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The SOLID-TIMI 52 Randomized Clinical Trial RM2007/00497/06 CONFIDENTIAL The GlaxoSmithKline group of companies SB-480848/033 Division: Worldwide Development Information Type: Protocol Amendment Title: A Clinical Outcomes Study of Darapladib versus Placebo in Subjects Following Acute Coronary Syndrome to Compare the Incidence of Major Adverse Cardiovascular Events (MACE) (Short title: The Stabilization Of pLaques usIng Darapladib- Thrombolysis In Myocardial Infarction 52 SOLID-TIMI 52 Trial) Compound Number: SB-480848 Effective Date: 26-FEB-2014 Protocol Amendment Number: 05 Subject: atherosclerosis, Lp-PLA2 inhibitor, acute coronary syndrome, SB-480848, darapladib Author: The protocol was developed by the members of the Executive Steering Committee on behalf of GlaxoSmithKline (MPC Late Stage Clinical US) in conjunction with the Sponsor. The following individuals provided substantial input during protocol development: Non-sponsor: Braunwald, Eugene (TIMI Study Group, USA); Cannon, Christopher P (TIMI Study Group, USA); McCabe, Carolyn H (TIMI Study Group, USA); O’Donoghue, Michelle L (TIMI Study Group, USA); White, Harvey D (Green Lane Cardiovascular Service, New Zealand); Wiviott, Stephen (TIMI Study Group, USA) Sponsor: Johnson, Joel L (MPC Late Stage Clinical US); Watson, David F (MPC Late Stage Clinical US); Krug-Gourley, Susan L (MPC Late Stage Clinical US); Lukas, Mary Ann (MPC Late Stage Clinical US); Smith, Peter M (MPC Late Stage Clinical US); Tarka, Elizabeth A (MPC Late Stage Clinical US); Cicconetti, Gregory (Clinical Statistics (US)); Shannon, Jennifer B (Clinical Statistics (US)); Magee, Mindy H (CPMS US) Copyright 2014 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. 1 Downloaded From: https://jamanetwork.com/ on 09/24/2021 RM2007/00497/06 CONFIDENTIAL The GlaxoSmithKline group of companies SB-480848/033 Revision Chronology: RM2007/00497/01 2009-OCT-08 Original RM2007/00497/02 2010-NOV-30 Amendment 01: The primary intent is to revise certain inclusion and exclusion criteria. These and other changes are summarized below. ! The Greenford address is deleted from the Sponsor Information Page. ! The address and phone number for Dr. Patrick Vallance on the Sponsor Information Page is updated. ! The Harlow address and phone number on the Sponsor Information Page is updated. ! It is clarified that a PCI planned prior to randomization but performed after randomization is not counted towards the composite measure of total coronary events. ! The reference for the guidelines for the management of patients with STEMI is updated in accordance with the latest guidelines issued by the American College of Cardiology/American Heart Association. ! For eligibility assessments, local laboratory values obtained from samples collected after the subject signs the ICF may now be used. ! In inclusion criterion 2, it is specified that, in Taiwan, subjects must be at least 20 years of age at randomization. ! Inclusion criterion 3c is revised to allow a diagnostic elevation in creatine kinase to be included in 2 Downloaded From: https://jamanetwork.com/ on 09/24/2021 RM2007/00497/06 CONFIDENTIAL The GlaxoSmithKline group of companies SB-480848/033 the definition of STEMI. ! The statement “Significant renal dysfunction refers to reduced eGFR based on serum creatinine prior to cardiac catheterization or PCI based on local laboratory values.” is deleted from footnote 6. ! In inclusion criterion 4e, it is clarified that polyvascular disease is defined as ACS plus at least one of either cerebrovascular disease or peripheral arterial disease. ! In exclusion criterion 2, it is clarified that “absence of obstructive coronary artery disease” would not include the scenario in which all lesions are successfully treated by PCI. ! In exclusion criterion 4 and footnote 10, the definition of liver disease is revised, AST is removed from the list of required liver function tests, and subjects with chronic stable hepatitis may be enrolled under certain circumstances. ! In footnote 12 for exclusion criterion 7, the requirement to obtain a mean of 3 BP measurements is no longer mandated. ! In footnote 13 for exclusion criterion 13, the list of examples of strong CYP3A4 inhibitors is updated. ! In exclusion criterion 12, the text is revised to clarify that subjects with alcohol or drug abuse within the past 6 months must not be enrolled regardless of the 3 Downloaded From: https://jamanetwork.com/ on 09/24/2021 RM2007/00497/06 CONFIDENTIAL The GlaxoSmithKline group of companies SB-480848/033 investigator’s assessment regarding the subject’s ability to comply with the study requirements. ! In exclusion criterion 14, the plasma Lp-PLA2 activity threshold for excluding subjects of Japanese, Chinese or Korean ancestry is revised from ≤10 to ≤20.0 nmol/min/mL. ! In footnote 14 for exclusion criterion 14, the reference for effect of the 279F variant on Lp-PLA2 activity is updated. ! Less frequent telephone follow-up in subjects who discontinue IP prior to the end of the study is now allowed. ! It is clarified that clinic visits may be used to collect data specified for telephone visits if desired. ! A new paragraph is added to emphasize the need to review and document all options for subject follow-up before confirming that the subject has withdrawn consent. ! Among the possible reasons for discontinuation of IP, “Sponsor terminated study treatment” is added. ! The description of the randomization number is corrected from a 5- to a 6-digit number ! It is clarified that the first dose of IP should be taken on the day of randomization. ! Expedited SAE reports sent to clinical investigators no longer identify the subject’s treatment assignment. 