Grand Rounds Archive

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

#pctGR, @Collaboratory1

Grand Rounds Ethics and Regulatory Series November 11, 2022: Data Sharing and Pragmatic Clinical Trials: Law & Ethics Amidst a Changing Policy Landscape (Stephanie Morain, PhD, MPH; Kayte Spector-Bagdady, JD, MBioethics)

Posted on by Elizabeth Mccamic

Speakers

Stephanie Morain, PhD, MPH
Assistant Professor
Berman Institute of Bioethics & Johns Hopkins Bloomberg School of Public Health

Kayte Spector-Bagdady, JD, MBioethics
Associate Director, Center for Bioethics & Social Sciences in Medicine
Assistant Professor of Obstetrics & Gynecology
University of Michigan Medical School

 

 

Keywords

Ethics, Data Sharing, Pragmatic Clinical Trials

 

Key Points

  • As one of the federal departments and agencies with the largest research and development budget, the NIH came out with one of the first federal data sharing policies in 2003 called the NIH Data Sharing Policy and Implementation Guidance.
  • The guidance has been updated over the years, and in 2020 NIH came out with the final iteration that goes into effect in January 2023 that applies to any research funded in whole or in part by NIH to maximize data sharing through the informed consent process. Additionally, in August 2022, the latest federal data-sharing memorandum, Ensuring Free, Immediate, and Equitable Access to Federally Funded Research Memorandum (2022 OSTP Memo), was released requiring articles resulting from federal funding be made “freely available and publicly accessible” without embargo or delay.
  • When you apply these rules to pragmatic clinical trials (PCTs), there are ethical challenges because PCTs often use waivers or alterations of informed consent and are embedded into ongoing clinical care using extant data.
  • Traditionally data sharing is presented as honoring the preferences of trial participants with a heavy emphasis on the role of informed consent to fulfill the ethical obligation to respect those whose data are shared. But if PCTs use a waiver/alteration of consent, the trial cannot assume sharing data is consistent with preferences of patient-subjects and cannot rely on informed consent to fulfill the ethical obligation of respect.
  • For PCTs, data volume is potentially larger, data may be “about” those beyond patient-subjects (i.e. clinicians, health systems), data may have been collective for administrative/clinical purposes, data may be more representative of “real world” conditions, and data may be controlled by a third party (e.g. CMS).
  • For investigators and health systems, there are substantial risks and burdens of data sharing with unclear benefits. There are substantial logistical burdens in preparing data for sharing, meaningful risks of reidentification, and concern for biased or misleading analyses, with little demonstrated demand for PCT data and relatively low social value from PCT data reuse.
  • Two takeaways: 1. Look beyond informed consent processes to fulfill obligations of respect when sharing individual level data from PCTs. 2. If public demand for greater data sharing is to be driven by awareness of its benefits, then PCTs need to do a better job measuring and communicating about the benefits.

Discussion Themes

-Can you better define data sharing, is it the publication? Data sharing has been in the context of the patient-level deidentified data from these studies. The government has made an interesting transition to focusing on sharing data that are generated in research for secondary analyses but then shifted to wanting access to data from the primary analysis.

–How can we include diverse communities in this discussion especially in terms of trust? The context of PCT data sharing support arguments made elsewhere for engaging individuals who are going to be enrolled in these studies. We need to look beyond informed consent when we look at ways we respect individuals and make sure we have an understanding of their values and preferences for the study itself and how data is shared downstream. There could be broader engagement of stakeholders in these communities, better transparency, and creative ways to demonstrate respect outside of informed consent.

Tags

#pctGR, @Collaboratory1

Grand Rounds November 4, 2022: The CardioNerds Clinical Trials Network: Pairing Equitable Enrollment with Trainee Development (Amit Goyal, MD, MAS)

Posted on by Elizabeth Mccamic

Speakers

Amit Goyal, MD, MAS
Interventional/Structural Fellow, Cleveland Clinic
Cofounder of CardioNerds

 

 

Keywords

Clinical Trial, Medical Education

 

