Monthly Webinar Series October 2020
Today’s Agenda Trial Updates/Reminders Sandi Cassard Highlights from TREAT-MS SAC Meeting #3 held in February 2020 Study Retention and Treatment Adherence Ellen Mowry & Scott Newsome Single Scull Regatta Competition Shannon Hillery & Ryan Majkowski Monthly Randomization Race Shannon Hillery Q&A All
Trial Updates / Reminders SANDI CASSARD
Trial Updates/Reminders As of September 30 th , 2020, 506 patients have been enrolled. 37 sites have now re-opened to enrollment over the past five months. Please bring your enrolled patients back in for follow-up as soon as possible for their standard of care visits and complete the study visit that is currently within window. Do your best to screen and enroll new patients every week to reach or exceed your commitment for the trial!!! Remaining sites on-hold need to request permission to re-open to enrollment and other research activities (reach out to Sandi Cassard). Biobanking: UAB re-opened and is receiving/processing samples.
Trial Updates/Reminders COVID-19 related substudy modification is under review with the IRB. ◦ PCORI and JHCC see value in extending the COVID-19 related substudy eligibility to patients who are newly enrolled after 09/15/20. ◦ We are asking to allow patients to participate in the substudy, even if they did not have an in-person or televisit between 03/16/20 and 09/15/20. ◦ Rationale: 1) The pandemic is on-going and relevant to patients enrolled in the trial, as well as those who will enroll into the early part of 2021. 2) Some sites have had difficulty scheduling the next follow-up visit for enrolled patients and need more time to bring the patients in or schedule the televisits to allow them to be eligible to participate in the substudy. ◦ If IRB-approved, we will not have an end date to enrolling in the substudy and will collect as much follow-up data as possible through 09/15/21.
Enrollment in the time of COVID-19 19 Many visits still happening by televisit, have to be creative! Our new (temporary) workflow: first visit by televisit, all relevant labs/imaging ordered to be completed within next couple of weeks, then in-person visit to complete neurological exam, confirm diagnosis, and discuss treatment ◦ Bring up treatment dilemma at first visit, mention that TREAT-MS attempting to answer dilemma and that the patient may be eligible ◦ Ensure TREAT-MS team on site for time of first in-person clinical visit ◦ Offer patient enrollment at that visit Please do your best to rebuild the enrollment steam!
Participant Retention & Treatment Adherence ELLEN M. MOWRY, M.D., M.C.R. SCOTT D. NEWSOME, D.O. PROFESSOR OF NEUROLOGY AND ASSOCIATE PROFESSOR OF EPIDEMIOLOGY NEUROLOGY JOHNS HOPKINS UNIVERSITY JOHNS HOPKINS UNIVERSITY
Missing data for primary endpoint… what’s the big deal? Can lead to bias especially when long-term follow-up varies by treatment ◦ E.g. First-line drop out more than higher-efficacy ◦ Randomization no longer valid Other forms of bias may exist in those lost ◦ Older, younger, sicker Even random loss to follow up could have impact ◦ Loss of power ◦ Other forms of bias
Strategies to enhance RETENTION: Design Pre-randomization ◦ 2 or more screening visits ◦ ►► Exclude those who will move outside of TREAT-MS site catchment or non-adherent ◄◄ Intervention: standard of care dosing (remind participants!) Study visits ◦ Close enough to maintain contact/not too close Study measurements ◦ Painless, interesting, useful ◦ Give patients results (when possible) ◦ Remember these are largely STANDARD OF CARE and patients paid for their extra time needed to complete the few study-specific outcomes!