4 Downloaded From: https://jamanetwork.com/ on 09/24/2021 RM2007/00497/06 CONFIDENTIAL The GlaxoSmithKline group of companies SB-480848/033 ! In the Time and Events Table 1, it is specified that the Baseline vital signs, full physical examination and ECG should be performed within 2 days prior to randomization. ! In the Time and Events Table 2, the modified Rankin Scale and pregnancy test are now optional for unscheduled visits. ! In the Time and Events Table 2, the IVRS call is removed from unscheduled visits. ! In the Time and Events Table 2, footnote 3, it is noted that the End- of-Treatment/Early Withdrawal Visit is not required if the subject cannot visit the clinic within the window for collecting the trough Lp-PLA2 activity sample (24 ± 2 hours after the final IP dose) or earlier, and that samples for Lp-PLA2 activity and stored biomarkers are not collected at the Follow-up Visit ! In the Time and Events Table 2, footnote 4, smoking status was included in error and is now deleted from the list of post- randomization full physical exam assessments. ! “All coronary revascularization procedures” is added as an “other” endpoint. ! The phrase “the first occurrence of” is deleted from the “other” endpoint of total vascular events. ! The list of “Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs” is revised to include all 5 Downloaded From: https://jamanetwork.com/ on 09/24/2021 RM2007/00497/06 CONFIDENTIAL The GlaxoSmithKline group of companies SB-480848/033 non-fatal strokes. ! It is clarified that the modified Rankin scale is performed in all subjects regardless of stroke history. ! The statement that the treatment effect will be assessed at a nominal 0.05 significance level for the integrated efficacy analyses is deleted. RM2007/00497/03 2012-APR-26 Amendment No 2: The primary intent is to allow the Follow-up visit to be conducted by telephone in subjects who meet pre-defined criteria. Other changes are summarized below. ! Replace Dr. Patrick Vallance on sponsor signatory and sponsor information pages. ! Update List of Abbreviations and correct format errors. ! Revise text regarding scheduling of the End of Treatment visit. ! Clarify that publically available information may be used to report endpoints/survival status in subjects who withdraw consent to participate in the study. ! Remove requirement for investigators to contact the sponsor prior to restarting IP in subjects who have been off IP for more than 1 month. ! Provide guidance to investigational sites regarding recording the non-adjudicated endpoint “hospitalization for non- coronary ischemic event” in Section 6.3.3. ! Edit text in Section 6.4.1 (Liver 6 Downloaded From: https://jamanetwork.com/ on 09/24/2021 RM2007/00497/06 CONFIDENTIAL The GlaxoSmithKline group of companies SB-480848/033 chemistry stopping and follow-up criteria) for improved consistency with algorithm in Appendix 7 (Liver Chemistry Stopping and Follow-up Criteria). ! Edit text in Section 6.4.3 (Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs) to clarify definition of Hy’s law. ! Allow restarting of IP in certain subjects who met liver stopping criteria. RM2007/00497/04 2012-OCT-22 Amendment No.: 03 - The primary intent is to allow increased collection of data on new cancer, recurrence of cancer, or progression of cancer; and adjudication of all gastrointestinal (GI) neoplasms (malignant and benign), and all GI polyps (malignant, benign, and non-neoplastic). Other changes are summarized below. ! Add PRIMARY CONTACTS FOR EXTERNAL COMMITTEES WITH OVERSIGHT OR ADMINISTRATIVE RESPONSIBILITIES. This information was inadvertently omitted from previous protocol amendment (Amendment #2). ! Request a final clinic visit for subjects who permanently discontinued IP prior to the end of the study. ! Correct text to be consistent regarding use of telephone and clinic visits to follow subjects who permanently discontinue IP prior to the end of the study. ! Clarify data collection for subjects who have discontinued IP and are 7 Downloaded From: https://jamanetwork.com/ on 09/24/2021 RM2007/00497/06 CONFIDENTIAL The GlaxoSmithKline group of companies SB-480848/033 in post-IP follow-up. ! Allow a subject who met liver chemistry stopping criteria to restart IP if liver chemistries have improved to within the normal range, even if >1.5 x Baseline. ! Clarify completion of Follow-up checklist for subjects who withdrew consent for participation in the study.
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