Key Points

  • The goal of the CardioNerds Clinical Trials Network is to pair equitable enrollment with trainee development. CardioNerds started as an educational podcast, which in the first month had 5,000 downloads and now has had more than 3 million downloads in 192 countries. The success of the podcast shows the need and value for asynchronous training.
  • The mission and the people involved with CardioNerds are the key ingredients for its success. The mission is to democratize cardiovascular education by creating and disseminating education, fostering wellness and humanism, promoting diversity, equity and inclusion, providing mentorship and sponsorship, and invigorating a love of cardiovascular science.
  • The biggest inflection point for CardioNerds was COVID-era recruitment, when residents were asked to decide where to train for fellowship without having in-person visits. CardioNerds collaborated with ACA to invite every fellowship to share case-based learning and the training opportunities of their program. They also included a message from the fellowship program director or leadership. Forty-four programs participated.
  • CardioNerds identified a need to develop a pilot clinical trials network for the PARAGLIDE-HF trial, a multicenter, randomized, double-blind, double-dummy, parallel group, active controlled study to evaluate the effect of sacubitril/valsartan verses valsartan on changes in NT-proBNP, safety, and tolerability in HFpEF patients with a WHF event who have been stabilized and initiated at the time of or within 30 days post-decompensation.
  • Like many trials during the COVID-19 pandemic, there were significant challenges and recruitment delays. To address these challenges, we decided to work with the CardioNerds network with a goal of pairing trial enrollment with trainee professional development. Among trial sites with affiliated programs, we invited program directors to nominate fellows to participate. We engaged fellows by making them part of the research team, ensured mentorship, networking, etc. We built the first trainee-based CardioNerds Clinical Trials Network that enhanced recruitment and education.
  • The network ended up with 20 sites and 22 trialists. The fellows were responsible for 45% of enrollment during the time of the trial. The CardioNerds fellows enrolled 54% women compared to 45% non-fellow enrolled and 71% BIPOC compared to 23% non-fellow enrolled patients. The network also built a community of fellows who took great pride in the work they were doing. For every of the 70+ recruitments an email went out celebrating the work of the fellows and site mentors, which reinvigorated interest and enthusiasm among the site PIs, who had the opportunity to mentor the next generation of trialists.
  • In the future, we would like to study this in greater detail and find out what happened at CardioNerd sites compared to other sites. We would like to do a qualitative study for everyone involved and understand the career impact for the fellows.

Learn more

Visit the CardioNerds website.

Discussion Themes

-What did this activity displace in a busy cardiology fellow’s day? What we tried to emphasis was engaging cardiovascular fellows in year 2 or 3 when there are less clinical responsibilities and more elective time. There are a lot of ways to use the available time. The emphasis was identifying fellows who are interested in developing careers in clinical science. We did not want the fellows to take the place of the site coordinators but to use their experience taking care of the patient. It was matched to their career goals, and it fit into the rubric of what they are already doing, caring for patients and being involved in education.

-Why do you think fellows were more successful in enrolling women and BIPOC? There can be a general level of mistrust. If a patient is approached by a fellow, the perspective of the fellow is to prioritize patient care, so there is a built-in level of trust that may come with that and is something we want to explore more. We asked site PIs to prioritize nominating fellows who were women and URMs. A lot of this was also related to the sites that were involved.

Tags

#pctGR, @Collaboratory1

Grand Rounds October 28, 2022: The HERO (Healthcare Worker Exposure Response & Outcomes) Program: An Online Community to Support Observational Studies, Randomized Trials, and Long-Term Safety Surveillance (Emily O’Brien, PhD, FAHA; Russell Rothman, MD, MPP)

Posted on by terren.green@duke.edu

Speakers

Emily O’Brien, PhD, FAHA
Associate Professor
Duke Clinical Research Institute
Duke University School of Medicine
Department of Population Health Sciences

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

 

 

Keywords

HERO Registry; HERO TOGETHER; Hydroxychloroquine; COVID-19; PCORI; PCORnet

 

Key Points

  • On March 21, 2020, in response to the COVID-19 pandemic, PCORI contacted leadership at Duke Clinical Research Institute and PCORnet and a decision was made to focus on the space of healthcare workers. The HERO Program was fully approved and began recruiting participants on April 22, 2020.
  • The HERO Registry aimed to create a diverse virtual community of healthcare workers and their families and communities, ready for future COVID-19 research.
  • The HERO Registry explored topics that mattered most to participants and found these topics changed with time. Important issues early on included COVID-19’s effects on the workplace, vaccine access and willingness, and impact on home life. Later, burnout and lack of appreciation and support became larger issues.
  • The first trial undertaken by the HERO Program, HERO-HCQ, evaluated the efficacy of hydroxychloroquine (HCQ) to prevent COVID-19 in healthcare workers. Over 1300 participants were recruited from the HERO Registry. No statistically significant benefit was found.
  • The HERO TOGETHER study leveraged the HERO Registry to estimate real-world incidence of safety events among vaccinated individuals. The most common safety events reported included non-hospitalized arthritis/arthralgia and non-hospitalized non-anaphylactic allergic reaction.

