These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert.
PROPRIETARY DRUG NAME®/GENERIC DRUG NAME:
Vyndaqel®/tafamidis meglumine PROTOCOL NO.: B3461028 PROTOCOL TITLE: 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).
Study Center(s):
This study was conducted at 48 centers in 13 countries: Belgium (1), Brazil (1), Canada (1), Czech Republic (3), France (2), Germany (2), Italy (3), Japan (3), Netherlands (1), Spain (2), Sweden (2), United Kingdom (2), and United States (25). Study Initiation Date and Primary Completion Date: Study Initiation Date: = 09 December 2013 Final Completion Date: = 07 February 2018 Phase of Development: Phase 3
Study Objective:
The primary objective of this study was to assess the efficacy of an oral dose of 20 mg or 80 mg tafamidis meglumine soft gel capsules based on all-cause mortality and on frequency of cardiovascular-related hospitalizations, as well as to assess safety and tolerability in comparison to placebo.  Tafamidis or placebo was administered once daily (QD), in addition to standard of care, for 30 months in subjects diagnosed with variant or wild-type transthyretin cardiomyopathy (TTR-CM, also known as ATTR-CM).
METHODS
Study Design:
This was a Phase 3, multicenter, international, three-arm, parallel design, placebo-controlled, randomized study with a 30-month double-blind treatment phase, to determine efficacy, safety, and tolerability of tafamidis on clinical outcomes in subjects with either variant or wild-type TTR-CM.  The study design is shown in Figure 1. 8f421208\Approved\Approved On: 19-Sep-2018 02:56 The targeted enrollment for the study was 400 subjects to be randomized in a 2:1:2 ratio (placebo:20 mg tafamidis:80 mg tafamidis).  The subjects were to be allocated to the 3 arms of the study in the following manner: n=160 in the placebo arm, n=80 in the 20 mg arm, and n=160 in the 80 mg arm.  Subjects who experienced adverse events (AEs) associated with poor tolerability to treatment with tafamidis that might impact dosing adherence had the option of blinded treatment re-assignment and potential dose reduction.  Subjects were stratified during enrollment for treatment assignment by TTR genotype (variant and wild-type) with the intent of enrolling greater than 30% of randomized subjects with variant TTR-CM and greater than 30% of subjects with wild-type TTR-CM, with the intent to enroll comparable numbers between the variant and wild-type groups. Additionally, stratification to treatment assignment was done for baseline severity of disease based on New York Heart Association Classification (NYHA) classification (NYHA Class I and NYHA Classes II and III combined).  Stratification was implemented to maintain a balance of treatment assignments within both TTR genotype and disease severity. Subjects were to be treated for 30 months.  For the purpose of this study, 30 months was defined as 910 days.  For any subject who discontinued prior to 30 months, the site was to ensure a Month 30 follow-up (also called the follow-up period) contact to determine the subject's vital status and whether the subject had a heart and/or liver transplant or implantation of a cardiac mechanical assist device.  To achieve this, subjects participating in the trial were required to provide consent for release of medical information to permit access to medical records as well as vital status/transplant status/cardiac mechanical assist device status follow up by the site with the subject or the subject's caregivers 30 months after study randomization in the event that the subject could not be reached. Upon completion of the study at the Month 30 visit, subjects were eligible for treatment with tafamidis in a separate extension study (B3461045), which permitted the collection of additional safety and efficacy data.  Eligibility for the extension study required subject participation in this study at least through Day 896 (Month 30 minus 2 weeks).  The schedule of activities shown in Table 1 provides an overview of the protocol visits and procedures. 3f421208\Approved\Approved On: 19-Sep-2018 02 Protocol B3461028 - 28 August 2018 - Final
hepatitis B; HCV = Hepatitis C virus; HIV = Human Immunodeficiency Virus; INR = International Normalized Ratio; KCCQ = Kansas City Cardiomyopathy Questionnaire; NT-proBNP = N-Terminal prohormone B-type Natriuretic Peptide; NYHA = New York Heart Association Classification; PGA = Patient Global Assessment; PT = prothrombin time; TTR = Transthyretin. The Week 2 "visit" allowed the subject to either come to the clinic, or consisted of a telephone call to the subject for specified data determination and had a. the subject go to a local laboratory or local physician's office to have their needed laboratory samples collected and shipped to the central laboratory. Baseline (Day 1) ECG pre dose. b. Systolic and diastolic blood pressure and pulse rate (supine at least 3 minutes and standing at least 2 minutes prior to assessment), respiration rate and body C. temperature.
Schedule of Activities
Table 1.

