1. Practical Implications Laura Lovato, Biostatistician
Statistical and Practical Considerations When Terminating a Trial Early: Contrasting early stopping due to harm (ACCORD) versus for benefit (SPRINT)
Practical Implications
Laura Lovato, Biostatistician
Liverpool, UK, May 8th, 2017
Invited Session Statistical Design and Trial Conduct

2. Coordinating center knowledge of the potential for early termination
Strict Confidentiality Maintained
Small group working on analyses, planning for early termination scenarios and developing materials for rapid cessation
Biostatisticians
Project Management
Programmers

3. Planning for potential early termination
2-3 most likely scenarios
Rapid plan for notifying Steering Committee, Clinical Sites, IRBs, and Participants
Development of Operational Materials
Data freeze and publication of results (data the DSMB used for decision, or updated data through stopping point, beyond?)
Earlier transfer of participant care
Training for closeout visits

4. Planning for potential early termination
Website and data management systems modified in the background
Documents (for sites, public, media)
Data entry systems to capture transfer of treatment/care
Closeout visit data entry and management
Made ‘live’ once public announcement occurs
ACCORD: continuation of Lipid and Blood Pressure trials
SPRINT: follow up for cognition and kidney outcomes

5. Study Leadership Involvement
ACCORD
MASKED: Site staff and principal investigators
UNMASKED: Some coordinating center staff, Some project office (NIH) personnel, and the Steering Committee Chair
All actively participated in the discussions.
SPRINT
None of the project office personnel were unmasked except for the NHLBI representative; he was not otherwise involved in the study.
The steering committee chair was masked.
Site principal investigators were masked.
This meant that the coordinating center had much less advice.

6. Materials Developed for Early Termination:
Publication Documents: obvious!
Press Release
Journal Article
Media talking points
Letter to major medical societies

7. Materials Developed for Early Termination:
Memo to Site PIs and Staff: explanation of result, reasons for stopping standard arm, overview of transition process, timeline for remainder of trial.
Memo to CCN/Site IRBs: explanation of result, reasons for stopping standard arm, overview of transition process, timeline for remainder of trial.
Q&A for Study Staff: anticipated questions and answers to address clinic operations during transition.
Treatment plan for transition of standard arm participants to intensive goal (SPRINT) or backing off therapy from intensive arm participants (ACCORD) including written algorithm for implementing intensive arm BP target among standard arm participants.

8. Materials Developed for Early Termination:
Modified Study Forms to be used during transition and remaining follow-up.
Meet me slides: slides for presentation to clinic staff that explanation of result, reasons for stopping standard arm, overview of transition process, timeline for remainder of trial.
Letter to drug companies currently donating medications: includes explanation of results and plans for transition and timeline for remainder of trial
Participant information document for website: explanation of result, reasons for stopping standard arm, overview of transition process, timeline for remainder of trial.
Model Consent Addendum

9. Materials Developed for Early Termination:
Materials for dissemination of results to participants, including resources for group sessions.
Letter to All participants explaining the result, clearly explaining what they should do next, and encouraging their continued follow-up (NEXT SLIDE)
Letter to non-study care provider regarding trial results and recommendations.
Talking Points for Participants: anticipated questions and answers for participants designed to be used in 1-1 discussion during transition visits.
FAQ for General Distribution: anticipated questions and answers for site PIs and others to aid in explanation of results to general (lay) audience.

10. Elements of a Participant Notification Letter
Introduction
What is the news?
What do these results mean for me?
What should I do now?
Thank you!
Signatures of Project Office and local Principal Investigator
(letter to hand to personal health care provider)

11. Participant Notification Letters
ACCORD
Template letters developed centrally, different for each study arm
Overnight mail from clinical sites
SPRINT
Generic letter, same for both arms
Printed, Labeled and Mailed from coordinating center to all participants, one day prior to clinical site notification

12. SPRINT Coordinating Center Staff
– Labor Day weekend

13. Which events to include?
Continued collection of events following early termination: implications for analysis
Which events to include?
Event Detected:
prior to DSMB decision
after DSMB decision
Event Occurred: A
BN BF F

14. Continued collection of events following early termination: WHAT DID SPRINT DO?
DSMB Data Freeze
July 5, 2015
NHLBI Director accepts DSMB Recommendation to Terminate Early
August 20, 2015
NEJM Paper Data Freeze
October 2015
NEJM Paper Published
November 9, 2015
SPRINT Follow-up Competed
June 30, 2016

15. Clinical Site Staff Concerns - stress
ACCORD
Devastated by news of possible harm
Counseling services offered for staff at many clinical sites
Emphasis on quickly and safely transferring participants to appropriate treatment (backing off intensive glycemia arm)
SPRINT
Emphasis on transferring participants to appropriate treatment, slower timeline
Continue follow-up for other outcomes

16. Clinical Site Staff Concerns – job security
ACCORD
Glycemia trial stopped 17 months early, but follow-up continued to full duration for the Blood Pressure and Lipid trials
SPRINT
Intervention stopped 11 months early, and follow-up stopped 4 months early

17. Practical Considerations When Terminating a Trial Early: Contrasting ACCORD And SPRINT trials
Early Termination due to harm (ACCORD)
Early termination due to benefit (SPRINT)
More sensitivity for study staff (counseling recommended)
Follow other outcomes to complete the picture
Rapid transition away from experimental treatment
Slower transition; focus on explanation of study results and letter to primary care provider
Publication based on data frozen for DSMB important to understand decision
Publication contained events known at the time of publication that occurred prior to termination announcement

18. Special thank you to… Bob Byington (ACCORD) Sharon Wilmoth (ACCORD)
Letitia Perdue (SPRINT)
David Reboussin (SPRINT)