Learn more

On the HERO Program website.

Discussion Themes

– The HERO Registry survey collected a large broad range of information. Participant feedback revealed that shorter more targeted surveys focusing on the most high-value information may have been less burdensome for participants..

– The creative multi-faceted approach to recruitment that includes diverse stakeholder engagement could be successful in creating research registries for other important health issues. .

Tags

#pctGR, @Collaboratory1

Grand Rounds October 21, 2022: Disinformation, Cyberthreat, and Choice: Protecting Patients and Clinical Research From the Digital Triple Threat (Eric Perakslis, PhD; Andrea Downing)

Posted on by Elizabeth Mccamic

Speakers

Eric Perakslis, PhD
Chief Science & Digital Officer
Duke Clinical Research Institute
Professor, Department of Population Health Sciences
Chief Research Technology Strategist
Duke University School of Medicine 

Andrea Downing
ePatient and Security Researcher
Co-Founder – The Light Collective

 

 

Keywords

Data Security, Disinformation, Cyberthreat

 

Key Points

  • Health care and the internet are intertwined. Patients use the internet to search for answers, and researchers use the internet to search for new solutions. The questions are how are you going to play online and how are you going to conduct your research in a way that is most effective and will keep everyone safe? Researchers need to overcome the risks of online tools and increase the benefits.
  • Perakslis said his definition of digital health is any time you mix medical information and the internet. There are 5 forces that drive the internet, including surveillance capitalism, attention economy, connectivity, social networks, and personification.
  • Case study: The U.K. coroner in the case of Molly Russell, a teenager who committed suicide, determined that she was suffering from a depressive condition, and, based on the sites she was visiting, the algorithms were feeding her very negative images without her request. Should social media for teenagers be regulated like a digital therapeutic, given how addictive they are and the behavior modification.
  • The Light Collective is an organization that represents collective rights, interests, and voices of patient communities in healthcare technology. It was started when Andrea discovered a vulnerability in Facebook’s group platform that allowed data to be scraped outside of the group. There should be no aggregation without representation.
  • Patients often turn to social media to find support and knowledge from peers due to the network effects of the platforms. The problem is patients can’t predict benefit or harm based on how their data is used.
  • In a recent paper, Health advertising on Facebook: Privacy and Policy Considerations, patients download their raw data, and found who was tracking them across the internet. Three out of 5 companies included in the study were not adhering to their privacy policies. The manuscript was shared with a news organization called The Markup, and they looked at the Meta Pixel installed by various hospital systems and found 30 out of the top 100 hospitals were using custom fields to share information with Facebook, which constitutes a data breech
  • There are doable ways to increase cybersecurity in health care. Researchers can be thoughtful about devices used in studies and how to keep patient information safe. Having a tech person on the study design team to advise on which devices are secure will allow as many people as possible to participate.

Learn more

Beyond privacy: A deeper understanding of the internet is required to protect digital trial participants

Health advertising on Facebook: Privacy and policy considerations

Discussion Themes

-What is the path forward? We need a new skill set or team member who studies cyber interaction, who can make sure your trial is safe. You need to involve them from the design phase. They can ask questions like who should I use for my digital campaign? Are you building the right tool? One of the things we are doing with the Light Collective is community members can shine a light on potential issues early on but we need a formalized path, training, a new role in research and clinical trials.

-How can we do research in states that are restricting access to reproductive health and keep patients safe? If we eliminate all the states where reproductive rights data could be harmful, is that going to impact site selection? We don’t want to create a disparity like that and have these women lose access to research. We need to think about how we are consenting and securing the data, and have a thoughtful approach to how we consent in these states. How do we maintain research access when health care access is limited in some of these states.