d. Biopsy was performed at Screening or had been performed and documented previously. INR and PT were determined at the site's local laboratory. e. f. For women of childbearing potential.  Pregnancy tests were repeated as per request of IRB/IECs or if required by local regulations. TTR stabilization, TTR oligomer concentration, and TTR concentration:  Baseline (Day 1) sample: collected at any time pre dose during the clinic visit. g Month 1 sample: collected pre dose and at 3 hours (± 1.5 hours) post dose; Month 6 sample: collected at 7 hours (+ 2.5 hours) post dose; Month 12 sample: collected at 7 hours (± 2.5 hours) post dose; Month 18 sample: collected at 1 hour (± 30 minutes) post dose; Month 24 sample:  collected at 1 hour (±30 minutes) post dose; Month 30 sample:  collected at any time during clinic visit. h.    Subjects at selected centers provided a urine sample to be used in assay development for measurement of TTR oligomer concentrations in urine.  For those subjects who provided consent, a 10 mL aliquot of urine was collected (starting at the earliest possible prospective visit for the subject) at Months 12, 18, 24, and 30 (or Early Study Discontinuation); this aliquot was obtained from the urine sample already collected for urinalysis at these visits. 1. Baseline (Day 1) tafamidis concentration sample:  collected at any time pre dose during the clinic visit.  Month 1 tafamidis concentration sample: collected pre dose and at 3 hours (±1.5 hours) post dose; Month 6 tafamidis concentration sample: collected at 7 hours (±2.5 hours) post dose; Month 12 tafamidis concentration samples: collected at 7 hours (± 2.5 hours) post dose; Month 18 tafamidis  concentration sample: collected at 1 hour (± 30 minutes) post dose; Month 24 tafamidis concentration sample: collected at 1 hour (± 30 minutes) post dose; Month 30 tafamidis concentration: collected at any time during the clinic visit. If a subject required dialysis or hemofiltration at any time after randomization while on study treatment, the subject should have had blood samples collected for tafamidis concentrations around the time of renal replacement therapy.  The timing of the sample collection would depend on the type of renal replacement therapy administered.  For hemodialysis or hemofiltration, samples should have been collected on the date of the renal replacement therapy both prior to administration and after administration.  If peritoneal dialysis was administered, the first sample should have been collected at initiation of the first exchange. The second sample should have been collected after the first exchange was completed (if performed outside of the home) or at least 24 hours after the initiation of the first exchange (if administered at home).  Every effort should have been made to collect these samples on the date of the subject's first administration of renal replacement therapy in the study; however, if this was not possible, the samples should have been obtained as soon as possible on the date of a renal replacement therapy treatment.  If necessary, the sample collection could have been obtained using the guidelines for lab sample collection in the Guidance for Remotely Conducted Study Visits provided for the study.  At the time of sample collection, the date and time of the last dose and the date and time of sample collection was recorded. k. Diflunisal concentration to determine if there was evidence of exposure to diflunisal prior to or during the study. Sample was collected at any time during the clinic visit, after the ECG blood pressure and vital signs. l. Kansas City Cardiomyopathy Questionnaire (KCCQ) was completed before the EQ-5D-and PGA. EuroQoL 5 Dimensions (3 Levels version) (EQ-5D-3L) was completed after the KCCQ. m.
Protocol B3461028 - 28 August 2018 - Final
Table 1.
Schedule of Activities

Except for subjects who are randomized into the extension study (Study B3461045), all other subjects had a 4 week (28 calendar days) safety follow up visit p. after the last dose of the study medication for collection of adverse events.  This visit could have been completed by telephone. When the Vital Status was determined, the subject was asked if they had undergone a heart and/or liver transplant or implantation of cardiac mechanical q. assist device.  This was especially important at the 30 month visit.  If a subject indicated that they had a transplant and they were still enrolled in the study, they should have been removed from the study. r.     For all subjects who, in the opinion of the investigator, were biologically capable of having children and were sexually active; at each study visit, the need to use highly effective contraception consistently and correctly was discussed with the subject, the subject was instructed to call immediately if a selected birth control method was discontinued or if pregnancy was known or suspected and such conversation documented in the patient chart.
Number of Subjects (Planned and Analyzed):
The targeted enrollment for this study was 400 subjects to be randomized in a 2:1:2 ratio (placebo:20 mg tafamidis:80 mg tafamidis).  The subjects were to be allocated to the 3 arms of the study in the following manner: n=160 in the placebo arm, n=80 in the 20 mg arm, and n=160 in the 80 mg arm.  Of the 548 subjects screened for entry into the study, 441 were randomized into treatment.  This included 88 subjects randomized into the tafamidis 20 mg group, 176 subjects randomized into the tafamidis 80 mg group, and 177 subjects randomized into the placebo group.  All randomized subjects received at least 1 dose of study drug (safety analysis set).
Diagnosis and Main Criteria for Inclusion and Exclusion:
Eligible subjects were between 18 and 90 years old at the time of randomization, willing to sign an informed consent and release of Medical Information Form and comply with scheduled visits, treatment plan, laboratory tests and other study procedures.  In order to qualify for this study, all potentially eligible subjects were required to have a medical history of heart failure with at least 1 prior hospitalization for heart failure or clinical evidence of heart failure (without hospitalization) manifested by signs or symptoms of volume overload or elevated intracardiac pressures (eg, elevated jugular venous pressure, shortness of breath or signs of pulmonary congestion on x-ray or auscultation, peripheral edema) that required treatment with a diuretic for improvement, evidence of cardiac involvement by echocardiography with an end diastolic interventricular septal wall thickness >12 mm, and presence of amyloid deposits in biopsy tissue and presence of a variant TTR genotype and/or TTR precursor protein identification by immunohistochemistry, scintigraphy or mass spectrometry. Exclusions for the study included subjects with: symptoms indicative of NYHA Classification IV at the Screening or Baseline visit, primary (light chain) amyloidosis and prior liver or heart transplantation, or implanted cardiac mechanical assist device.
