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Foldrx Pharmaceuticals, a Pfizer Company a Multicenter, International, Phase 3, Double-Blind, Placebo-Controlled, Randomized

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Foldrx Pharmaceuticals, a Pfizer Company a Multicenter, International, Phase 3, Double-Blind, Placebo-Controlled, Randomized PF-06291826 Tafamidis Meglumine B3461028 Final Protocol Amendment 3, 24 May 2016 FOLDRX PHARMACEUTICALS, A PFIZER COMPANY A MULTICENTER, INTERNATIONAL, PHASE 3, DOUBLE-BLIND, PLACEBO-CONTROLLED, RANDOMIZED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF DAILY ORAL DOSING OF TAFAMIDIS MEGLUMINE (PF-06291826) 20 MG OR 80 MG IN COMPARISON TO PLACEBO IN SUBJECTS DIAGNOSED WITH TRANSTHYRETIN CARDIOMYOPATHY (TTR-CM) Compound: PF-06291826 Compound Name: tafamidis US IND Number: IND 71,880 European Clinical Trial Database 2012-002465-35 (EudraCT) Number: Protocol Number: B3461028 Phase: 3 Page 1 PF-06291826 Tafamidis Meglumine B3461028 Final Protocol Amendment 3, 24 May 2016 Document History Document Version Date Summary of Changes Original protocol 31 Jul 2013 N/A Amendment 1 16 Apr 2014 Following initiation of the study the following changes were made to the study protocol: 1. Typographical corrections and clarifications. 2. Added the results of the B3461031 study indicating a lack of tafamidis effect on QTc. 3. Clarified the target sample size as 400 subjects. 4. Added “Smoking and Alcohol Classification” to the Schedule of Activities. 5. Removed Serum Amyloid A from required Screening analysis as it is an indicator of an active inflammatory process and does not contribute to defining an appropriate subject for this study. 6. Amended the Week 2 follow-up to allow for flexibility in scheduling a visit to either the investigator’s clinic or their primary care physician’s office or a visit to a local laboratory for blood collection (which would also include, a phone call). 7. The second 6MWT during Screening was removed in order to ease the burden of site visits. 8. Removed chest x-ray as a required Screening test. 9. Clarified the duration of a Screening extension as being 2 weeks. 10. Clarified language for eligibility requirements for the extension study that include completion of at least 896 days in this study. 11. Change to provide additional diagnostic evaluations via IHC and scintigraphy to support diagnosis of TTR-CM. Page 2 PF-06291826 Tafamidis Meglumine B3461028 Final Protocol Amendment 3, 24 May 2016 12. Added procedures for confirming TTR cardiomyopathy in TTR genotype positive subjects with elevated kappa and lambda light chain values. 13. Removed the 5 year limitation on biopsies for TTR determination. 14. Added examples of calcium channel blockers that should be excluded from use in this study (eg verapamil, diltiazem). 15. Updated the method of determining glomerular filtration. 16. Added tauroursodeoxycholate and doxycycline to the list of excluded medications. 17. Added that the discontinuation of NSAIDs must be 30 days before the Baseline visit. 18. Expanded 30 month Vital Status determination to include Transplant Status. 19. Added diflunisal assay. 20. Changed exclusion language for “prior myocardial infarction” to exclude subjects who in the opinion of the investigator do not have heart failure caused by TTR cardiomyopathy. 21. Added 30 day exclusion for use of tauroursodeoxycholate and doxycycline prior to enrollment and their exclusion from use during the study. 22. Clarified that all follow-up visits need to be referenced to the date of the Baseline visit and that the anticipated study duration is 910 days. 23. Added language clarifying the term “down-titration”. 24. Removed the Endocrine, Immunologic / Allergic, and Hematologic / Lymphatic systems from the Screening physical examination because they had been entered in error. Page 3 PF-06291826 Tafamidis Meglumine B3461028 Final Protocol Amendment 3, 24 May 2016 25. Entered echocardiographic parameters for the assessment of Longitudinal, Circumferential and Radial Echo Strain. 26. Clarified that coagulation variables will be measured in the local laboratory. 27. Removed the “Total Blood Volumes ” chart and indicated the central lab manual as the source of the blood volumes at each visit. 28. Removed the 15 month time frame from the enrollment period. 29. Clarified the wording for “censoring” of subjects in the statistical section. 30. Added supportive references, 31. Removed the “6 Minute Walk Test Worksheet” as it doesn’t match the eCRF. 32. Replaced “appointment card” with “Subject Daily Dosing Diary”. 33. Replaced “study medication card” and “blister pack” with “study medication wallet”. 34. Added TTR oligomer concentration as an exploratory endpoint. 35. Needed to add and rearrange language because of a company global change to the protocol template. Amendment 2 26 Feb 2015 1. Added contraception discussion to schedule of activities, as described in the protocol (section 4.3.1). 