Tags

#pctGR, @Collaboratory1

Grand Rounds Ethics and Regulatory Series October 14, 2022: Responding (or Not) to Signals of Potential Clinical Significance in Pragmatic Clinical Trials (Joseph Ali, JD; Tanya Matthews, PhD; Leslie J. Crofford, MD)

Posted on by Elizabeth Mccamic

Speakers

Joseph Ali, JD
Assistant Professor, Dept. of International Health
Johns Hopkins Bloomberg School of Public Health
Core Faculty & Associate Director for Global Programs
Johns Hopkins Berman Institute of Bioethics

Tanya Matthews, PhD
HRPP Director
Kaiser Permanente Washington

Leslie J. Crofford, MD
Wilson Family Chair in Medicine
Professor of Medicine and Pathology, Microbiology & Immunology
Chief, Division of Rheumatology
Vanderbilt University Medical Center

 

 

Keywords

Ethics, IRB, FM-TIPS

 

Key Points

  • Trials are getting larger and collecting greater volumes of clinical data than ever before, often as part of Common Data Elements (CDEs). These data increasingly include info that might signal physical, mental health or behavioral health risks to patient-subjects (e.g. substance use, depression, anxiety, suicidality). This raises a lot of questions: Whose responsibility is it to monitor those risk factors? What should be monitored and how? Who can and should act/respond? What do patients and other stakeholders desire?
  • There are additional complexities with pragmatic clinical trials (PCTs), including overlapping roles and responsibilities of clinical and research staff; collection of broad sets of CDEs can make data monitoring more challenging; various and combined methods for data collection (e.g. extraction from health records and/or have treating clinicians or patients complete measures); and trials may operate under waivers of consent. There is a possible for risk-signaling data to “slip between the cracks.”
  • When trials collect risk-signaling data related to study outcomes, researchers and other stakeholders should understand and align stakeholder expectations; consider characteristics of the trial and study population to inform response; define triggers, thresholds, and responsibilities for action; identify appropriate response mechanisms and capabilities; integrate responses with clinical practices and systems; and address privacy demands. No single factor is more important than another.
  • Case Study: The Fibromyalgia Tens In Physical Therapy (FM-TIPS) trial was designed to demonstrate the feasibility of adding TENS to treatment of patients with FM in a real-world PT practice setting and determine if addition of TENS to standard PT for FM reduces pain, increases adherence to PT and allows patients with FM to reach their specific functional goals with less drug use.
  • FM-TIPS prospectively defined possible ethical concerns for the trial including concerns around mental health and substance use disorders, that led the study team to add language to the consent document about unexpected findings and the team decided to conduct monthly monitoring of data to identify any signals but to otherwise rely on clinicians to manage issues as is standard in PT practice.
  • Due to the low referral rates of fibromyalgia patents to PT (~30%), FM-TIPS had an emergent ethic issue related to patient recruitment and whether the study team could include the American College of Rheumatology criteria to screening to increase eligibility. In the end, the study team determined that making a new diagnosis unknown to the participant was beyond the scope of a PCT in a PT setting.

Learn more about FM-TIPS.

Discussion Themes

-Does it matter if the trial is being done at an integrated delivery system and a more traditional? There is a different level of decision making between the two cases Leslie described in the FM-TIPs trial. Setting is king when you are making some of these decisions; some settings are more academic and are used to these trials. Others are not used to doing trials. The setting really does matter, and it is a different way of thinking about the research enterprise.

–Actionable to whom by whom is a good question. Another way to think about this topic is when should or should not a trial take on a clinical role? In the FM-TIPS example, there was one case where the data collected by the trial team would also be collected by the clinical team. The timeliness of the response is also important; if the trial is monitoring something they need to be able to respond timely. In the second example, they were not able to. The context of the trial matters a lot in addition to actionability.