Study Treatment:
Subjects were assigned to blinded treatment with either tafamidis 20 mg or 80 mg or matching placebo capsules OD, in addition to standard of care (eg, diuretics) for 30 months. In order to achieve the proper dosage and maintain the blind in the study, capsules were dispensed in a blinded fashion to achieve a daily dose of 4 capsules.  Each dose of 4 capsules consisted of either 3 capsules of matching blinded placebo and 1 capsule of blinded tafamidis 20 mg, 4 capsules of blinded tafamidis 20 mg, or 4 capsules of matching blinded placebo.  In the event of a dose reduction, the dose consisted of 2 capsules of blinded tafamidis 20 mg and 2 capsules of matching blinded placebo.
Efficacy Endpoints:
Primary Analysis The primary analysis used a hierarchical combination, applying the method of Finkelstein-Schoenfeld to: 1. All-cause mortality and 2. Frequency of cardiovascular-related hospitalizations over the duration of the trial, which was defined as the number of times a subject was hospitalized (ie, admitted to a hospital) for cardiovascular-related morbidity. Subjects who discontinued for transplantation (ie, heart transplantation and combined heart and liver transplantation) or for implantation of a cardiac mechanical assist device were handled in the primary analysis in the same manner as death. Key Secondary Endpoints 1. Change from Baseline to Month 30 in the distance walked during 6-Minute Walk Test (6MWT). 2. Change from Baseline to Month 30 in the Kansas City Cardiomyopathy Questionnaire (KCCQ) - Overall Summary (OS) score. Secondary Endpoints 1. Cardiovascular-related mortality. 2. Frequency of cardiovascular-related hospitalization. 3. All-cause mortality. 4. TTR stabilization at Month 1.
Safety Evaluations:
Safety and tolerability were assessed in comparison to placebo with AE reporting as well as the conduct of electrocardiograms (ECGs), clinical laboratory testing, vital signs, and physical examinations. The safety analysis set included all subjects who were enrolled (randomized) and received at least 1 dose of double-blind medication.
Statistical Methods:
The safety analysis set included all randomized subjects who received at least 1 dose of study drug.  The intent-to-treat (ITT) analysis set included all subjects in the safety analysis set who had at least 1 post-baseline efficacy evaluation (ie, post-baseline hospitalization, study visit, or date of death).  The per protocol (PP) analysis set included all subjects in the ITT set who did not violate inclusion/exclusion criteria and who did not have protocol violations considered to impact the interpretation of the primary efficacy analysis.
Primary Analysis
The primary analysis used a hierarchical combination applying the method of Finkelstein-Schoenfeld to all-cause mortality and frequency of cardiovascular-related hospitalizations (which is defined as the number of times a subject was hospitalized [ie, admitted to a hospital] for cardiovascular-related morbidity) over the duration of the trial. Subjects, who discontinued for transplantation (ie, heart transplantation and combined heart Protocol B3461028 - 28 August 2018 - Final and liver transplantation) or for implantation of a cardiac mechanical assist device, were handled in the primary analysis in the same manner as death.  The primary analysis combined the subjects in the tafamidis 20 mg and tafamidis 80 mg groups (including subjects in the 80 mg group that may have had a dose reduction to 40 mg) into 1 pooled group.  This pooled tafamidis group was compared with the placebo group. Key Secondary Analyses The key secondary endpoints were evaluated using a mixed model repeated measures analysis of covariance (ANCOVA). To maintain the type 1 error rate at or below the specified level, a pre-specified hierarchical order for testing of the primary analysis and then key secondary endpoints as indicated above was used to maintain the overall alpha at 0.05 for the primary analysis and the two key secondary endpoints.  The multiplicity procedure was applied to the ITT analysis set only. Statistical significance of the key secondary analyses was dependent on first achieving statistically significant results in the primary analysis (p ≤0.05).  If the p-value of the primary analysis was >0.05, then statistical significance could not be achieved for the subsequent tests on 6MWT and KCCQ-OS score.  In this hierarchical approach of key secondary endpoints, the change from baseline to Month 30 in distance walked during the 6MWT was first tested at the 0.05 level.  If the p-value for the test of 6MWT was ≤0.05, the second variable in the list, the change from baseline to Month 30 in the KCCQ-OS score was tested at the 0.05 level.  If the p–value of the test for 6MWT was >0.05, then statistical significance could not be achieved for the subsequent test on KCCQ-OS score. Secondary Analyses The "cardiovascular-related mortality" in all analyses, unless otherwise specified, combined deaths adjudicated as cardiovascular-related with deaths adjudicated as indeterminate. The cardiovascular-related mortality and all-cause mortality were analyzed using survival analysis methods. Frequency of cardiovascular-related hospitalizations was analyzed using the Poisson regression analyses. All the analyses on the secondary endpoints described above are additionally presented by TTR genotype (variant and wild-type), NYHA baseline classification, as well as dose (randomized dose group) and were considered exploratory. The proportion of subjects who achieved TTR stabilization in each treatment group at Month 1 was compared using a Cochran-Mantel-Haenszel test. A similar test of proportion was done on TTR stabilization at all other time points and was considered exploratory.  