A Phase 3 Global, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Nucresiran in Patients with Transthyretin-Mediated Amyloidosis with Cardiomyopathy
Investigation of an Investigational Medication for Heart Disease Caused by Protein Build-up
Noel Dasgupta
Primary Investigator
Brief description of study
This is a Phase 3, global, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, PK, and PD of nucresiran in adult patients with ATTR amyloidosis (hereditary or wt) with cardiomyopathy.
The purpose of this study is to:
- Evaluate the efficacy of nucresiran compared to placebo on reducing all-cause mortality and cardiovascular (CV) events
- Evaluate the efficacy of nucresiran compared to placebo on additional assessments of CV events and/or death
- Evaluate the efficacy of nucresiran compared to placebo on patient-reported health status and health-related quality of life
Detailed description of study
Patients will be randomized 2:1 to receive either nucresiran or placebo.
The study consists of 4 periods:
1. Screening Period: Up to 45 days, during which patients will undergo screening
assessments to determine eligibility.
2. Double-blind (DB) Period:
• Eligible patients will be randomized in a 2:1 ratio on Day 1 to receive 300 mg of
nucresiran or placebo via SC injection once every 6 months (q6M).
• Assessments will be collected throughout the DB Period as outlined in the Schedule
of Assessments (Table 1).
• Using an event-driven trial design, the primary analysis will be conducted after a
prespecified number of events has been reached, but no earlier than 24 months after
the last patient is randomized. Given an expected enrollment period of approximately
30 months, the length of the DB period will vary for each individual patient, ranging
from a minimum of 24 months to a maximum of 5 years, with an anticipated average
duration of 32 months.
3. Open-label Extension (OLE) Period: Up to 2 years during which all patients will receive
300 mg of nucresiran via SC injection q6M. Patients are eligible to enter the OLE Period
after the DB Period has ended for the study (Section 7.2.11 describes when the study’s
DB Period can end) or after they have completed 5 years of participation in the DB
Period, whichever comes first. Patients must enter the OLE Period within 9 months after
their last dose of study drug in the DB Period.
4. Safety Follow-up Period:
Clinical Study Protocol ALN-TTRSC04-003 ALN-TTRSC04 (nucresiran)
Original: 21 March 2025
Alnylam Pharmaceuticals Confidential 33
• Patients who discontinue study drug to start on TTR lowering therapy will be
followed for 6 months after their last dose of study drug
• Patients who discontinue for any other reason will be followed for 12 months after
their last dose of study drug (24 months for women of childbearing potential)
• Assessments will be collected throughout the Safety Follow-up Period as outlined in
the Schedules of Assessments (Table 1 and Table 2)
Patients may receive nucresiran on the study until the end of the OLE Period or until 1 of the
following occurs: 1) they meet any of the study discontinuation criteria; 2) nucresiran becomes
commercially available in the patient’s country of residence, nucresiran is accessible to the
patient, and the patient has completed their OLE Month 12 Visit; 3) they start TTR lowering
therapy as part of clinical care or another clinical study; or 4) the nucresiran development
program is discontinued.
Eligibility of study
You may be eligible for this study if you meet the following criteria:
- Conditions: Transthyretin Amyloidosis With Cardiomyopathy
-
Age: 18 years - 85 years
-
Gender: All
Inclusion Criteria
- Has documented diagnosis of ATTR amyloidosis with cardiomyopathy including those with hereditary ATTR (hATTR) or wild-type ATTR (wATTR) amyloidosis.
- Has medical history of heart failure (HF) with at least 1 prior hospitalization for HF or signs and symptoms that require treatment with a diuretic.
- Has screening N-terminal prohormone B-type natriuretic peptide (NT-proBNP) >300 ng/L and <8500 ng/L; In patients with permanent or persistent atrial fibrillation, screening NT-proBNP >600 ng/L and <8500 ng/L.
- Patients may be receiving approved TTR stabilizers for ATTR amyloidosis (eg, tafamidis, acoramidis) and may be receiving background therapy for HF at the discretion of the Investigator.
Exclusion Criteria
- Has New York Heart Association (NYHA) Class IV HF; or NYHA Class III heart failure AND ATTR Amyloidosis Disease Stage 3.
- Has a polyneuropathy disability (PND) Score IIIa, IIIb, or IV.
- Has an estimated glomerular filtration rate eGFR of <30 mL/min/1.73m^2 at screening.
- Has received prior or currently receiving TTR-lowering therapy
This study investigates the effects of an investigational medication for patients with transthyretin-mediated amyloidosis (ATTR) with cardiomyopathy. ATTR amyloidosis is a condition where abnormal proteins build up in organs, including the heart, which can lead to heart problems. Cardiomyopathy refers to diseases of the heart muscle that make it harder for the heart to pump blood to the rest of the body. In this study, patients will be randomly assigned to receive either the investigational medication or a placebo, which is an inactive substance that looks like the investigational medicine but does not contain any medicine.
Participants will undergo several procedures during the study. They will receive injections every six months and will have regular assessments to monitor their health. The study will include different periods: a screening period, a double-blind period where neither the participants nor the researchers know who is receiving the investigational medication or placebo, an open-label extension where all participants receive the investigational medication, and a follow-up period to check on participants' health after the study treatment ends.
- Who can participate: Adults aged 18 to 85 years with a documented diagnosis of heart disease caused by protein build-up may participate. Key eligibility includes having heart involvement and being stable without recent heart-related hospitalizations.
- Study details: Participants will receive injections of the investigational medication or placebo every six months and be monitored through health assessments.
- Study timelines: The study will last a minimum of 24 months and a maximum of 5 years.
