Transthyretin (TTR) Amyloid Cardiomyopathy
Conditions
Keywords
amyloidosis, amyloid, transthyretin, TTR
Brief summary
This Phase 3 study will investigate the efficacy, safety and tolerability of an oral daily dose of 20 mg or 80 mg tafamidis meglumine capsules compared to placebo in subjects with either transthyretin genetic variants or wild-type transthyretin resulting in amyloid cardiomyopathy.
Detailed description
Phase 3, multicenter, global, three-arm, parallel design, placebo-controlled, double-blind, randomized study to determine efficacy, safety and tolerability of tafamidis on clinical outcomes (all-cause mortality and frequency of cardiovascular-related hospitalizations) in subjects with either transthyretin genetic variants or wild-type transthyretin resulting in amyloid cardiomyopathy.
Interventions
DRUGTafamidis
Tafamidis 20 mg in soft gel capsules administered once a day for 30 months
DRUGPlacebo
Placebo in soft gel capsules administered once a day for 30 months
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
* Medical history of Heart Failure (HF) with at least 1 prior hospitalization for HF or clinical evidence of HF (without hospitalization) manifested by signs or symptoms of volume overload or elevated intracardiac pressures (e.g., elevated jugular venous pressure, shortness of breath or signs of pulmonary congestion on x-ray or auscultation, peripheral edema) that required/requires treatment with a diuretic for improvement, * Evidence of cardiac involvement by echocardiography with an end-diastolic interventricular septal wall thickness \> 12 mm, * 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
Exclusion criteria
* A New York Heart Association (NYHA) classification of IV. * Presence of primary (light chain) amyloidosis. * Prior liver or heart transplantation or implanted cardiac mechanical assist device.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hierarchical Combination of All-Cause Mortality and Frequency of Cardiovascular-Related Hospitalizations | Baseline up to Month 30 | All-cause mortality and frequency of cardiovascular hospitalization were analyzed using Finkelstein-Schoenfeld method. The method combines all-cause mortality and frequency of CV-related hospitalizations in a hierarchical fashion using all-cause mortality first. The method compares every participant with every other participant within strata, assigning a +1 to the better participant and a -1 to the worse participant and 0 if they are tied. Participants who discontinued for transplantation (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. 'Win' represents a participant doing better based on hierarchical comparison. The reported unit is the total wins for each treatment group from performing such a hierarchical comparison across all 4 strata in the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-Cause Mortality | Baseline up to Month 30 | Number of deaths due to any cause was analyzed. Participants who discontinued for transplantation (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. |
| Change From Baseline in the Total Distance Walked During 6 Minute Walk Test (6MWT) at Month 30 | Baseline, Month 30 | 6MWT is the total distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. |
| Frequency of Cardiovascular-Related Hospitalizations | Baseline to Month 30 | CV related hospitalizations per year is calculated as participant's number of CV related hospitalizations upon duration on study in years. |
| Number of Participants With Cardiovascular-Related Mortality | Baseline up to Month 30 | Deaths adjudicated as CV-related and indeterminate are reported. Participants who discontinued for transplantation (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. |
| Percentage of Participants With Stabilized Transthyretin (TTR) at Month 1 | Month 1 | TTR stabilization is a measure of the degree of stabilization afforded the TTR molecule by tafamidis. |
| Change From Baseline in Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) at Month 30 | Baseline, Month 30 | KCCQ is a 23-item participant-completed questionnaire that assesses health status and health-related quality of life in participants with heart failure. Eight domain scores were calculated for the KCCQ: Physical limitation, Social limitation, Quality of life, Self-efficacy, Symptom stability, Symptom frequency, Symptom burden, and Total symptoms (calculated as the mean of Symptom frequency and Symptom burden scores). Two summary scores were also calculated: Clinical Summary (calculated as mean of Physical limitation and Total symptom scores) and Overall Summary (calculated as mean of Physical limitation, Social limitation, Total symptoms, and Quality of life scores). Domain and summary scores were scaled to range from 0 (minimum) to 100 (maximum); higher scores represent better health status. |
Countries
Belgium, Brazil, Canada, Czechia, France, Germany, Italy, Japan, Netherlands, Spain, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
Pooled analysis of the tafamidis treatment groups \[20 milligrams (mg) and 80 mg\] was performed in comparison to placebo group.