No subgroup analyses were done at these other time points. :18f421208\Approved\Approved On: 19-Sep-2018 02:5 Except for the analyses by dose group, all analyses of the secondary endpoints, including the proposed exploratory analyses of these endpoints compared the pooled tafamidis group with the placebo group. Safety Analysis The following 3-tier approach was used to summarize AEs.  Under this approach, AEs were classified into 1 of 3 tiers.  While the AEs were additionally analyzed by subgroups, the 3-tier approach only applied to the overall AE analyses. . Tier-1 events: These were pre-specified events of clinical importance and were maintained in a list in the product's Safety Review Plan.  This list was updated as more was understood about the drug. . Tier-2 events: These were events that were not Tier-1 but were "common."  A Medical Dictionary for Regulatory Activities (MedDRA) Preferred Term (PT) was defined as a Tier-2 event if there were at least 4 in any treatment group. . Tier-3 events: These were events that were neither Tier-1 nor Tier-2 events. The analysis of AEs under the 3-tier approach was considered exploratory.  There was no adjustment for multiple comparisons or stratification factors in the analyses.  For Tier-1 and Tier-2 events, the proportion of AEs observed in each of the treatment groups was presented along with the point estimates and associated 95% confidence intervals of the risk difference for the pooled tafamidis group compared with placebo. For Tier-1 events, p-values were included in the presentations.  AEs were arranged in the output sorted in descending point estimate of the risk difference within system organ class. Footnotes in the outputs included the methods used to derive any p-values and confidence intervals as per Pfizer standards.  The Tier 1 AEs were analyzed using the approach of Chang and Zhang who inverted two 1-sided tests at half the significance level each for calculating p-values and confidence intervals. For Tier 2 AEs, both proportion and 95% confidence intervals (CIs) were generated using an asymptotic approach (Proc Binomial).  A MedDRA PT was defined as a Tier-2 event if there were at least 4 in any treatment group.  A cross-industry expert team on safety planning, evaluation, and reporting suggested to use the "Rule of 4" to define Tier-2 events.  The "Rule of 4" states that if a trial has 400 or fewer subjects per group and there are 4 or more subjects with a given MedDRA PT in any treatment group, then that PT will be categorized as a Tier-2 event. For Tier 3 events, simple proportions were presented.
RESULTS
Subject Disposition and Demography:
A summary of subject disposition is provided in Table 2.  Of the 548 subjects screened for entry into the study, 441 were randomized into treatment.  This included 88 subjects randomized into the tafamidis 20 mg group, 176 subjects randomized into the tafamidis 80 mg group, and 177 subjects randomized into the placebo group.  Subjects were stratified by TTR genotype and NYHA baseline classification.  All randomized subjects received at least 1 dose of study drug (safety analysis set).  A total of 6 subjects requested a blinded dose reduction: 2 in the tafamidis 80 mg group and 4 in the placebo group.  Of the 441 subjects included in the safety analysis set, 258 (58.5%) completed the study and 106 (24.0%) discontinued the study.
Total = pooled tafamidis + placebo. a. The number of subjects completed is derived from the subject summary electronic case report form. b. Discontinued from study other than death. C. Analyzed for safety tabulates the number of subjects treated. d. Adverse events tabulates the number of subjects who have reported an AE. e. Laboratory data tabulates the number of subjects who have at least 1 lab result. f. A summary of demographic and baseline characteristics for the ITT analysis set is provided in Table 3.  Overall, the baseline characteristics of the tafamidis and placebo groups were similar. e18f421208\Approved\Approved On: 19-Sep-2018 02:5 Public Disclosure Synopsis Protocol B3461028 - 28 August 2018 - Final
7e18f421208\Approved\Approved On: 19-Sep-2018 02: PFIZER CONFIDENTIAL Page 12
mass index; Min = Minimum; Max = Maximum; n = number of subjects, N = total number of subjects; NYHA = New York Heart Association classification; SD = Standard Deviation; TTR = Transthyretin Age at screening.  Age is calculated as screening date year – birth year.  If the screening date month is less a. than the DOB month, or the screening date month = DOB month and the screening date day is less than the DOB day, then age = (screening date year - DOB year) – 1. b. BMI is defined as weight/(height*0.01)**2. The modified BMI (mBMI) is calculated by multiplying the body mass index [weight (kg)/height (meters C. squared)] by serum albumin concentration (g/L). NYHA class: I = without resulting limitations, II = slight limitation, III = marked limitation, IV = inability d. to carry on any physical activity without discomfort.  Given the very low number of enrolled subjects with a baseline classification of NYHA Class I, the baseline groupings used for efficacy analyses were changed from ‘NYHA Class I and NYHA Classes II and II combined’ to NYHA Classes I and II combined and NYHA Class III'. Formula for pack years cigarettes = (average number of cigarettes per day divided by 20) x years of e. smoking.  Formula for pack years tobacco = ounces per week x 2 divided by 7 x years of smoking.
