Long-term Safety of Tafamidis in Subjects With Transthyretin Cardiomyopathy

Time to all-cause mortality was calculated from first dose of randomized treatment in parent study (B3461028) to all-cause mortality events. All-cause mortality events included deaths, heart transplants and cardiac mechanical assist devices implantation treated as death. Treated participants from the parent study who discontinued prior to the start of this study were also included in this analysis as planned. Data from participants who dropped out for a liver-only transplantation were handled in the same manner as the data from all other censored participants. Censored participants were participants who completed study or discontinued from the study (including discontinued by sponsor or participants withdrew, or discontinued due to Adverse event (AE), or alive at the time of analysis. Kaplan Meier method was used for analysis. Therefore, this analysis was based on the pooled dose groups, as per the statistical analysis plan (SAP).

All-cause mortality included all participants who had discontinue for transplantation (i.e. heart transplantation and combined heart and liver transplantation) or for implantation of a cardiac mechanical assist device, were handled in the same manner as death. Data from participants who dropped out for a liver-only transplantation were handled in the same manner as the data from all other censored participants. Censored participants were participants who completed study or discontinued from the study (including discontinued by sponsor or participants withdrew, or discontinued due to AE), or alive at the time of analysis. Kaplan Meier method was used for analysis.

An AE was any untoward medical occurrence in a participant who received investigational product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment or worsened during the treatment period relative to the pretreatment state. AEs included both SAEs and all Non-SAEs. A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; was life-threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/ incapacity; resulted in congenital anomaly/birth defect; considered an important medical event.

Time to cardiovascular-related mortality was calculated from first dose of randomized treatment in B3461028 . Participants who discontinued for transplantation (that is heart transplantation and combined heart and liver transplantation) or for implantation of cardiac mechanical assist device were treated as a death. Treated participants from the parent study who discontinued prior to the start of this study were also included in this analysis as planned. Kaplan-Meier method was used. Therefore, this analysis was based on the pooled dose groups, as per the SAP.

Deaths adjudicated as cardiovascular-related and indeterminate were reported. Cardiovascular-related mortality events included deaths, heart transplants and cardiac mechanical assist devices implantation treated as death. Cardiovascular relatedness was based on clinical judgement.

Mean annual rate of all cause hospitalization was calculated for each participant as the participant's number of all cause hospitalizations divided by this participant's duration on study in years. Hospitalization was defined as any initial admission (even less than 24 hours) in a hospital or equivalent healthcare facility or any prolongation of an existing admission. Only all cause hospitalizations where the participant was admitted to a hospital during the current extension study were included in this analysis. Any hospitalizations prior to randomization date were not included.

Mean annual rate of CV related hospitalization was calculated for each participant as the participant's number of CV related hospitalizations divided by this participant's duration on study in years. CV-related hospitalizations included hospitalizations due to heart failure, arrhythmia, myocardial infarction, stroke, and other cardiovascular-related events. Hospitalization was defined as any initial admission (even less than 24 hours) in a hospital or equivalent healthcare facility or any prolongation of an existing admission. Admission also included transfer within the hospital to an acute/intensive care unit (example: from the psychiatric wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a tuberculosis unit).

KCCQ: 23-item, self-administered questionnaire that assesses health status and health-related quality of life in participants with heart failure. KCCQ quantifies 8 domains: physical limitations, symptom stability, symptom frequency, symptom burden, total symptom (mean of symptom frequency and symptom burden), self-efficacy, quality of life and social limitations). Scores were generated for each domain and scaled from 0 (worst) to 100 (best possible status). KCCQ-clinical summary score was calculated as mean of the following domains- physical limitation and total symptoms and transformed to a single score which ranged from 0 (worst) -100 (best possible status), higher scores = better health status. Data for change from baseline was reported as least square (LS) mean.