Strategies to enhance RETENTION: Implementation ***Educate participants*** ◦ Importance of science and their on-going participation ◦ Expectations for participation in study ***Warm and fuzzy stuff*** ◦ Participants to feel appreciated ◦ Staff in clinic spend enough time ◦ Sensitive to scheduling needs Ease of logistics/transportation to clinics ◦ Compensation to offset travel-related costs/extra time
Additional strategies to enhance RETENTION Information, Newsletters, other Emphasize early follow-up ◦ Most drop outs occur in early study period ◦ Example from another trial…FIT (4 years total); 2/3 of drop outs occurred in first year, most of those in first 6 months ◦ JHU coordinator and PIs work hard to encourage ongoing participation (call, email)… extra TLC goes a long way
Retention: Follow-up visits Goal: visits all on time (within window) ◦ TREAT-MS window intentionally broad in alignment with pragmatic study… but should not be used to justify a lot of missing visits or measurements ◦ Keep in mind that collecting EDSS, timed 25-foot walk, and 9- hole peg test are THE MOST IMPORTANT parts of the study Set appointments flexibly Reminders prior to appointments Listen to concerns/problems
Patient Retention: How to Re-Engage ◦ Have all participants come to final “close out” visit (even if missed other visits) ◦ Contact by telephone ◦ Use surrogate contacts ◦ Send certified letters ◦ Use external data sources (National Death Index, Medicare, Kaiser, etc). ◦ WE DON’T CONSIDER ANYONE LOST TO FOLLOW -UP UNTIL THEY HAVE MISSED MULTIPLE STUDY TIME POINTS
Patient Retention: COVID-19 19 ◦ Dynamic and Flexible with visits ◦ Conventional clinic visits ◦ Telemedicine visits ◦ Hybrid clinic visits ◦ Leverage uniqueness of COVID substudy ◦ Emphasize the importance of working with an MS specialist during these uncertain times
Adherence to medication is not the same as adherence to visit schedule Can have perfect visit adherence (come to all visits on time) but-- ◦ Not take a single study med pill ◦ Take only 60% of pills If miss visits or stop coming to visits, then generally don’t take study medication ◦ Exceptions do occur; could take study medications but not attend follow-up visits
Medication adherence: Goals Ideal in an explanatory trial: all participants continue to take medication (perfectly) throughout the trial and attend all follow-up visits until the very end Goal in a pragmatic trial: still prefer full adherence… or at least similar to “real world” Why might participants stop medication? ◦ Side effects (real or perceived) or worry about possible AEs ◦ Worry about getting COVID-19 ◦ Perceived lack of need ◦ Want to take a perceived “better” medication ◦ New info on old medication ◦ New competing medication ◦ Actual breakthrough disease (with or without re-randomization) ◦ Protocol-based switch
Effect of Stopping Medication: Classical interpretation Examples: First-line medication users switch to higher-efficacy therapy==>become more like higher-efficacy patients Higher-efficacy switch to first-line==>become more like first-line ◦ Two groups become more similar ◦ Treatment effect is underestimated/conservative
Follow-up visits for those who have stopped study medications? Practice varies dramatically across studies Option 1: Stop follow-up as soon as drug stops Option 2: Continue to collect follow-up info Advantages of each ◦ For TREAT-MS we want to continue to follow participants, ideally getting them back on the therapy class to which they were assigned….
Follow-up visits for those who have stopped study medications? Practice varies dramatically across studies Option 1: Stop follow-up as soon as drug stops Saves money Won’t see long term negative effects Option 2: Continue to collect follow-up info (highly recommended) Can do formal intention to treat analysis Can do all sorts of subsets and per protocol analyses Increase costs
Completion of follow-up for all participants regardless of adherence? Yes, very important ◦ All included, according to original randomization ◦ Follow-up completed on all participants ◦ Events are included even when they occurred after medications stopped Most rigorous approach Generally conservative estimate of treatment effect Per protocol or as-treated analyses are possible as secondary analyses
Retention and medication adherence: Summary Best trial: ◦ All participants remain on medication ◦ All participants are followed for primary outcome until end of study ◦ Pre-planned analysis and handling of deviations from protocol Design and implementation of study can help move toward that goal Important to report details in trial manuscripts (and how lack of adherence may affect results)
Single Scull Regatta: COVID Sub-study Additions SHANNON HILLERY RYAN MAJKOWSKI
Single Scull Regatta Current Points: Original Balancing Designed through end of June Bonuses added through Sept 30 remain COVID Substudy: Fresh Start for October 1 st No additional balancing Bonuses for substudy enrollments Bonuses for each successful follow-up visit in the substudy
COVID Substudy Phase: Metrics Recap Current Metrics with Points • Webinars Visits within time period Primary Outcome Assessments ePRO within time period • • • Screened • M6 EDSS ePRO: Baseline • • • Randomized • M12 25-Foot Walk Test ePRO: M3 • • • % Queries within 2 weeks • M18 9-Hole Peg Test ePRO: M9 • • M24 ePRO: M21 • • M30 ePRO: M33 • M36 • M42
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