APOLLO-B: A Study to Evaluate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy (ATTR Amyloidosis With Cardiomyopathy)

Phase 3

Active, not recruiting

Conditions: Transthyretin Amyloidosis (ATTR) With Cardiomyopathy

Interventions: Drug: Placebo
Drug: Patisiran

Registration Number: NCT03997383

Lead Sponsor: Alnylam Pharmaceuticals

Brief Summary: The purpose of this study is to evaluate the efficacy and safety of patisiran in participants with ATTR amyloidosis with cardiomyopathy.

Detailed Description: Not available

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 360

Inclusion Criteria

Documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either hereditary ATTR amyloidosis with cardiomyopathy or wild-type ATTR amyloidosis with cardiomyopathy
Medical history of heart failure with at least 1 prior hospitalization for heart failure, or current clinical evidence (signs and symptoms of heart failure)
Clinically stable with no cardiovascular related hospitalizations within 6 weeks of study start
Has never taken tafamidis before (tafamidis naïve) or currently on tafamidis for ≥6 months with evidence of disease progression while on tafamidis treatment
Able to complete ≥150 m on the 6-minute walk test
Screening N-terminal pro B-type natriuretic peptide (NT-proBNP), a blood marker of heart failure severity, >300 ng/L and <8500 ng/L; in participants with permanent or persistent atrial fibrillation, screening NT-proBNP> 600 ng/L and <8500 ng/L

Exclusion Criteria

Known primary amyloidosis (AL) or leptomeningeal amyloidosis.
Received prior TTR lowering treatment
New York Heart Association heart failure classification of III and at high risk
New York Heart Association heart failure classification of IV
Neuropathy requiring cane or stick to walk, or is wheelchair bound
Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m^2
Abnormal liver function
Has hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection
Has non-amyloid disease that significantly affects ability to walk (e.g., severe chronic obstructive pulmonary disease, severe arthritis, or peripheral vascular disease affecting ambulation)
Prior or planned heart, liver, or other organ transplant
Other cardiomyopathy not related to ATTR amyloidosis

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participants will be administered multiple doses of placebo in the double-blind period. In the open-label extension period, participants will be administered multiple doses of patisiran.
Patisiran	Patisiran	Participants will be administered multiple doses of patisiran in the double-blind and open-label extension period.
Placebo	Patisiran	Participants will be administered multiple doses of placebo in the double-blind period. In the open-label extension period, participants will be administered multiple doses of patisiran.

Primary Outcome Measures

Name	Time	Method
Change From Baseline at Month 12 in Six-Minute Walk Test (6-MWT)	Baseline, Month 12	Distance in meters walked in 6 minutes, longer distances indicate greater functional capacity. Missing 6MWT values due to non-COVID-19 death or inability to walk due to ATTR disease progression were imputed using the worst 10th percentile change observed in the DB period. Missing 6-MWT values due to other reasons are multiply imputed to create 100 complete datasets. The change from baseline is averaged across the 100 complete datasets.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline at Month 12 in Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) Score	Baseline, Month 12	The KCCQ is a 23-item self-administered questionnaire quantifying 6 domains (symptoms, physical function, quality of life, social limitation, self-efficacy, and symptom stability) and 2 summary scores (clinical and overall summary \[OS\]). Scores are transformed to a range of 0-100, in which higher scores reflect better health status.
Composite Endpoint of All-Cause Mortality, Frequency of Cardiovascular (CV) Events (CV Hospitalizations and Urgent Heart Failure [HF] Visits) and Change From Baseline in 6-MWT Analyzed by Win Ratio	Up to Month 12	The composite endpoint was analyzed using the stratified win ratio method, stratified by baseline tafamidis use. This method combines all-cause mortality, frequency of CV events (CV hospitalizations and HF visits) and change from baseline in 6-MWT in a hierarchical fashion. This method makes within-stratum pairwise comparisons for all patisiran-placebo participant pairs in a sequential manner (first mortality, then CV events, then 6-MWT), with later steps evaluated only in the case of a tie on the prior step. Within each stratum, the win ratio is the total number of 'winners' divided by the total number of 'losers' in the active group. A win ratio \>1 represents a favorable outcome for patisiran.
Composite Endpoint of All-cause Mortality and Frequency of All-cause Hospitalizations and Urgent HF Visits in All Participants	Up to Month 12	The hazard rate of all-cause mortality and all-cause hospitalizations and urgent HF visits was compared between treatment groups using a modified Andersen-Gill model. A hazard ratio \<1 represents a favorable outcome for patisiran.
Composite Endpoint of All-Cause Mortality and Frequency of All-Cause Hospitalizations and Urgent HF Visits in Participants Not on Tafamidis at Baseline	Up to Month 12	The hazard rate of all-cause mortality and all-cause hospitalizations and urgent HF visits will be compared between treatment groups using an Andersen-Gill model. A hazard ratio \<1 represents a favorable outcome for patisiran.