2. Added subjects who undergo surgery for Implantation of a cardiac mechanical assist device will be treated in the analysis similarly to subjects receiving a heart transplant. 3. Added conversion of NT proBNP to SI units. 4. Added clarification for Hepatitis and HIV exclusion. Page 4 PF-06291826 Tafamidis Meglumine B3461028 Final Protocol Amendment 3, 24 May 2016 5. Added clarifying text to Contraindicated Therapies (section 5.8.1). 6. Added language to comply with the new Pfizer protocol template (Endpoint Adjudication and Communication of Results by Pfizer). Amendment 3 24 May 2016 1. Clarified the term “down-titration” to “dose reduction” to more accurately represent the change in dose that may occur when a subject is unable to tolerate the randomized dose. 2. Removed reference to the color of the capsules under ‘Appearance’ in tabular summary of the investigational product (active and matching placebo), to eliminate confusion with a change in investigational product manufacture (implemented in protocol administrative change letter dated 11 Apr 2016). 3. Added the collection of urine samples at Months 12, 18, 24, and 30 or (Early Study Discontinuation) to be used in assay development for measurement of TTR oligomer concentrations in urine to be performed at selected centers. 4. Added the collection of blood samples for testing of tafamidis concentrations in subjects who require dialysis or hemofiltration after randomization and while on study treatment. 5. Removed the requirement for blood samples at Months 12 and 24 for testing of diflunisal concentrations. 6. Clarified that subjects who do not enroll in the extension study will be followed for 28 calendar days after the last dose of study medication for collection of adverse events. Subjects who enroll in the extension study will continue to be monitored for adverse events within the extension study. 7. Clarified that the Endpoint Adjudication Committee (EAC) Guidelines have been incorporated into the updated EAC Charter. 8. Better delineated the analysis planned for Kansas City Cardiomyopathy Questionnaire (KCCQ) scores related to subject symptoms. Page 5 PF-06291826 Tafamidis Meglumine B3461028 Final Protocol Amendment 3, 24 May 2016 9. Incorporated the discontinuation of enrollment of subjects with wild-type genotype in order to increase the numbers of subjects with variant genotype (implemented in protocol administrative change letter dated 30 Jun 2015). 10. Provided the study number for the extension study and clarified that all subjects in the extension study will receive tafamidis; however, the dose will be blinded in order to maintain blinding in the B3461028 study. 11. Clarified that dosing is permitted in the PM when the timing of pharmacokinetic samples is prohibitive for adherence with AM dosing. 12. Added the requirement that urine should be sent for microscopic evaluation following any positive test on urine dipstick, not just a positive test for blood or protein. 13. Removed inconsistent information found in Section 7.8 Hospitalization Determination on the follow-up required for Month 30 vital status / transplant / cardiac mechanical assist device to reflect what is being collected. Follow-up at Month 30 for this information is still included in Section 6.3 Subject Withdrawal and Vital Status / Transplant / Cardiac Mechanical Assist Device Status Follow-up. 14. Clarified that events resulting in organ transplantation or cardiac mechanical assist device should be considered “medically important” and, therefore, reported as serious adverse events. 15. Redefined the baseline groupings for New York Heart Association (NYHA) Functional Classification that will be used for efficacy analyses, grouping subjects with NYHA Class I and II together to be compared against NYHA Class III 16. Amended the description and frequency of data review by the External Data Monitoring Committee (E-DMC) to be consistent with the E-DMC charter. Page 6 PF-06291826 Tafamidis Meglumine B3461028 Final Protocol Amendment 3, 24 May 2016 17. Added or revised language to comply with the updated Pfizer protocol template (Section 4.3.1 Contraception, Section 5.6 Drug Storage, Section 5.7.1 Destruction of Investigational Product Supplies, Section 10 Quality Control and Quality Assurance, Section 12.3 Subject Information and Consent). 18. Deleted Section 12.4 Subject Recruitment as this language is now included in revised Pfizer protocol template language under Section 12.3 Subject Information and Consent. 19. Several typographical and formatting errors were corrected. This amendment incorporates all revisions to date, including amendments made at the request of country health authorities, institutional review boards/ethics committees (IRBs/ECs), etc. Page 7 PF-06291826 Tafamidis Meglumine B3461028 Final Protocol Amendment 3, 24 May 2016 This is a list of abbreviations Abbreviation Term 6MWT 6 Minute Walk Test 99mTC-DPD Technetium-99m-3,3-diphosphono-1,2-propano-dicarboxylic
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