly integrated into a specific EHR and the ability to disseminate them widely. Developers worked to find the “sweet spot” in a solution that balanced the two priorities. The tool’s success is attributed to workflow analysis, rapid prototyping, usability testing and its integration with the EHR.
  • The high baseline rate of appropriate in-hospital and at-discharge Thromboprophylaxis in the academic control hospitals suggests that the solution has an even greater potential for positive impact at non-academic or rural hospital settings.

 

Discussion Themes

– How was usability tested and how does the tool fit into a clinician’s daily routine? With every iteration of testing, the team worked to identify barriers in provider workflow. The number of testing rounds, as well as the quality of usability testing, was critical in understanding workflows and the best moment to launch the tool. The team also engaged with a diverse array of providers from multiple hospitals and specialties. It was important to observe behaviors in real time and be open to making changes at multiple points during the design and testing process.

– How did you derive and evaluate the evidence that was used in the IMPROVE-DD VTE CDS tool? The team derived the evidence based on a multivariate analysis from an international prospective registry. The team also conducted multiple external validation projects using the same weights and scores. In doing this, they were able to replicate the data among different populations.

– How can tools like this contribute to clinical decisions based on data for subgroups instead of broader guidelines? The study team is hopeful that this effort and others like it will promote clinical decisions that are based on evidence for patient subgroups. Clinical recommendations should be based on more specific data, as there are public health implications for guideline statements that are too broad.

-What is the explanation for the excess deaths at 30 days in the intervention group? The trial was designed before the COVID-19 pandemic, but it was conducted during the height of the pandemic in New York. Because of rebalancing of physicians, there were more COVID-19 patients in the intervention group. Researchers considered this an epiphenomenon that likely reflects the imbalance of the COVID-19 patients in the intervention group. More analysis is needed to confirm that hypothesis

Tags

#pctGR, @Collaboratory1

Grand Rounds Ethics and Regulatory Series December 9, 2022: The Stepped Wedge Cluster Randomized Trial: Friend or Foe? (Monica Taljaard, PhD; David Magnus, PhD)

Posted on by Elizabeth Mccamic

Speakers

Monica Taljaard, PhD
Senior Scientist, Clinical Epidemiology Program
Ottawa Hospital Research Institute
Full Professor, Epidemiology and Community Medicine
University of Ottawa

David Magnus, PhD
Thomas A. Raffin Professor of Medicine and Biomedical Ethics and Professor of Pediatrics, Medicine, and by courtesy of Bioengineering
Director, Stanford Center for Biomedical Ethics
Associate Dean for Research

 

 

Keywords

Ethics, Stepped Wedge Cluster Randomized Trial, Study Design

 

Key Points

  • There are two main types of clinical trials: patient randomized trial and cluster randomized trial (CRT). The patient randomized trial is always preferable; cluster randomized trials should only be used when there is no other choice because CRTs will always require a larger sample size, have higher risks of bias, be more vulnerable to chance imbalance between arms, and are more complicated to design and analyze.
  • There are several good reasons to adopt a cluster randomization trial, including that the intervention is a cluster-level intervention or the research question of interest pertains to cluster-level effects.
  • If a cluster randomized trial is justified there are different types of CRT designs, the parallel arm CRT, parallel arm before and after CRT, cluster cross-over, and stepped wedge. Investigators should provide a justification for choice of stepped wedge CRT.
  • Five methodological arguments for stepped wedge CRTs are to improve rigor, to facilitate recruitment, to reduce the required sample size, to simplify logistics, and to reduce bias; however, most methodological arguments in favor of stepped wedge trials have a counter argument. Trialists should work with a biostatistician to come up with the most scientifically robust design given the practical constraints of the study. In most cases, a parallel arm or cluster cross would be a better choice.
  • In a study of more than 100 stepped wedge cluster randomized trials, the most common reason for the design was to be able to make the intervention available to all clusters by the end of the trial based on ethical or equity grounds rather than anything methodological.
  • During the Ebola crisis, the ethical argument for stepped wedge CRTs was that anything involving a placebo in the control arm was automatically considered unethical if the intervention arm holds a chance of benefit. This led to a shift to stepped wedge design trials, but in Ebola there was no evidence that benefits outweighed the harms of proposed therapeutics and vaccines and there was confusion that all participants get the intervention in a stepped wedge CRT, where each cluster may get the intervention but all participants may not get the intervention, depending on the design.
  • Arguments in favor often confuse individual belief in the benefit of intervention with equipoise (which requires consensus in the field that the intervention is of benefit). If truly not in equipoise, delay in providing the intervention is no more justified than the placebo. True protection is clinical equipoise and it is neutral between stepped wedge CRT and parallel research designs.