Tags

#pctGR, @Collaboratory1

Grand Rounds October 7, 2022: Impact Of Handovers Of Anesthesia Care On Morbidity And Mortality (Melanie Meersch-Dini, MD)

Posted on by Elizabeth Mccamic

Speakers

Melanie Meersch-Dini, MD
Professor
Department of Anesthesiology, Intensive Care and Pain Medicine
University Hospital Münster, Germany

 

 

Keywords

HandiCAP Trial, Pragmatic Clinical Trial

 

Key Points

  • There is an increasing frequency of surgical procedures and the need for anesthesia care, and the number of care transitions is increasing. The HandiCAP trial asked the question do intraoperative handovers of anesthesia care have an impact on patient outcomes?
  • The trial included adults 18 and older, ASA physical status III or IV, who had a major inpatient surgery with an anticipated duration of 2 hours or longer. Patients were registered and randomized centrally in a 1:1 ratio to receive either a handover of anesthesia care or no handover.
  • In Germany, there are two levels of anesthesia, in-room anesthesiologists who are either trainees or a medical specialist (non-management). Then there is an attending anesthesiologist who is a supervisor responsible for 3-4 ORs.
  • The primary endpoint was a composite of all-cause of death, readmission to hospital or major postoperative complications within 30 days. The secondary endpoints were individual criteria of the primary endpoint, hospital length of stay and ICU length of stay. The trial randomized 1,817 patients, with 908 randomized to the handover group and 909 to the no handover group.
  • There was no significant different in the primary endpoint between the handover and no handover groups, and none of the composites were a significant difference. We performed a multivariable regression analysis for the primary endpoint and none of the factors were significantly different between the two groups. Short-term outcomes, surgery length of time, and level of training of the anesthesiologist were also not different between the two groups.
  • There are some limitations and remaining questions from the trial: The trial did not include weekend and nighttime surgeries, so one remaining question is are handovers harmful during off-hours when fatigue and stress may play a bigger role? What affect does the experience of the surgeons and anesthesia and surgical nurses have on outcomes? Are the results generalizable to all patient cohorts and to other health care systems?

Learn more about the HandiCAP Trial.

Discussion Themes

-What instructions or guidance did you provide for the handover? We left them to their daily routine that they perform. We told them what they needed to tell the new anesthesiologist but not how to do the handoff.

–What didn’t go as you expected and what were some of the lessons that you learned that would inform a follow-on trial to this trial? We planned this trial with three centers and then the third center did not get the approval by the ethics committee, so we had to include 12 centers. The COVID situation was another aspect we could not control. We had to the change the protocol once to correct a wording mistake. What I learned from designing this trial is that you can never plan that centers will recruit the same amount of patients as we would do in the initiating center. You have to include more centers to reach your goal during the course of the study.

Tags

#pctGR, @Collaboratory1

Grand Rounds September 30, 2022: CTTI’s Digital Health Trials Hub Recommendations and Resources to Run Your Digital Health Trial (Marianne Chase, MGH, CTTI Team Lead, Jörg Goldhahn, ETH Zurich, CTTI Team Lead)

Posted on by terren.green@duke.edu

Speakers

Marianne Chase
Senior Director Clinical Trial Operations
Neurological Clinical Research Institute
Massachusetts General Hospital

 

Jörg Goldhahn, MD
Medical Director
Director of Institute for Translational Medicine
ETH Zurich

 

 

Keywords

Clinical Trial Transformation Initiative (CTTI); Decentralized Clinical Trials (DCTs); Digital endpoints; Developing novel endpoints

 

Key Points

  • The Clinical Trial Transformation Initiative (CTTI) envisions an evidence generating system with trials that are patient-centered, integrated into health processes, quality, leverage all available data, and improve population health.
  • Digital Health Trials can help research obtain better and more reliable information, conduct more patient-centric research, and move at higher speed and efficiency. We need to work together to find ways to evaluate the potential benefits and share lessons learned broadly.
  • CTTI’s Decentralized Clinical Trials Project was a 1 year accelerated project to deliver updated recommendations and best practices for Decentralized Clinical Trials (DCTs).
  • DCTs range from near-traditional to hybrid to fully remote trials that conduct study visits away from the central study site using strategies such as tele-visits or home delivery of investigational products.
  • Decentralized trials require novel technology and digital endpoints. CTTI wants to increase meaningful novel digital endpoints that are clinically relevant and fit-for-purpose.
  • CTTI has developed 35 tools to help study teams develop meaningful measures, map individual medical product development, navigate regulatory requirements, and help implement other CTTI recommendations.