Efficacy Results:
Primary Analysis The primary analysis used a hierarchical combination applying the method of Finkelstein-Schoenfeld to: All-cause mortality, and . . Frequency of cardiovascular-related hospitalizations over the duration of the trial, which was defined as the number of times a subject was hospitalized (ie, admitted to a hospital) for cardiovascular-related morbidity. The Finkelstein-Schoenfeld method is based on the combination of all-cause mortality and cardiovascular-related hospitalization frequency and gives higher priority to mortality.  The 7e18f421208\Approved\Approved On: 19-Sep-2018 02:56 method is based on a pairwise ranking procedure and only uses cardiovascular-related hospitalization frequency when the 2 given subjects are not able to be ranked based on mortality.  The Finkelstein-Schoenfeld analysis was applied by 2 strata (TTR genotype and NYHA baseline classification) and combined to produce the overall test statistic.  As a result, subject to subject pairwise comparisons were done within the group of similarly severe subjects and then combined. Subjects who discontinued for transplantation (ie, heart transplantation and combined heart and liver transplantation) or for implantation of a cardiac mechanical assist device were handled in the primary analysis in the same manner as death. Finkelstein-Schoenfeld analysis of all-cause mortality and frequency of cardiovascular-related hospitalizations for the ITT analysis set is provided in Table 4.  The primary analysis of the pooled active treatment demonstrated a statistically significant and clinically meaningful treatment effect favoring tafamidis (p=0.0006).  The percentage of subjects alive at Month 30 in the pooled tafamidis and placebo groups was 70.5% and 57.1%. respectively.  The average frequency per year of cardiovascular-related hospitalizations through Month 30 among subjects alive at Month 30 was 0.297 for the pooled tafamidis group and 0.455 for the placebo group.  The descriptive mean was not adjusted for covariates.  The model-based covariate-adjusted means for cardiovascular-related hospitalization frequency are presented in Table 7.
Finkelstein-Schoenfeld Analysis of All-Cause Mortality and Frequency of
Cardiovascular Related Hospitalizations by Pooled Active Treatment (ITT

Note: Only CV-related hospitalizations where the subject is admitted to a hospital over the duration of the trial are included in this analysis; any hospitalizations prior to randomization date are not included. CV-related hospitalizations per year is calculated as (Subject's number of CV related hospitalizations) / a. (duration on study in years). The Finkelstein-Schoenfeld test is a hierarchical comparison of mortality and CV-hospitalization.  Each b. subject in the clinical study is compared with every other subject within each stratum in a pairwise manner (4 stratum based on NYHA Class and TTR genotype).  Subjects, who discontinued for transplantation (ie, heart transplantation and combined heart and liver transplantation) or for implantation of a cardiac mechanical assist device, were handled in the primary analysis in the same manner as death stratum in a pairwise manner.  The primary comparison tests if at least 1 and possibly both all-cause mortality and frequency of CV related hospitalizations are different between the tafamidis and placebo treatment groups. :18f421208\Approved\Approved On: 19-Sep-2018 02:5 The 2 components of the Finkelstein-Schoenfeld analysis, all-cause mortality and frequency of cardiovascular-related hospitalization, were analyzed separately as secondary endpoints but are presented below in order to aid understanding of the primary analysis. A summary of mortality and hospitalizations for all subjects is provided in Table 5.  The occurrences of death were higher in the placebo group (72 [40.7%] subjects) than in the pooled tafamidis group (72 [27.3%] subjects) (heart transplants and cardiac mechanical assist devices not treated as death).  Total subjects hospitalized were similar in the pooled tafamidis and placebo groups (190 [72.0%] and 136 [76.8%] subjects, respectively).
