Posting of the draft protocol for public review and comment

January 2016
Dr. Matthew Roe, co-principal investigator of the ADAPTABLE study, talks about the rationale and process involved in posting the ADAPTABLE draft protocol for public review and comment and how the feedback received impacted the final protocol.

Q: What does the ADAPTABLE study represent beyond the aspirin-dosing question?

MR: Although the primary aim of ADAPTABLE is to determine the optimal dose of aspirin for patients who have coronary heart disease, ADAPTABLE represents a transformative approach to developing a new, efficient, and interactive clinical trial model. It is a pragmatic trial, reflecting “real-world” experience and using streamlined study procedures. In addition to being pragmatic, ADAPTABLE is a patient-centered trial. We seek—and will continue to seek—patient engagement at every critical step, from protocol development and consent design, through dissemination of final study results.

Q: ADAPTABLE is perhaps one of the first clinical study protocol that has been posted publicly for review and comment. Tell us the reasoning behind that decision.

MR: ADAPTABLE is a very different type of study. From the beginning, patient and stakeholder engagement has been a priority to the ADAPTABLE study leadership.

The ADAPTABLE Steering Committee (SC) is responsible for the protocol and the scientific conduct of the study. The Committee includes both patient and physician representatives from each participating Clinical Data Research Network (CDRN) and physician representatives from the Health-e-Heart Patient-Powered Research Network (PPRN), along with selected members with expertise in clinical research in antiplatelet therapies, cardiovascular disease, and analytical methods. Additionally, representatives from the American College of Cardiology (ACC) and the American Heart Association (AHA) are on the Steering Committee.

As the SC met during the summer of 2015 to finalize the ADAPTABLE protocol, a number of questions kept recurring regarding the key eligibility criteria. The SC had good collaborative debate and discussions, but could not come to a full consensus on the eligibility criteria. The SC believed it critical that study eligibility criteria reflect the best judgment of clinicians in practice to help achieve the most generalizable study population possible to address the main study hypotheses. Therefore, it made sense to post our questions on these eligibility criteria in a public forum to the research and public communities. This is in line with the aim of ADAPTABLE and is keeping with PCORI’s and PCORnet’s goals of stakeholder input, open science, and transparency. We decided to go one step further and not only post our questions, but make the complete draft protocol open for review and comment. This is an unprecedented step in the development of a clinical trial protocol.

Q: What were the recurring questions surrounding the key eligibility?

MR: There were four key areas where we wanted input:

  1. Should the ADAPTABLE trial only include patients already taking aspirin at the time of screening?

We assumed most patients recruited for trial participation would be on aspirin but we wondered whether to exclude aspirin-naive patients. The majority (57.8 percent) of survey respondents suggested we should not exclude patients who were not already taking aspirin at screening. As a result, we decided to open the patient population to those currently taking and not taking aspirin.

  1. Should patients taking ticagrelor at the time of screening be allowed to enroll into the ADAPTABLE trial?

After much discussion, we decided to exclude patients taking ticagrelor, a platelet aggregation inhibitor that is often prescribed to heart disease patients to reduce the risk of heart attack or stroke. Because of its bleeding side effect, ticagrelor carries a warning against its use along with high-dose aspirin (more than 100 mg). In our survey, nearly half (49.8 percent) of respondents advised us to include patients taking ticagrelor; 36.2 percent advised us not to include these patients. However, some representatives of Clinical Data Research Networks (CDRNs) stated that their sites would exclude patients taking ticagrelor or voiced concern that their IRB or ethics committees would not approve the protocol. As a result of these and other concerns, we decided to exclude these patients taking ticagrelor.

  1. Should patients with a clear indication for an oral anticoagulant (i.e., atrial fibrillation, recent deep venous thrombosis, pulmonary embolus, or prosthetic heart valve) be excluded from the trial, even if they are not currently taking an oral anticoagulant?

Our concern with this criterion was the risk of bleeding and trial drop out if we included patients who may require treatment with an oral anticoagulant after randomization, such as patients with a history of atrial fibrillation or those with a history prior deep venous thrombosis or pulmonary embolism. Polling results were fairly equal, with slightly less than half of the respondents (48.2 percent) voting to exclude these patients. In the final protocol, we opted to exclude both patients taking oral anticoagulants and those likely to require an oral anticoagulant.

  1. In your opinion, will clinicians agree to keep patients on their assigned aspirin dose after an event (hospitalization for MI, stroke) or a revascularization procedure?

This question was purely hypothetical to gauge interest and support from clinicians. We were encouraged that 60 percent of survey respondents said that clinicians will agree to maintain patients in the study on their assigned aspirin dose after a cardiovascular event or procedure. However, we recognize that ongoing educational efforts will be needed to educate clinicians about the ADAPTABLE trial and secure their support to keep enrolled patients on their randomized aspirin dose throughout the trial follow-up period.

Q: What was the process for posting and capturing feedback?

MR: After agreeing on the questions to post, we used an online survey tool that consisted of seven questions: one demographic, four eligibility-related, and two protocol related. On June 26, 2015, the invitation with link to the survey was made available to patients, clinicians, research staff, and the general public through the Duke Clinical Research institute (DCRI) and PCORnet professional and social media channels. Patient representatives, known as Adaptors, who are members of the SC were invited to comment. Also invited to comment, was the DCRI site community, which is a group of site investigators and study coordinators from more than 35,000 sites worldwide. The DCRI Communications team monitored survey results and provided interim reports of the results that were presented to the SC. The survey was closed in late July 2015 and the complete results were reviewed and helped formulate the eligibility criteria in the final version of the protocol.

Q: Overall, what did the SC think of this process and response from the public and research community?

MR: The SC was pleased and encouraged with the respondents thorough review of the protocol and the thoughtful input provided. We collected more than 100 free-text comments from investigators, study coordinators, and patients with heart disease on the overall study conduct and design. The trial operations team continues to consult and review the comments as they outline and refine the study operational plans.

The majority of respondents were overwhelming positive and grateful for the opportunity to provide input on the ADAPTABLE protocol. In an era of open science and transparency, we hope that by sharing our protocol and requesting feedback that we have set the stage for other clinical trial stakeholders including academic organizations, government organizations (National Institutes of Health), and pharmaceutical industry sponsors to utilize this approach for future randomized clinical trials.

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