KCCQ: 23-item, self-administered questionnaire that assesses health status and health-related quality of life in participants with heart failure. KCCQ quantifies 8 domains: physical limitations, symptom stability, symptom frequency, symptom burden, total symptom (mean of symptom frequency and symptom burden), self-efficacy, quality of life and social limitations). Scores were generated for each domain and scaled from 0 (worst) to 100 (best possible status). KCCQ-overall score was calculated as mean of the following domains- physical limitation, total symptoms (average of symptom frequency & symptom burden), quality of life, social limitation and transformed to a single score which ranged from 0 (worst) -100 (best possible status), higher scores = better health status. Data for change from baseline was reported as LS mean.

KCCQ: 23-item, self-administered questionnaire that assesses health status and health-related quality of life in participants with heart failure. KCCQ quantifies 8 domains: physical limitations, symptom stability, symptom frequency, symptom burden, total symptom (mean of symptom frequency and symptom burden), self-efficacy, quality of life and social limitations). Scores were generated for each domain and scaled from 0 (worst) to 100 (best possible status). KCCQ Total Symptoms score was calculated as mean of the following domains- symptom frequency and symptom burden and transformed to a single score which ranged from 0 (worst) -100 (best possible status), higher scores = better health status. Data for change from baseline was reported as LS mean.

KCCQ: 23-item, self-administered questionnaire that assesses health status and health-related quality of life in participants with heart failure. KCCQ quantifies 8 domains: physical limitations, symptom stability, symptom frequency, symptom burden, total symptom (mean of symptom frequency and symptom burden), self-efficacy, quality of life and social limitations). Scores were generated for each domain and scaled from 0 (worst) to 100 (best possible status). KCCQ-clinical summary score was calculated as mean of the following domains- physical limitation and total symptoms and transformed to a single score which ranged from 0 (worst) -100 (best possible status), higher scores = better health status. Data for change from baseline was reported as mean.

KCCQ: 23-item, self-administered questionnaire that assesses health status and health-related quality of life in participants with heart failure. KCCQ quantifies 8 domains: physical limitations, symptom stability, symptom frequency, symptom burden, total symptom (mean of symptom frequency and symptom burden), self-efficacy, quality of life and social limitations). Scores were generated for each domain and scaled from 0 (worst) to 100 (best possible status). KCCQ-overall score was calculated as mean of the following domains- physical limitation, total symptoms (average of symptom frequency & symptom burden), quality of life, social limitation and transformed to a single score which ranged from 0 (worst) -100 (best possible status), higher scores = better health status. Data for change from baseline was reported as mean.

KCCQ: 23-item, self-administered questionnaire that assesses health status and health-related quality of life in participants with heart failure. KCCQ quantifies 8 domains: physical limitations, symptom stability, symptom frequency, symptom burden, total symptom (mean of symptom frequency and symptom burden), self-efficacy, quality of life and social limitations). Scores were generated for each domain and scaled from 0 (worst) to 100 (best possible status). KCCQ Total Symptoms score was calculated as mean of the following domains- symptom frequency and symptom burden and transformed to a single score which ranged from 0 (worst) -100 (best possible status), higher scores = better health status. Data for change from baseline was reported as mean.

NYHA classification: Class I: Participants with cardiovascular disease (CVD) but without resulting limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or anginal pain; Class II: Participants with CVD resulting in slight limitation of physical activity and were comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or angina pain; Class III: participants with CVD resulting in marked limitation of physical activity and were comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnea, or anginal pain; Class IV: participants with CVD resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity was undertaken, discomfort was increased.

BMI was calculated as: body weight in kilogram (kg) divided by (/) square of body height measurement in meters square (m^2).

Modified (m)BMI of participants was calculated to determine if there was any gastrointestinal involvement in participants. The mBMI was calculated by multiplying BMI by serum albumin concentration gram/liter (g/L).

Troponin I is the cardiac markers. Higher level of the marker was indicative of heart damage. It was measure in nanogram per milliliter (ng/mL). Safety analysis population included all participants (Cohorts A and B) who were enrolled in this study and taken at least 1 dose of study medication.

NT-proBNP was a cardiac marker which had the prognostic value for participants with heart failure or left ventricular dysfunction. It was measure in picomole per liter (pmole/L). Higher level of the marker was indicative of heart damage. Safety analysis population included all participants (Cohorts A and B) who were enrolled in this study and taken at least 1 dose of study medication.