 

Discussion Themes

– Should we be allowing stepped wedge trials in the Collaboratory? As a statistician, I agree but it’s important to do the extra work and look at alternative designs. If stepped wedge design is the best option, you have to ensure that the analysis is robust and sound and that there is not recruitment bias. The policy level point is well taken; saying that they are prohibited might be too strong, but you do need a justification or rationale for stepped wedge design, especially over parallel.

– Could stepped wedge be a good design for implementation trials? It’s still important to look at how effective it is and is the juice worth the squeeze in this context? You should use the best statistical methods to answer the question you are trying to answer.

Tags

#pctGR, @Collaboratory1

Grand Rounds December 2, 2022: A Randomized Controlled Trial of Mobile Health Intervention in Heart Failure and Diabetes: Lessons Learned (G. Michael Felker, MD, MHS)

Posted on by Elizabeth Mccamic

Speakers

Michael Felker, MD, MHS
Professor of Medicine
Director, Cardiovascular and Metabolism Research, DCRI

 

 

Keywords

Pragmatic Clinical Trials, Heart Failure, Diabetes

 

Key Points

  • Making lifestyle changes is difficult especially for people living with chronic diseases, where healthy behaviors could make a big difference. Medication adherence can be a barrier to effectiveness. This study asks how can we better facilitate health behaviors in patients with chronic diseases and can we leverage technology?
  • The TARGET-HF-DM is a pragmatic multicenter randomized controlled trial held at 6 sites in the U.S. that focused on patients with heart failure and diabetes, two rapidly growing conditions that are highly morbid. The focus of the study was on physical activity and medication adherence. The primary endpoint was change in mean daily step counts from baseline to 3 months. Secondary endpoints were change in medication adherence, change in HRQOL, change in NT-proBNP, and change in hemoglobin A1C from baseline to 3 months. There were two exploratory endpoints: change in mean daily step counts from baseline to 6 months and change in metabolomic profiling from baseline to 3 months.
  • The trial enrolled 187 patients, with 35% women, 47% African American, 10% Hispanic, age 59 years. Enrollment halted before planned sample size of 200 due to COVID-19. There was 1:1 randomization of participants to either the mHealth intervention or usual care.
  • Both groups received a step counter and weekly text reminder to wear it. In the intervention group patients received 3 text messages weekly that were personalized encouraging them to be more active based on the past week’s activity. After 3 months of active intervention, there was an additional 3 months of data collection.
  • In patients with both heart failure and diabetes, the 3-month mHealth intervention significantly improved daily volitional physical activity as measured by step counts; health related quality of life as measured by KCCQ, and metabolomic profiles of peripheral blood. Adherence to medical therapy was not measurably different between the arms.
  • This trial turned out to be more challenging than anticipated. Lifestyle intervention trials have unique challenges, such as compliance/engagement challenges that lead to varying “dose” of intervention; unequal ascertainment of outcomes – patients in control group may be less engaged and more likely to discontinue follow up; intervention may interact with human behavior in complex ways; lack of blinding leads to strong “placebo” effects, and challenges of using a commercial step counter, which relied on people’s phones and thus software updates, etc.
  • For the step-down RCT, patient recruitment started in August 2019 with 587 patients consenting and 552 included in the primary analysis. The median time to liberation in the HFNC group was 50 hours and the CPAP group was 43 hours. HFNC was not noninferior to CPAP following extubation.

 

Discussion Themes

– Did the mHealth group receive text messages on pill adherence? Can you talk about the compensation of participants? Patients did not get text messages about pill adherence. Compensation was modest and the same regardless of which group you were in.