subjects. a. b. c. Note: CV-related as determined by Adjudication Committee. Deaths (Notice of Death case report form recorded) up to 30 months post randomization are counted. Hospitalizations where the subject is admitted to a hospital over the duration of the trial are included in this analysis; any hospitalizations prior to randomization date are not included.  A subject may be counted for each category of hospitalization that applies. Heart Transplants include heart and heart-combo transplantations. A Kaplan-Meier plot of time to event all-cause mortality with heart transplants and cardiac mechanical assist devices treated as death is presented in Figure 2. Table 6 presents the results from the analysis of time to event all-cause mortality for ITT analysis set (heart transplants and cardiac mechanical assist devices treated as death).  This analysis treats the 7 (2.7%) and 4 (2.3%) heart transplants in the pooled tafamidis and placebo groups, respectively, and the 2 (0.8%) cardiac mechanical assist device implantations in the pooled tafamidis group as death.  Overall, all-cause mortality for the pooled tafamidis and placebo groups was 78 (29.5%) and 76 (42.9%) subjects, respectively.  There were 186 (70.5%) and 101 (57.1%) subjects in the pooled tafamidis and placebo groups, respectively, censored because they were alive at the time of analysis.  The hazard ratio from the all-cause mortality Cox-proportional hazard model for pooled tafamidis was 0.698 (95% CI 0.508, 0.958), indicating a 30.2% reduction in the risk of death relative to the Public Disclosure Synopsis Protocol B3461028 - 28 August 2018 - Final placebo group (p=0.0259).  The observed effect on overall survival emerged after approximately 18 months of treatment (Figure 2). 77e18f421208\Approved\Approved On: 19-Sep-2018 02:50 (G PFIZER CONFIDENTIAL Page 16 Figure 2.    Kaplan-Meier Plot of Time to Event All-Cause Mortality³ - Pooled Active Treatment (ITT Analysis Set)
99 78 51
75 76 Note: o indicates censored observations. a.     Heart transplantation and combined heart and other organ transplantation or for implantation of a cardiac mechanical assist device, are handled in the same manner as death.
subjects; NE = not estimable; NYHA = New York Heart Association; TTR = transthyretin. Heart transplantation and combined heart and other organ transplantation or for implantation of a cardiac a. mechanical assist device, are handled in the same manner as death. Calculated using Kaplan-Meier method b. Hazard Ratio from a Cox Proportional Hazards model with TTR genotype (Variant and Wild-type) and c. NYHA baseline classification (NYHA Classes I and II combined and NYHA Class III) in the model. Results from analysis of the frequency of cardiovascular-related hospitalization are summarized for the ITT analysis set in Table 7.  Overall, there were 138 (52.3%) and 107 (60.5%) subjects with at least 1 cardiovascular-related hospitalization in the pooled tafamidis and placebo groups, respectively.  The frequency of cardiovascular-related hospitalization was 0.4750 (95% CI 0.4181, 0.5396) and 0.7025 (95% CI 0.6174, 0.7993) for the pooled tafamidis and placebo groups, respectively.  The relative risk ratio between the pooled tafamidis and placebo groups was 0.6761, indicating a 32.39% reduction in the risk of cardiovascular-related hospitalization in the tafamidis group relative to placebo (p <0.0001). e18f421208\Approved\Approved On: 19-Sep-2018 02:5
number of subjects; n = number of subjects; NYHA = New York Heart Association; SD = standard deviation; TTR = transthyretin. CV-related hospitalizations per year is calculated as (subject's number of CV-related hospitalizations) / a. (duration on study in years). Poisson regression analysis with treatment, TTR Genotype (variant and wild-type), NYHA baseline b. classification (NYHA Classes I and II combined and NYHA Class III), treatment-by-TTR genotype interaction, and treatment-by-NYHA baseline classification interaction terms as factors adjusted for treatment duration.  Only CV-related hospitalizations where the subject is admitted to a hospital over the duration of the trial are included in this analysis; any hospitalizations prior to randomization date are not included.
Key Secondary Analyses
Change from Baseline to Month 30 in the distance walked during the 6MWT The pooled tafamidis LS mean change from Baseline 6MWT difference from placebo for the ITT analysis set is shown in Figure 3.  A statistically significant treatment effect favoring tafamidis was observed at Month 30 (p <0.0001).  The significant difference between pooled tafamidis and placebo was first observed at Month 6 (p=0.0067) and remained significant through Month 30. Change from Baseline to Month 30 in the distance walked during the 6MWT for the pooled active treatment (ITT analysis set) is provided in Table 8.  At Baseline, mean (standard deviation [SD]) 6MWT distance for the pooled tafamidis and placebo groups was 350.55 (121.296) and 353.26 (125.983) meters, respectively.  At Month 30, the least squares (LS) mean (standard error [SE]) change from Baseline for the pooled tafamidis and placebo groups was -54.87 (5.068) and -130.55 (9.798) meters, respectively.  The pooled tafamidis LS mean SE change from Baseline difference from placebo was 75.68 (9.236) meters (p <0.0001). e18f421208\Approved\Approved On: 19-Sep-2018 02:56 Figure 3. Distance Walked During 6-Minute Walk Test LS Means (SE) Change From Baseline to Month 30 - Pooled Active Treatment (ITT Analysis Set) TTR = transthyretin. LS means are from an ANCOVA (MMRM) model with an unstructured covariance matrix; center and subject within center as random effects; treatment, visit, TTR genotype (variant and wild-type), and visit by treatment interaction, as fixed effects and baseline score as covariate. 177e18f421208\Approved\Approved On: 19-Sep-2018 02:50 (GM
squares; max = maximum; min = minimum; MMRM = Mixed Model Repeated Measure; N = total number of subjects; n = number of subjects; SD = standard deviation, SE = standard error; TTR = transthyretin. Note: LS means are from an ANCOVA (MMRM) model with an unstructured covariance matrix (or as appropriate); center and subject within center as random effects; treatment, visit, TTR genotype (variant and wild-type), and visit by treatment interaction, as fixed effects and baseline score as covariate.
