MAGNITUDE: A Phase 3 Study of NTLA-2001 in Participants With Transthyretin Amyloidosis With Cardiomyopathy (ATTR-CM)

Study Overview
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Brief Summary
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To evaluate the efficacy and safety of a single dose of NTLA-2001 compared to placebo in participants with ATTR-CM.

Detailed Description
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This is a multinational, multicenter, double-blind, placebo-controlled study in approximately 765 participants, who will be randomized to receive a single infusion of either NTLA-2001 or placebo.

Official Title
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MAGNITUDE: A Phase 3, Multinational, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of NTLA-2001 in Participants With Transthyretin Amyloidosis With Cardiomyopathy (ATTR-CM)

Conditions
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Transthyretin Amyloidosis (ATTR) With Cardiomyopathy

Intervention / Treatment
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* Biological: NTLA-2001
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented diagnosis of ATTR amyloidosis with cardiomyopathy Medical history of heart failure (HF) Symptoms of HF are optimally managed and clinically stable within 28 days prior to administration of study intervention Screening NT-proBNP, a blood marker of HF severity, greater than or equal to 1000 pg/mL (or greater than or equal to 2000 pg/mL if participant has known atrial fibrillation) Exclusion Criteria: New York Heart Association (NYHA) Class IV HF Polyneuropathy Disability score of IV (confined to wheelchair or bed) Has hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection History of active malignancy within 3 years prior to screening RNA silencer therapy (patisiran, inotersen and/or eplontersen) within 12 months prior to dosing. Any prior vutrisiran use is not allowed Initiation of tafamidis within 6 months prior to study dosing Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m^2 Liver failure Uncontrolled blood pressure Unable or unwilling to take vitamin A supplementation for the duration of the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized in a 2:1 ratio to NTLA-2001 or placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NTLA-2001<br>Single intravenous (IV) infusion of NTLA-2001 | Biological: NTLA-2001<br>* NTLA-2001 (55mg) by IV infusion<br>|
| Placebo Comparator: Placebo<br>Single IV infusion of normal saline | Drug: Placebo<br>* Normal saline (0.9% NaCl) by IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite outcome of cardiovascular (CV) mortality and CV events |  | Maximum study duration is dependent on event rates and is estimated to be at least 18 months and up to 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in baseline to month 18 in serum TTR |  | Baseline, Month 18 | 
| Change from baseline to month 18 in KCCQ-OS score |  | Baseline, Month 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TTR, Amyloidosis, Cardiomyopathy, NTLA-2001, ATTR-CM, Transthyretin, ATTR, TTR-mediated amyloidosis, Amyloidosis, Hereditary, Amyloidosis, Hereditary, Transthyretin-Related Amyloidosis, Transthyretin amyloid cardiomyopathy, TTR cardiomyopathy, Wild-type TTR, V122I, Amyloidosis, Wild Type