Participants by arm
| Arm | Count |
|---|---|
| Tafamidis 20 mg Participants with variant transthyretin cardiomyopathy (TTR-CM) genotype or wild-type TTR-CM genotype received one tafamidis 20 milligram (mg) capsule + 3 placebo capsules (matched to tafamidis) orally once daily for 30 months. | 88 |
| Tafamidis 80 mg Participants with variant TTR-CM genotype or wild-type TTR-CM genotype received tafamidis 80 mg (4 capsules of 20 mg each) orally once daily for 30 months. | 176 |
| Placebo Participants with variant TTR-CM genotype or wild-type TTR-CM genotype received 4 placebo capsules matched to tafamidis orally once daily for 30 months. | 177 |
| Total | 441 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 12 | 11 |
| Overall Study | Cardiac Device Implantation | 0 | 2 | 0 |
| Overall Study | Death | 14 | 25 | 38 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | No longer willing to participate | 8 | 17 | 37 |
| Overall Study | Organ Transplantation | 1 | 5 | 5 |
| Overall Study | Protocol Violation | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Tafamidis 20 mg | Tafamidis 80 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 73.3 years STANDARD_DEVIATION 7.07 | 75.2 years STANDARD_DEVIATION 7.24 | 74.1 years STANDARD_DEVIATION 6.69 | 74.3 years STANDARD_DEVIATION 7.01 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 4 Participants | 7 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 84 Participants | 171 Participants | 170 Participants | 425 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 11 Participants | 5 Participants | 18 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 26 Participants | 26 Participants | 63 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 75 Participants | 136 Participants | 146 Participants | 357 Participants |
| Sex: Female, Male Female | 5 Participants | 18 Participants | 20 Participants | 43 Participants |
| Sex: Female, Male Male | 83 Participants | 158 Participants | 157 Participants | 398 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 23 / 88 | 49 / 176 | 72 / 177 |
| other Total, other adverse events | 86 / 88 | 170 / 176 | 171 / 177 |
| serious Total, serious adverse events | 66 / 88 | 133 / 176 | 140 / 177 |
Outcome results
Primary
Hierarchical Combination of All-Cause Mortality and Frequency of Cardiovascular-Related Hospitalizations
All-cause mortality and frequency of cardiovascular hospitalization were analyzed using Finkelstein-Schoenfeld method. The method combines all-cause mortality and frequency of CV-related hospitalizations in a hierarchical fashion using all-cause mortality first. The method compares every participant with every other participant within strata, assigning a +1 to the better participant and a -1 to the worse participant and 0 if they are tied. Participants who discontinued for transplantation (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. 'Win' represents a participant doing better based on hierarchical comparison. The reported unit is the total wins for each treatment group from performing such a hierarchical comparison across all 4 strata in the study.
Time frame: Baseline up to Month 30
Population: ITT analysis set:participants in safety population(randomized participants who received at least 1 dose of double-blind medication)having at least 1 post baseline efficacy.Pre-specified intent of study was to compare results between tafamidis with placebo,irrespective of tafamidis doses. Analysis based on pooled dose groups,as per study protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tafamidis | Hierarchical Combination of All-Cause Mortality and Frequency of Cardiovascular-Related Hospitalizations | 8595 wins |
| Placebo | Hierarchical Combination of All-Cause Mortality and Frequency of Cardiovascular-Related Hospitalizations | 5071 wins |
p-value: 0.0006Finkelstein-Schoenfeld Method
Secondary
All-Cause Mortality
Number of deaths due to any cause was analyzed. Participants who discontinued for transplantation (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.
Time frame: Baseline up to Month 30
Population: ITT analysis set: all participants in the safety population who had at least 1 post baseline efficacy evaluation. The pre-specified intent of this study was to compare the results between tafamidis with placebo, irrespective of the tafamidis doses. Therefore, this analysis was based on the pooled dose groups, as per the study protocol.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tafamidis | All-Cause Mortality | Cardiac Mechanical Assist Devices | 2 Participants |
| Tafamidis | All-Cause Mortality | Deaths (all causes) | 69 Participants |
| Tafamidis | All-Cause Mortality | Heart transplants | 7 Participants |
| Placebo | All-Cause Mortality | Cardiac Mechanical Assist Devices | 0 Participants |
| Placebo | All-Cause Mortality | Deaths (all causes) | 72 Participants |
| Placebo | All-Cause Mortality | Heart transplants | 4 Participants |
p-value: 0.025995% CI: [0.508, 0.958]Cox proportional hazards model
Secondary
Change From Baseline in Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) at Month 30
KCCQ is a 23-item participant-completed questionnaire that assesses health status and health-related quality of life in participants with heart failure. Eight domain scores were calculated for the KCCQ: Physical limitation, Social limitation, Quality of life, Self-efficacy, Symptom stability, Symptom frequency, Symptom burden, and Total symptoms (calculated as the mean of Symptom frequency and Symptom burden scores). Two summary scores were also calculated: Clinical Summary (calculated as mean of Physical limitation and Total symptom scores) and Overall Summary (calculated as mean of Physical limitation, Social limitation, Total symptoms, and Quality of life scores). Domain and summary scores were scaled to range from 0 (minimum) to 100 (maximum); higher scores represent better health status.