Change from Baseline to Month 30 in the KCCQ-OS Score
The pooled tafamidis LS mean change from Baseline KCCQ-OS score difference from placebo for the ITT analysis set is shown in Figure 4.  A statistically significant treatment effect favoring tafamidis was observed at Month 30 (p <0.0001).  The significant difference between pooled tafamidis and placebo was first observed at Month 6 (p=0.0113) and remained significant through Month 30. Change from Baseline to Month 30 in the KCCQ-OS score for the ITT analysis set is provided in Table 9.  At Baseline, mean (SD) KCCQ-OS score for the pooled tafamidis and placebo groups was 67.274 (21.3561) and 65.898 (21.7357), respectively.  At Month 30, the LS mean (SE) change from Baseline for the pooled tafamidis and placebo groups was -7.16 (1.415) and -20.81 (1.971), respectively.  The pooled tafamidis LS mean (SE) difference from placebo was 13.65 (2.130) (p <0.0001). 7e18f421208\Approved\Approved On: 19-Sep-2018 02:56
Figure 4.
Kansas City Cardiomyopathy Questionnaire Overall Summary Score LS Means (SE) Change From Baseline to Month 30 - Pooled Active Treatment (ITT Analysis Set) TTR = transthyretin. Notes: Overall Summary score is calculated as the mean of Physical Limitation, Symptom Frequency, Symptom Burden, Quality of Life, and Social Limitation Scores.  LS means are from an ANCOVA (MMRM) model with an unstructured covariance matrix; center and subject within center as random effects; treatment, visit, TTR genotype (variant and wild-type), and visit by treatment interaction, as fixed effects and baseline score as covariate. 177e18f421208\Approved\Approved On: 19-Sep-2018 02:50 (GI
KCCQ-OS = Kansas City Cardiomyopathy Questionnaire Overall Summary; LS = least squares; max = maximum; min = minimum; MMRM = Mixed Model Repeated Measure; N = total number of subjects; n = number of subjects; SD = standard deviation, SE = standard error; TTR = transthyretin. Note: LS means are from an ANCOVA (MMRM) model with an unstructured covariance matrix (or as appropriate); center and subject within center as random effects; treatment, visit, TTR genotype (variant and wild-type), and visit by treatment interaction, as fixed effects and baseline score as covariate. Overall Summary is calculated as the mean of Physical Limitation, Symptom Frequency, Symptom a. Burden, Quality of Life, and Social Limitation Scores.
Secondary Analyses
Cardiovascular-Related Mortality
Results for time to event cardiovascular-related mortality for ITT analysis set are provided in Table 10.  Overall, cardiovascular-related mortality for pooled tafamidis and placebo groups was 64 (24.2%) and 63 (35.6%) subjects, respectively.  There were 200 (75.8%) and 114 (64.4%) subjects in the pooled tafamidis and placebo groups, respectively, who were censored.  Subjects in the pooled tafamidis and placebo groups were censored because they were alive at the time of analysis (186 [70.5%] and 101 [57.1%] subjects, respectively) and deaths for all other reasons (14 [5.3%] and 13 [7.3%] subjects, respectively).  The hazard ratio from the cardiovascular-related mortality Cox-proportional hazard model was 0.691 (95% CI 0.488, 0.980), indicating a 30.9% reduction in the risk of cardiovascular-related death in the pooled tafamidis group relative to the placebo group (p=0.0383). 7e18f421208\Approved\Approved On: 19-Sep-2018 02:50
subjects; n = number of subjects; NYHA = New York Heart Association; TTR = transthyretin. Deaths adjudicated as CV-related and Indeterminate. a. Heart transplantation and combined heart and other organ transplantation or for implantation of a cardiac b. mechanical assist device, are handled in the same manner as death.  For cardiovascular-related mortality, subjects who died for reasons other than cardiovascular (including 'indeterminate') are designated as censored at the time of death. Calculated using Kaplan-Meier method C. Hazard Ratio from a Cox Proportional Hazards model with TTR genotype (Variant and Wild-type) and d. NYHA baseline classification (NYHA Classes I and II combined and NYHA Class III) in the model.
All-Cause Mortality
Pooled tafamidis results for all-cause mortality are provided above in Table 6 as supporting analyses for the primary efficacy analysis. Frequency of Cardiovascular-Related Hospitalizations Pooled tafamidis results for the frequency of cardiovascular-related hospitalizations are provided above in Table 7 as supporting analyses for the primary efficacy analysis.
TTR Stabilization at Month 1
TTR stabilization at Month 1 is shown for the ITT analysis set in Table 11.  At Month 1 (pre-dose sample), a significantly greater proportion of subjects in the pooled tafamidis group (211/245 [86.1%] subjects) demonstrated TTR stabilization than was observed for subjects in the placebo group (6/170 [3.5%] subjects) (p <0.0001).  Similar results were obtained from 7e18f421208\Approved\Approved On: 19-Sep-2018 02:50 Protocol B3461028 - 28 August 2018 - Final the sample collected which targeted the time of maximum concentration (Month 1, 4 hours 30 minutes).
