POINT: Amendment 3 Protocol Changes



Title Page: Changed Version # and dateFooter: Changed Version # and dateTable of Contents: Adjusted page numbering THROUGHOUT THE DOCUMENT: Changed loading and maintenance doses of aspirin from 50-325 mg/day (with a dose of 162 mg daily for 5 days followed by 81 mg daily strongly recommended) to 50-325 mg/day (with a dose of 150-200 mg daily for 5 days followed by 75-100 mg daily strongly recommended).THROUGHOUT THE DOCUMENT: Changed units of measurement of serum creatinine from serum creatinine >2 mg/dL to serum creatinine >2 mg/dL or 176.8umol/LTHROUGHOUT THE DOCUMENT: Changed number of centers from 210 to 350.THROUGHOUT THE DOCUMENT: Changed sample size from 4150 to 5840 subjects.THROUGHOUT THE DOCUMENT: Changed Sanofi-Aventis to Sanofi.THROUGHOUT THE DOCUMENT: Added Ethics Committee approval to list of approving institutions.Page 11, Section 1.1 Graphical Study Design: Updated graphic.Page 21, Section 2.4.3 Combination Clopidogrel-Aspirin: AddedCHANCE (Clopidogrel in High-Risk Patients with Acute Non-disabling Cerebrovascular Events) was a randomized, double-blind, placebo-controlled trial conducted at 114 centers in China. 5170 patients were randomly assigned within 24 hours after the onset of minor ischemic stroke or high-risk TIA to clopidogrel plus aspirin vs. aspirin alone for 21 days, followed by clopidogrel vs. aspirin for the subsequent 69 days.The primary outcome, ischemic or hemorrhagic stroke (ischemic or hemorrhagic) occurred in 8.2% in the clopidogrel-aspirin arm, and 11.7% in the aspirin arm, a significant hazards reduction, with no increase in major hemorrhage.[185] The result supports that more intense antiplatelet therapy is beneficial and superior to aspirin alone in this patient population. Whether this is generalizable to non-Chinese populations is unknown. The POINT DSMB reviewed the accrued data in POINT, the CHANCE results and the opinion of a Bioethics Committee engaged by the National Institute of Neurological Disorders and Stroke (NINDS) to assess the ethics of continuing POINT in light of the CHANCE results. Following that review, the DSMB approved a modification to the informed consent to address the CHANCE results, and recommended POINT proceed as planned.Page 26, Section 4.2 Study Milestones: Changed Recruitment and Follow-Up Milestone from 66 months to 90 months, and Total Duration from 84 months to 108 months.Page 27, Section 4.3 Organizational Structure and Communication Flow: Updated POINT Trial Organization graphic.Page 30, Section 4.5 Contact Schedule and Measurements: Added Stroke and TIA events can be evaluated via telemedicine when necessary.Page 33, Section 5.1 Study Population: Changed 2075 to 2920 subjects.Page 36, Section 7.1 Supply and Storage: Changed There will be at least two drug shipments for the study: Sanofi-aventis will initially ship clopidogrel and placebo to the UCSF DPSL in April 2010 with a second shipment scheduled for 2012. There may be a need for a third shipment depending on study drug expiration dates, enrollment rates for the trial and the addition of sites outside the US.toThere will be at least three drug shipments for the study: Sanofi will initially ship clopidogrel and placebo to the UCSF DPSL in April 2010 with a second shipment in 2012 and a third shipment will be sent in the second quarter of 2014. Page 38, Section 7.4.1: Prohibited Concomitant Treatments: Changed …see listing on CRF 18, page 2. to …see listing on CRF 18.Page 40, Section 7.6 Blinding System and Emergency Unblinding Procedure: Added telephone number for OUS sites, 415-663-4444.Page 41, Section 8.2.1 Management of SAEs/Clinical Outcomes: Added The CRC Medical Monitor is notified when an event is determined to be a serious, unexpected, adverse reaction by the CEC. The CRC Medical Monitor completes the Council for International Organizations of Medical Sciences (CIOMS) form and sends it to the country-level Regulatory Manager for sites outside the US. The country level manager submits the form to the country level regulatory agency.Page 44, Section 8.5.3: Procedure for Expedited Reporting of SAEs/Clinical Outcomes: Added Timelines for completion of CIOMS Form by the CRC Medical Monitor:7-day reportable events- within 48 hours of receipt of the notification email (CEC assessment).15-day reportable events- within 7 days of receipt of the notification email (CEC assessment). Page 44, 8.5.5Clinical Outcome Event Reporting: Added Documents requiring translation will be checked for deletion of PHI by the country level manager, and a request for translation will be made to the CRC. The CRC will provide the translated documents back to the country level manager for upload. Page 47, Section 9.1 Screening Evaluation: Changed A screen failure log will be completed for all patients who are screened but not randomized into the study; this will not include any personal identifiers and thus will not require consent. toFor sites having trouble meeting their enrollment goals, a screen failure log will be completed for all patients who are screened but not randomized into the study. This log will not include any personal identifiers and thus will not require consent.Page 47, Section 9.1 Screening Evaluation: Changed A screen failure log will be completed for all patients who are screened but not randomized into the study; this log will not include any personal identifiers and thus will not require consent. These screen failure logs will be useful in determining whether specific groups of patients are under-represented in the study, to confirm participation of sites, and to determine the most common reasons for failure to randomize.toFor sites having trouble meeting their enrollment goals, a screen failure log will be completed for all patients who are screened but not randomized into the study. This log will not include any