PERFORM Aspirin 100 mg/day vs terutroban 30 mg/d TP receptor antagonist (thromboxane and prostaglandin endoperoxide PGG2-PGH2 receptors) Data until 07/09/09. Mean patient follow-up 2.1 years How many primary end points were analyzed ? n=1863 Prematurely stopped because terutorban v.v. unlikely to offer benefit over aspirin No evidence of harm form terutroban Oct 2009 publication to follow Reason for premature discontinuation What finding has led to this decision ? The Data Monitoring Committee (DMC), during their last meeting, based on their review of the endpoint data, concluded that no evidence of harm was observed but that the study was most unlikely to demonstrate any benefit from the use of the drug as compared to aspirin. Is there a safety concern ? No evidence of harm was observed, according to the DMC who reviewed the endpoint data. Are there more bleedings with S18886 ? The DMC did not express any concern about bleedings, and the reason for stopping the trial is not a safety issue. Are there signs that aspirin is better than S18886 ? No, the DMC did not say that aspirin was better than S18886. They concluded that the study was most unlikely to demonstrate any benefit from the use of the drug as compared to aspirin. Is there an ethical concern or is it more an economical concern ? Since, the DMC stated that the study was most unlikely to demonstrate any benefit from the use of the drug as compared to aspirin, the Executive Committee in agreement with the Sponsor decided that the study should be stopped. Should we consider the stopping of the trial as a safety measure ? No, the DMC stated that there is no evidence of harm. When was this decision taken ? During the last Executive Committee meeting, on 23 October 2009. By whom was this decision taken ? By the Executive Committee, in agreement with the Sponsor, based on the recommendation of the DMC.   Regulatory aspects When should we inform EC/CA about this decision ? Before 6 November (within 15 days after decision, according to SOP STE/004/03). How should we inform EC/CA about this decision ? According regulatory requirements, based on documentation prepared by presubmission division and TRD. Will it be necessary to wait for their approval before starting to perform the final visits ? No, there is no approval to be expected since it is an information letter, except if local regulatory requirement. Will you prepare a protocol amendment to describe the premature end of the trial ? No need for amendment, premature discontinuation of the study was planned in protocol (see section 8.5). When do you plan to finish the intermediate premature end-of-trial report and the final study report ? Dates are not planned yet. Patients How and when should we inform the patients about this decision ? During the next visit, the investigator will inform the patient about this decision. The investigator will be instructed how he will have to proceed as soon as possible. Will they receive an information letter (to be signed) at their final visit ? We will follow the local regulatory requirements. Should we ask the patients to come back for a visit as soon as possible ? Investigators will be encouraged to anticipate the last visit in order to finish all final visits before ( date on discussion with the Top Management). Do investigators have the right to call back all their patients immediately and get them off study medication ? Since the DMC stated that there is no harm, it is not mandatory to call back all the patients immediately and get them off study medication, but the investigators are free to do so. Practical organisation When can investigators start to perform final visits ? After notification to ECs, i.e. 6 November 2009, except if local regulatory requirement. How will this final visit look like ? Complete final visit (section 8.2.2 of the protocol). When will be the LVLP ? LVLP on discussion by Top Management. The decision will be made in the next days. When will the data base be locked ? Date is not planned yet. In the new context, is it still necessary to perform the dementia evaluation at the final visit ? Yes, it will be a planned final visit. Will the ancillary projects continue until the last visit or will they be stopped immediately ? They will not be stopped immediately. Specific instructions will be given in the next days. Are investigators free to choose the follow-up medication after the last visit ? Yes. General consequences Is this the end of the development of S18886 ? Will the other trials with S18886 be stopped as well ? Yes; however there is no ongoing trial with patients. Will Servier develop S18886 in other indications ? No (patent). Is there a second follower for S18886 in the pipeline? What is the impact of this decision on Servier (R&D) as a company ? It is a risk inherent to the development of any new drug, and thus was taken into account. Other projects are ongoing and new molecules will arrive. What will happen with all the people working on this trial ? The PERFORM study must be closed in a proper fashion. Full results will be published. Thus, people working on this trial will be involved until finalisation (more or less next summer), and then will participate in other projects Communication Will the results of the trial be published ? Where and when ? Not yet decided. Will there be a press release on this topic ? No. Will there be a national meeting ? Can we still proceed with the planned investigator’s meeting ? Should we adapt the agenda ? No, except for local reasons to be discussed case by case. Data Monitoring Committee Is an advice of the DMC always binding ? No. As stated in the protocol section 8.5, if safety concerns are detected at any time during the study, or superiority/inferiority as well as futility rules are meet during the planned formal analyses, the DMC could recommend an early termination of the trial to the Executive Committee who will take the final decision in collaboration with the Sponsor. Who are the members of the DMC ? RoleTitle. Initial Forename. Name. SpecialityChairmanProf. D. JULIAN, Cardiology (GBR)MemberProf. C. FIESCHI, Neurology (ITA)MemberProf. G. BOYSEN, Neurology (DNK) MemberProf. S. POCOCK, Statistics (GBR)MemberProf. J. CONARD, Haematology (FRA) What is the exact role of the DMC ? The DMC is independent from the Sponsor. The DMC has access to the randomisation code and the Critical Events Committee validations. At any time if necessary, the Committee may ask for any supplementary information. The DMC makes appropriate recommendations to the Executive Committee Chairman concerning the conduct of the study: continuation, amendment, suspension. The DMC is free to perform any analyses without informing the Sponsor, as they are an independent committee How are they organised ? See protocol amended version section 12.3.3. What kind of analyses do they perform ? At which timepoints ? Did they conclude on the basis of both the non-inferiority and superiority approach ? Does this implicate that S18886 was not even expected to be non-inferior to aspirin ? This cannot be excluded but the chance that S 18886 will be non-inferior to aspirin is very low, and even though, in these conditions, such finding would not be clinically relevant. How do they communicate with the sponsor ? Through the Executive Committee by giving a written recommendation. Have they written a report about their findings which can be used for EC/CA information ? The written recommendation is the only document provided by the DMC; it will be attached to the information sent to EC/CA   Statistical aspects On which data was the analysis based ? Data until 07/09/09. What was the mean patient follow-up at the time of analysis ? 2.1-year mean follow-up. How many primary end points were analyzed ? 1863. Did the analysis only include adjudicated primary end points ? No, all primary endpoints (out of them 67% were adjudicated). What are the thresholds for futility ? Are they described in international guidelines ? Described in the DMC charter, document restricted for the use of DMC members. They are not described in international guidelines: How are they calculated ? Described in the DMC charter, document restricted for the use of DMC members. Do we have information about the effect of the product on the secondary endpoints ? Was the Sponsor already alerted about futility at the previous analysis ? No and the first recommendation from the DMC for stopping for futility was given on 12 October 2009 to the Executive Committee. How low is the chance to demonstrate superiority if we would have continued until the end ? No chance at all. Why a second interim analysis was performed as it was not foreseen? The DMC is free to perform any analyses that they want without informing the Sponsor, as they are an independent committee. Scientific questions Do you have an idea about the underlying reason for this result ? Not yet. Data will be analysed carefully at the end of the study to try to understand. Are there indications that the TP-receptor pathway is not a good therapeutic target ? Could concomitant treatments such as dypiridamole, statins and ACE-inhibitors have played a role ? The role of concomitant treatments cannot be excluded at this step. Data will be analysed carefully at the end of the study to try to understand.