Long-term stability duration was exceeded for 119 samples.  Results from these samples were excluded from any summarization or analyses. Based on Chi-square test for proportions. a.
Safety Results:
All-Causality Non-Serious Adverse Events: All-causality non-serious treatment-emergent adverse events (TEAEs) that occurred in >5% of subjects are summarized by system organ class (SOC) and preferred term (PT) in Table 12.  The most frequently reported non-serious AE by PT was fall in the tafamidis 20 mg and 80 mg treatment groups and dyspnea in the placebo group.  Other frequently reported non-serious AEs by PT in all treatment groups were atrial fibrillation, fatigue, and edema peripheral. e18f421208\Approved\Approved On: 19-Sep-2018 02:5
treatment emergent all causalities adverse events; n2 = the number of occurrences of treatment emergent causally related to treatment adverse events. Notes: Except for "n1" and "n2," subjects are only counted once per treatment for each row.  Includes events occurring up to 28 days after last dose of study drug.  MedDRA (Version 20.1) coding dictionary applied Public Disclosure Synopsis Protocol B3461028 - 28 August 2018 - Final All-Causality Treatment-Emergent Serious Adverse Events: The incidence of SAEs by SOC and PT are summarized in Table 13 .  The most frequently reported SAEs by SOC were Cardiac disorders and Infections and infestations.  There were 3 SAEs in the tafamidis 20 mg group, 3 SAEs in the tafamidis 80 mg group, and 6 SAEs in the placebo group that were considered by the investigator to be treatment-related. e18f421208\Approved\Approved On: 19-Sep-2018 02:50
n2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 l 0 0 0 0 0 0 0 0 0 0 0 0 0 0
n2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
n2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0
n2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0
n2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
n2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 l 0 0 0 0 0 1 0 0 0 0 0
n2 0 0 0 0 0 0 2 0 0 0 0 0 0 0 l 0 0 0 0 0 0 0 l 0 0 0 0 0 0 0 0 0 0 0
n2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 l 0 0 0 0 0 0 l 0
n2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 Public Disclosure Synopsis Protocol B3461028 - 28 August 2018 - Final
causalities adverse events; n2 = the number of occurrences of treatment emergent causally related to treatment adverse events. Notes: Except for "n1" and "n2," subjects are only counted once per treatment for each row.  Includes events occurring up to 28 days after last dose of study drug.  MedDRA (Version 20.1) coding dictionary applied. Table 13.   Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred Term
Withdrawals of Subjects from the Study
Discontinuations from the study are summarized in Table 14.  A greater proportion of subjects in the placebo group (52.0%) discontinued from the study compared with the tafamidis 20 mg and 80 mg treatment groups (31.8% and 35.8%, respectively).
All assessments where the relation to study drug was not defined. Relationship is determined by investigator's assessment of relationship to study treatment on the adverse event case report form page.
Deaths:
A total of 144 subjects died; 77 occurred during the study period (14 [15.9%], 25 [14.2%], and 38 [21.5%] subjects in the tafamidis 20 mg, tafamidis 80 mg, and placebo groups, respectively) and 67 occurred during the follow-up period (9 [10.2%], 24 [13.6%], and 34 [19.2%] subjects in the tafamidis 20 mg, tafamidis 80 mg, and placebo groups, respectively).  None of the deaths were assessed as related to treatment.  The majority of deaths in the study were considered the result of underlying disease.
CONCLUSION(S):
. This Phase 3 study demonstrated the efficacy of tafamidis as therapy for subjects with TTR-CM, with statistically significant reduction at Month 30 in on all-cause mortality and the frequency of cardiovascular-related hospitalizations. . In addition to a positive primary analysis, this study demonstrated significant and clinically meaningful effects of tafamidis on the individual components of the primary analysis (all-cause mortality and frequency of cardiovascular-related hospitalizations). a. b. Public Disclosure Synopsis Protocol B3461028 - 28 August 2018 - Final . Tafamidis treatment also significantly reduced the decline in functional capacity (6MWT) and quality of life (KCCO-OS score).  The effect of tafamidis treatment was seen at Month 6 in functional capacity (6MWT) and quality of life (KCCQ-OS score) whereas effect on overall survival emerged after approximately 18 months. . The efficacy of tafamidis was supported by all other secondary efficacy endpoints (cardiovascular-related mortality, frequency of cardiovascular-related hospitalization, all-cause mortality, and TTR stabilization at Month 1). . Significant treatment effects were observed for both the 20 mg and 80 mg tafamidis doses in the primary, key secondary, and secondary analyses when compared with placebo. . Tafamidis treatment was generally safe and well tolerated in the study subject population, with few dose reductions and a similar frequency of TEAEs and serious TEAEs between the treatment groups.  A greater proportion of deaths were observed in the placebo group compared with the tafamidis group.  None of the deaths were related to study treatment, and most were considered as a result of the disease under study. . The demonstrated efficacy and safety profile of tafamidis in this study population supports tafamidis as a treatment option for TTR-CM. 8f421208\Approved\Approved On: 19-Sep-2018 02:5