personal identifiers and thus will not require consent. These screen failure logs will be useful in determining whether there are modifiable approaches available to increase enrollment.Page 48, Section 9.1 Screening Evaluation: Changed …specific groups of patients are under-represented in the study, to confirm participation of sites, and to determine the most common reasons for failure to randomize. to…there are modifiable approaches available to increase enrollment.Page 48, Section 9.3 Randomization: In item 6, Changed … matches the study Drug ID (RVF). to… (RVF) that matches the study Drug ID.Page 49, Section 9.3 Randomization: Added and witness to item 8Page 52, Section 9.4.2.1 Subjects Considered Lost to Follow-up: Removed …at trying…Page 52, Section 9.4.2.1 Subjects Considered Lost to Follow-up: Added be…Page 54, Section 10.1.2 Sample Size Estimates: Changed The maximum sample size to detect a relative risk reduction (RRR) of 23% is 4,150 subjects. The sample size estimation is based on 90% power and a two-sided alpha of 0.05, 12% crossovers, and 2% losses to follow-up. The RRR of 23% translates to a hazard ratio of 0.75 assuming the proportion of subjects with events in the placebo group to be 15%, and inflation to account for two interim analyses for efficacy at equal intervals using O’Brien and Fleming stopping boundaries. Following the first interim analysis, the maximum sample size has been re-estimated based on the observed placebo event rate.to The original maximum sample size to detect a relative risk reduction (RRR) of 23% is 4,150 subjects. As stipulated in the Statistical Analysis Plan, following the first interim analysis, the maximum sample size has been re-estimated to be 5,840 subjects. The original sample size estimation is based on 90% power and a two-sided alpha of 0.05, 12% crossovers, and 2% losses to follow-up. The RRR of 23% translates to a hazard ratio of 0.75 assuming the proportion of subjects with events in the placebo group to be 15%, and inflation to account for two interim analyses for efficacy at equal intervals using O’Brien and Fleming stopping boundaries. Page 54, Section 11.3 Institutional Review Board (IRB): Changed Institutional Review Board (IRB) to Institutional Review Board (IRB) or Ethics Committee (EC)Page 55, Section 11.1 Ethical Considerations: ChangedThe study will be conducted in accordance with the U.S. Food and Drug Administration’s (FDA) Code of Federal Regulations (CFR Title 21), ICH Good Clinical Practice (GCP) guidelines, and the relevant regulations for clinical trials for each investigational site.toThe study will be conducted in accordance with the U.S. Food and Drug Administration’s (FDA) Code of Federal Regulations (CFR Title 21), ICH Good Clinical Practice (GCP) guidelines, and the relevant regulations for clinical trials for each investigational site.Page 55, Section 11.2 Regulatory Requirements: Changed Prior to initiating the study, each site will obtain IRB approval for the protocol, Informed Consent Forms and materials used to recruit subjects. In addition, each investigator will sign an Investigator Agreement. IRB-approved informational videos and quizzes designed to inform physicians and supplement the informed consent process may be presented on tablet devices and online to study physicians and potential subjects. Signatures will be collected on paper as well as digitally via tablet device and subjects will be provided printed paper copies of the consent form, as required by 21 CFR 50.27. Protocol amendments are not allowed by any investigator without prior approval from the Executive Committee. All changes to the protocol should be submitted to the site’s IRB for review and approval as appropriate. The trial has received an IND waiver from the rior to initiating the study, each site will obtain IRB or Ethics Committee approval for the protocol, Informed Consent Forms and materials used to recruit subjects. In addition, each investigator will sign an Investigator Agreement with the study sponsor. IRB/IEC-approved informational videos and quizzes designed to inform physicians and supplement the informed consent process may be presented on tablet devices and online to study physicians and potential subjects. Signatures of study subjects documenting their consent will be collected on paper and/or digitally. Prior to their participation, subjects will be provided printed paper copies of the signed consent form, as required by ICH GCP 4.8.11 and 21 CFR 50.27. Protocol amendments are not allowed by any investigator without prior approval from the Executive Committee. All changes to the protocol approved by the Executive Committee must be submitted to the site’s IRB/IEC for review and approval as appropriate. The trial has received a waiver from IND requirements from the FDA. However, each investigator at sites outside the U.S. must assure that any necessary approvals, or applicable waiver(s), have been obtained from the appropriate regulatory authority and/or national competent health authority, with authorization to proceed.Page 55, Section 11.4 Informed Consent: ChangedThere will be no surrogate consent in the study.toThere will be no surrogate consent in the study. Subjects must personally consent to participation and sign the approved consent form(s) which will be retained by the investigator and may be reviewed by the sponsor’s authorized monitors or auditors, and authorized representatives from regulatory authoritiesPage 56, Section 12.1.1 Site Visits: Changed The POINT CRC monitoring staff will perform all site visits to CRC investigators, on a jointly acceptable schedule. toThe POINT CRC monitoring staff or contractors will perform all site visits to CRC investigators, on a jointly acceptable schedule.Page 58, References: Added reference 185. ................
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