– Were there specific approaches that you used to recruit under-represented populations? A huge part is where your sites are located. One of our leading sites was in Brooklyn, NY, and the patients there were largely African American and Hispanic. As we are thinking about trials in general we should be thinking about where the trial sites will be and who are the leaders and teams.

–Was it easier or harder than expected to recruit participants? It was harder than we expected. It’s almost always harder in my experience. It was a labor of love; the site payment was low; we asked friends to be sites in the trial. Sites have a lot of trials that are competing. One pays more than another. We did what we could to make the entry criteria as easy as possible.

Tags

#pctGR, @Collaboratory1

Grand Rounds November 18, 2022: The FIRST-ABC Pragmatic Trials of Non-Invasive Respiratory Support In Children (Padmanabhan Ramnarayan, MBBS, MD, FRCPCH, FFICM)

Posted on by Elizabeth Mccamic

Speakers

Padmanabhan Ramnarayan, MBBS, MD, FRCPCH, FFICM
Reader in Pediatric Critical Care
Imperial College London

 

 

Keywords

Pragmatic Clinical Trials

 

Key Points

  • Sick children, when they are acutely ill, start with standard oxygen therapy, which escalates to noninvasive respiratory support (CPAP/BIPAP or high flow nasal cannula) before invasive ventilation support in the ICU. The difficulty with pediatric respiratory support is that the step-up and step-down of respiratory care is very evidence poor even though these therapies are used commonly.
  • In 2016, we published a pilot trial looking at high-flow nasal cannula (HFNC) therapy compared to CPAP in pediatric critical care. What we found from the pilot RCT, was that there were two distinct populations, step-up (i.e., acutely ill patients) and step-down, which is the extubation or post-extubation part of the care pathway.
  • The trial team established that it was feasible to randomize around 50% of patients and assessed the acceptability of deferred consent or retrospective consent, which was justified because the therapy often happens under emergency situations during a time of high stress for parents. The team was also able to generate some pilot data on outcomes such as reintubation rate and length of respiratory support to try and understand how we could take this forward in a trial.
  • The trial team decided to create a master protocol, FIRST-line support for Assistance in Breathing in Children (FIRST-ABC), to compare HFNC with CPAP and package up both the acute illness (Step-up pragmatic RCT) and the post-extubation (Step-down pragmatic RCT) patients into this protocol to have two independently powered trials that shared the infrastructure and the cost effectiveness analysis.
  • The FIRST-ABC trial adopted a pragmatic design with a heterogenous patient cohort where the indication to start NRS was based on physiological criteria, which allowed the results to be applicable to all situations where HFNC is started. There were pragmatic inclusion criteria of being admitted to PICU/HDU, age 36 weeks and older and less than 16 years, and assessed by the treating clinician to require noninvasive respiratory support either for an acute illness or within 72 hours of extubation following a period of invasive ventilation.
  • The primary outcome for was the time to liberation from respiratory support defined as the start of a 48-hour period during which the child was free of all forms of respiratory support (excluding supplement oxygen). The step-up trial started recruitment in August 2019, 1,449 children were eligible, 600 children were randomized, and 595 consented. The primary analysis showed that HFNC was noninferior to CPAP in acutely ill children in critical care. The median time to liberation was 53 hours for the HFNC group and 48 hours for the CPAP group.
  • For the step-down RCT, patient recruitment started in August 2019 with 587 patients consenting and 552 included in the primary analysis. The median time to liberation in the HFNC group was 50 hours and the CPAP group was 43 hours. HFNC was not noninferior to CPAP following extubation.

Learn more

Read more about the study in JAMA.

Discussion Themes

– Did you find there are clusters of clinicians that consistently found that they were unwilling to randomize someone? We had monthly teleconferences – some clinicians were not fussed about it. We did not see specific site patterns, but we did see some cohort patterns.

– What challenges did you face due to COVID-19? Many other trials in the country were behind and everyone else had to stop. We were fortunate that when the lockdowns were lifted everyone came back into action to complete recruitment during the time scheduled.

Tags

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