Discussion Themes

– One of the key challenges in the field of decentralized trials and digital measures is sharing tools and collaboration between companies. There’s a growing understanding that we have to collaborate on the endpoints and digital technology to advance the field.

– A feasibility study is a good way to gain insight into possible snags when participants may not be tech savvy. Tech support at the site level is important to addressing problems in a study.

 

Read more about the Clinical Trial Transformation Initiative and CTTI’s vision for clinical trials in 2030. Find CTTI’s recommendations and resources.

 

Tags

#pctGR, @Collaboratory1

Grand Rounds September 23, 2022: Effect Of An Intensive Nurse Home Visiting Program On Adverse Birth Outcomes In A Medicaid-Eligible Population (Margaret McConnell, PhD)

Posted on by Elizabeth Mccamic

Speakers

Margaret McConnell, PhD
Associate Professor
Department of Global Health and Population
Harvard T.H. Chan School of Public Health

 

 

Keywords

Randomized controlled trial

 

Key Points

  • This trial took place in South Carolina at a time when Medicare was thinking about how to improve outcomes and if expanding home nursing services could improve health outcomes. The trial was part of a “Pay for Success” contract that enabled the state to promise funds for further expansion conditional on positive evidence of impact from the randomized trial. The home visit services were covered through a Medicaid waiver that allowed the Nurse Family Partnership (NFP) to serve about 4,000 people over 4 years (up to 40 visits at home).
  • The Nurse Family Partnership (NFP) delivered bi-weekly home visits with a registered nurse for the first 2 years of the child’s life and targeted first-time, low-income pregnant people. The types of services NFP nurses provide include health assessments, such as prenatal health assessment, monitoring weight and blood pressure; screening for depression, anxiety, intimate partner violence; referrals to health care providers and community resources; educational content; and psychosocial support.
  • This was a randomized controlled trial that enrolled 5,670 mothers into the evaluation between 2016 and 2020, with 2/3 allocated to the intervention group. The control group received standard of care in South Carolina. To be eligible, patients needed to be first-time mothers aged 15 and older who met the income-eligibility criteria for Medicaid and were no more than 28-weeks gestation at enrollment.
  • The primary evaluation question for the trial was what is the impact of NFP on health outcomes when delivered at scale? The primary outcome was a composite of at least one of small for gestational age, or low birth weight, or preterm birth or perinatal mortality. Secondary outcomes included neonatal outcomes and maternal outcomes.
  • There also were primary outcomes related to 2-year outcomes. The primary outcomes were a composite of at least one of health care encounter or mortality from major injury or concern for abuse or neglect and birth interval of less than 21 months. The study will be able to follow longer-term outcomes observed following moms and babies for up to 30 years, including health care utilization, timing of subsequent pregnancies, use of social services, criminal justice involvement, educational outcomes and economic opportunity.
  • 98% of participants enrolled in the treatment group received at least one visit from NFP. Visits were mostly spent on personal health and maternal role topics. The median home visit length was 65 minutes. Some referrals were made for general services (25%) and health care (23%). The median number of visits is 9.
  • There was not much of a difference in birth outcomes between the nurse home visit and control groups. There were substantial adverse outcomes (26% for the full sample control group) and large racial disparities. There was no impact on primary or secondary outcomes and no improvement in outcomes for any subgroup

Discussion Themes

-The program itself was disappointed but the state would much rather know that the program is not working. With birth outcomes there is not a large stable of interventions that do work and that address racial inequities. It’s hard to use existing literature to figure out what to do next.

–Is there a loss to follow up due to families moving out of state? We are largely looking at state data but are thinking about federal data that we can access. We are working to see if we can set up agreements with North Carolina and Georgia to capture the majority of migration from South Carolina.

