1. on behalf of the TARDIS Investigators
Continue or Stop: the rationale for early closedown of a clinical trial as a result of stopping rules within the Data Monitoring Committee charter
Lisa J Woodhouse, Jason P Appleton, Lelia Duley, Ian Ford, Didier Leys, Stuart Pocock, Nikola Sprigg, Catherine Sudlow, Matthew Walters, and Philip M Bath;
on behalf of the TARDIS Investigators

2. Disclosures TARDIS funded by: British Heart Foundation
NIHR Health Technology Assessment programme
Indirect funding from:
The Stroke Association (for funding of Division of Stroke Medicine, University of Nottingham)
NIHR Stroke Research Network/CRN Stroke
No commercial relationships:
Drugs supplied by recruiting hospitals
Drugs:
Individual drugs are licensed for use after stroke/TIA

3. Trial
Triple Antiplatelet for Reducing Dependency after Ischaemic Stroke (TARDIS)
International, multicentre, parallel-group, prospective, randomised, open-label, blinded-endpoint controlled trial [1]
1. TARDIS Investigators. Int J Stroke 2015;10: 3

4. Design ADC AD or C AD or C AD or C
Randomised to either intensive (combination of Aspirin, Dipyridamole and Clopidogrel) or guideline (either Aspirin plus Dipyridamole or Clopidogrel alone) antiplatelet therapy
Start up phase, 3.5 years April 2009 to Sept 2012
902 (aim 350+) patients from UKSRN centres
Main Phase , 5 years Oct 2012 to Sept 2017
Start-up phase shows acceptable safety
Expand recruitment to 4,100 patients
Day 0
Day 30
Day 90
ADC AD or C R
AD or C AD or C 4

5. Aim
Assess if 30 days of intensive (triple) antiplatelet therapy is safe and effective in reducing recurrent cerebral ischaemic events after non-cardioembolic stroke or TIA in comparison with guideline antiplatelet therapy

6. Main outcomes of interest
Primary efficacy outcome (90 days):
Recurrent Stroke/TIA by severity, using mRS
See poster for more information
Primary safety outcome:
Bleeding by severity 6

7. Recruitment Commenced 7 April 2009
Halted 18 March 2016 on the advice of the independent Data Monitoring Committee (DMC)
3096 participants recruited (75.5% of planned 4100)

8. Data Monitoring Committee (DMC)
Followed a pre-defined charter
Included stopping rules for safety and efficacy
Did not include any stopping rules for futility

9. DMC: Charter stopping rules
SAFETY:
Primary outcome favoured the control group, P<0.01 (nominal, 2-sided)
Combined outcome of fatal or non-fatal stroke or major bleeding favoured the control group, P<0.01 (nominal, 2-sided)
Overall rate of symptomatic intracranial haemorrhage exceeded 2%
During start-up phase, major bleeding favoured the control group, P<0.01 (nominal, 2-sided)
EFFICACY:
Conduct formal interim analyses, after 40% and 70% of participants completed day 90 outcome assessment
Combined outcome of fatal or non-fatal stroke or major bleeding event favoured the control group, P<0.001 (2-sided)

10. DMC: Stopping rules
Before making any decision, the DMC was asked to consider:
Overall internal and external evidence
Multiplicity of testing
Possibility that trends in the data might be reversed with longer follow-up or increased recruitment

11. DMC: Meetings Reviewed unblinded data in confidence every 6 months
Met on 13 occasions
Recommended trial continuation for all but the last data review

12. Recommendation to stop was based on three observations
DMC: Stop decision
Recommendation to stop was based on three observations

13. DMC: Stop reason 1
“More than doubling of the risk of bleeding in all categories of bleeding, with a clearly statistically significant increase in the risk of the composite of major and fatal bleeds”
Not present during the start-up phase (as per the pre-defined stopping rules)
38 vs 17, HR 2.16, 95% CI ( ), p=0.009

14. DMC: Stop reason 2
“No compensatory evidence of benefit for the primary outcome” 100 vs 109, HR 0.90, 95% CI ( ), p=0.47

15. DMC: Stop reason 3
A conditional power futility analysis suggested the trial was highly unlikely to ever demonstrate a significant difference in the primary outcome
Conditional analysis performed by DMC
Charter did not request or define this

16. DMC: Stop decision Following the DMCs recommendation:
All patients on active treatment moved to control treatment
Trial Steering Committee (TSC) reviewed the same data (and subsequent additional analyses) one month later
Both TSC and DMC Chairs agreed that the trial should stop recruitment and complete follow-up

17. TSC: Additional interpretation
Overall neutral findings with no difference in the net balance of death, stroke, myocardial infarction and major bleeding
Adjusted
Unadjusted
Outcome I G
OR (95% CI) 2p
Any stroke or Major/Fatal bleed 92 74
1.23 ( )
0.20
1.24 ( )
0.17
Stroke/TIA/ACS/ Death
124
139
0.87 ( )
0.30
0.87 ( )
0.29
Vascular death/NF stroke/NF MI/Major bleed 98 87
1.11 ( )
0.50
1.12 ( )
0.45
Death/Stroke/MI 90 93
0.95 ( )
0.75
0.96 ( )
0.76
Death/NF stroke/NF MI/Major bleed/Fatal bleed
111
104
1.04 ( )
0.77
1.06 ( )
0.68

18. Stopping: Conclusion
DMC’s decision to stop was based on a combination of three observations:
Significant increase in major (including fatal) bleeding
No compensatory decrease in recurrent events
Futility (on basis of conditional power analysis)
TSC: Overall neutral findings
Both DMC and TSC agreed to stop the trial with these findings
> DMCs may need to recommend stopping trials in certain circumstances not defined in charter

19. Thank you