Time frame: Baseline, Month 30
Population: Analysis performed on ITT analysis set. The pre-specified intent of this study was to compare the results between tafamidis with placebo, irrespective of the tafamidis doses. This analysis was based on the pooled dose groups, as per the study protocol. Here, 'number analyzed' = participants evaluable for this outcome at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tafamidis | Change From Baseline in Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) at Month 30 | Change at Month 30 | -3.855 units on a scale | Standard Deviation 19.3075 |
| Tafamidis | Change From Baseline in Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) at Month 30 | Baseline | 67.274 units on a scale | Standard Deviation 21.3561 |
| Placebo | Change From Baseline in Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) at Month 30 | Baseline | 65.898 units on a scale | Standard Deviation 21.7357 |
| Placebo | Change From Baseline in Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS) at Month 30 | Change at Month 30 | -14.637 units on a scale | Standard Deviation 21.4078 |
Comparison: Change at Month 30p-value: <0.000195% CI: [9.48, 17.83]Mixed Model Repeated Measures ANCOVA
Secondary
Change From Baseline in the Total Distance Walked During 6 Minute Walk Test (6MWT) at Month 30
6MWT is the total distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed.
Time frame: Baseline, Month 30
Population: Analysis performed on ITT analysis set. The pre-specified intent of this study was to compare the results between tafamidis with placebo, irrespective of the tafamidis doses. This analysis was based on the pooled dose groups, as per the study protocol. Here, 'number analyzed' = participants evaluable for this outcome at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tafamidis | Change From Baseline in the Total Distance Walked During 6 Minute Walk Test (6MWT) at Month 30 | Baseline | 350.55 meters | Standard Deviation 121.296 |
| Tafamidis | Change From Baseline in the Total Distance Walked During 6 Minute Walk Test (6MWT) at Month 30 | Change at Month 30 | -30.46 meters | Standard Deviation 87.886 |
| Placebo | Change From Baseline in the Total Distance Walked During 6 Minute Walk Test (6MWT) at Month 30 | Baseline | 353.26 meters | Standard Deviation 125.983 |
| Placebo | Change From Baseline in the Total Distance Walked During 6 Minute Walk Test (6MWT) at Month 30 | Change at Month 30 | -89.67 meters | Standard Deviation 105.159 |
Comparison: L.S. means are from an ANCOVA (MMRM) model with an unstructured covariance matrix; center and participant 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.p-value: <0.000195% CI: [57.56, 93.8]Mixed Model Repeated Measures ANCOVA
Secondary
Frequency of Cardiovascular-Related Hospitalizations
CV related hospitalizations per year is calculated as participant's number of CV related hospitalizations upon duration on study in years.
Time frame: Baseline to Month 30
Population: ITT analysis set: all participants in the safety population who had at least 1 post baseline efficacy evaluation. The pre-specified intent of this study was to compare the results between tafamidis with placebo, irrespective of the tafamidis doses. Therefore, this analysis was based on the pooled dose groups, as per the study protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tafamidis | Frequency of Cardiovascular-Related Hospitalizations | 0.999 CV hospitalization per year | Standard Deviation 2.2777 |
| Placebo | Frequency of Cardiovascular-Related Hospitalizations | 0.884 CV hospitalization per year | Standard Deviation 1.2032 |
p-value: <0.000195% CI: [0.5639, 0.8107]Poisson regression analysis
Secondary
Number of Participants With Cardiovascular-Related Mortality
Deaths adjudicated as CV-related and indeterminate are reported. Participants who discontinued for transplantation (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.
Time frame: Baseline up to Month 30
Population: ITT analysis set: all participants in the safety population who had at least 1 post baseline efficacy evaluation. The pre-specified intent of this study was to compare the results between tafamidis with placebo, irrespective of the tafamidis doses. Therefore, this analysis was based on the pooled dose groups, as per the study protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tafamidis | Number of Participants With Cardiovascular-Related Mortality | 64 Participants |
| Placebo | Number of Participants With Cardiovascular-Related Mortality | 63 Participants |
p-value: 0.038395% CI: [0.488, 0.98]Cox proportional hazards model
Secondary
Percentage of Participants With Stabilized Transthyretin (TTR) at Month 1
TTR stabilization is a measure of the degree of stabilization afforded the TTR molecule by tafamidis.
Time frame: Month 1
Population: Analysis performed on ITT analysis set. The pre-specified intent of this study was to compare the results between tafamidis with placebo, irrespective of the tafamidis doses. This analysis was based on the pooled dose groups, as per the study protocol. Here, 'number of participants analyzed' = participants evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tafamidis | Percentage of Participants With Stabilized Transthyretin (TTR) at Month 1 | 86.1 percentage of participants |
| Placebo | Percentage of Participants With Stabilized Transthyretin (TTR) at Month 1 | 3.5 percentage of participants |
p-value: <0.0001Chi-squared