Tags

#pctGR, @Collaboratory1

Grand Rounds September 16, 2022: Using Nationwide Registries to Conduct Pragmatic Randomized Trials: The DANFLU Program (Tor Biering-Sørensen, MD, PhD, MPH)

Posted on by Elizabeth Mccamic

Speaker

Tor Biering-Sørensen, MD, PhD, MPH
Professor in Translational Cardiology and Pragmatic Randomized Trials
Head of Center for Translational Cardiology and Pragmatic Randomized Trials
Department of Biomedical Sciences
Faculty of Health and Medical Sciences
University of Copenhagen
Head of Cardiovascular Non-Invasive Imaging Research Laboratory
Department of Cardiology
Copenhagen University Hospital – Herlev and Gentofte

 

Keywords

DANFLU-1, Pragmatic Clinical Trials

 

Key Points

  • The Danish Nationwide Registries include the Danish Patient Registry (a registry of every inpatient and outpatient contact in the Danish free-for-all public healthcare system); the Danish Medicines Registry (a registry of every filed prescription at any pharmacy in Denmark including information on pill strength, pack size, etc.); and the Danish Registry of Causes of Death (a registry of long-term clinical outcomes including hospitalizations, outpatient visits, procedures, prescriptions, mortality). Denmark also has registries tracking socioeconomic data such as income and level of education and other types of data that can be linked together for study.
  • Denmark also has a mandatory electronic mailbox (e-BOKs) system that is required for all Danish citizens older than 18 and is linked to each citizen’s social security number. The system is used by approximately 5.8 million people, representing more than 95% of the population. The system is used for priority communications from government agencies, hospitals, banks, and others, and allows for rapid delivery of recruitment letters and implementation interventions
  • The national registries can be used to identify potential study participants who meet specific criteria and the e-BOKs system allows researchers to easily send invitations to potential participants, as well as follow up communications. Researchers can track participants through their medical records regardless of location and through the national registries. This infrastructure can be used to conduct pragmatic Phase II trials, large-scale pragmatic RCTs, such as DANFLU, and nationwide implementation trials.
  • The COlchicine Hypertension Trial (COHERENT) is a pragmatic Phase II trial that looked at only hypertension by using registry data to identify patients that receive at least two hypertension drugs. The DECODE trial used registry data to identify patients with chronic kidney disease.
  • The DANFLU-1 trial is a large-scale pragmatic RCT that looked at high-dose vs standard-dose flu vaccine to test whether high-dose vaccines might reduce hospitalizations among the elderly, age 65 and older. The DANFLU-1 trial evaluated the feasibility of integrating an individually randomized trial into routine seasonal influenza vaccination practice using administrative health registries for data collection. 34,000 study invitations were sent out and 12,551 participants consented and were randomized in the study. One hypothesis-generating outcome was that participants randomized for the high-dose vaccine had a 64% lower risk for hospitalization than the standard-dose vaccine.
  • With the success of DANFLU-1, the team is launching the fully powered DANFLU-2 trial, which will be conducted the next two years, randomizing 208,000 patients over two flu seasons. The team will send out 800,000 invitations. Hospitalization of flu is the primary outcome.
  • The NUDGE-FLU trial is a nationwide implementation study that will randomize all Danish citizens above 65 who receive a free vaccine by Danish government. 1.2 million citizens will be randomized to receive 10 different communications. The aim is to test communication strategies for optimizing the update of the flu vaccine. Another trial is called NUDGE-DM using the same system for identifying patients with diabetes to test communication strategies for optimizing the use of guideline directed medical therapy for T2D patients with established CVD

Discussion Themes

-I was struck by the number of people that were approached and joined the DANFLU study. For most trials it’s 2-4%. What was the type of engagement; were people aware clinicians were involved? These are participants who are already in the vaccine company’s registry. They have been vaccinated and were seeking the flu vaccine. We would not expect this recruitment rate in other trials.

–What clinicians are involved in the trial? It wasn’t the intention to bypass clinicians but the only ones involved are in the study lab and with the vaccine company. We are bypassing the normal ways because we are not in the hospitals. We are using the vaccine clinics where it’s nurses who are administering the vaccine at clinics in all of the cities, not just at hospitals. During the vaccine season they have pop-ups. We can do this work cheaply because we are not using local sites, we are not paying participants. The DANFLU-1 trial was close to $1.5 million U.S. dollars.

-These one-time interventions, like vaccines, contact people, deliver intervention, what about chronic care that is needed for a trial where more monitoring is needed? You can always use the system to identify potential candidates and then guide them to the local cardiology, kidney department. To keep the cost down, we are thinking about how to use vaccine clinics. It was the first try at testing the systems, so now we are testing whether mailing out potential interventions or using the vaccine clinics where they have to go in to draw a blood sample

Learn more

Read about DANFLU-1.

Tags

#pctGR, @Collaboratory1