A Study to Evaluate the Safety of mRNA-0184 in Participants With Heart Failure

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety and tolerability of single and multiple doses at escalating dose levels of mRNA-0184.

Detailed Description
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The study includes a SAD stage and MAD stage; the stages of SAD and MAD may overlap. The SAD stage will begin first, and data from this stage will inform decisions about dose levels in subsequent SAD cohorts and in the MAD stage.

Official Title
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A Phase 1, Adaptive, Open-Label, Single Ascending Dose to Single-Blind, Placebo-Controlled, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of mRNA-0184 in Participants With Chronic Heart Failure

Conditions
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Chronic Heart Failure

Intervention / Treatment
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* Drug: mRNA-0184
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Documented diagnosis of heart failure (HF) based on medical records. Left ventricular ejection fraction (LVEF) ≥ 35% and < 50% at Screening, or documented within the 3 months before Screening, measured by transthoracic echocardiogram (TTE) or cardiac magnetic resonance imaging (MRI). New York Heart Association (NYHA) HF Class I or II. On a stable regimen of cardiovascular medication(s) for a duration of at least 4 weeks before Screening. Key Exclusion Criteria: Hospitalized for cardiovascular causes within 3 months before Screening. Decompensated HF, acute myocarditis, hypertrophic and/or restrictive/constrictive cardiomyopathy, or moderate or severe valvular heart disease (as classified by echocardiography) at Screening or within the 3 months before Screening. Moderate tricuspid regurgitation is not exclusionary. Congenital heart disease as the primary etiology for heart failure will be excluded. Symptoms of angina pectoris at Screening. Severe obstructive or restrictive pulmonary pathology, including chronic obstructive pulmonary disease Gold Stage III or IV, current use of oxygen therapy, or Group 1, 3, 4, or 5 pulmonary hypertension. Group 2 pulmonary hypertension is not exclusionary. History of sustained ventricular tachycardia or atrial fibrillation/atrial flutter with a ventricular response ≥ 110 beats per minute (bpm) at the time of Screening. History of hypersensitivity to any components of the investigational product (IP). Participant has received or is expected to receive a COVID-19 vaccination within 7 days of the planned date of IP administration. For SAD cohort participants to be rolled over into the MAD stage, have experienced a dose-limiting toxicity (DLT) in a SAD cohort. Participation in another clinical study of another IP within 30 days before Screening or within 5 terminal elimination half-lives of the IP, whichever is longer. Any other clinically significant medical condition that, in the Investigator's opinion, could interfere with the interpretation of study results or limit the participant's participation in the study, including poorly controlled diabetes mellitus.

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Interventional Model Description: The single ascending dose (SAD) stage of this study is open-label and the multiple ascending dose (MAD) stage of this study is single-blind and placebo-controlled.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAD Stage: mRNA-0184<br>Participants will receive a single dose of mRNA-0184. | Drug: mRNA-0184<br>* mRNA-0184 dispersion for intravenous (IV) infusion<br>|
| Experimental: MAD Stage: mRNA-0184<br>Participants will receive up to 4 doses of mRNA-0184 administered over a treatment period of up to 16 weeks. | Drug: mRNA-0184<br>* mRNA-0184 dispersion for intravenous (IV) infusion<br>|
| Placebo Comparator: MAD Stage: Placebo<br>Participants will receive placebo matching to mRNA-0184 administered over a treatment period of up to 16 weeks. | Drug: Placebo<br>* 0.9% sodium chloride (normal saline) injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) |  | Baseline up to Day 296 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Concentrations of mRNA Encoding Relaxin-2-variable Light Chain Kappa (Rel2- vlk mRNA) |  | Day 1 (within 60 minutes predose) up to Day 183 | 
| Maximum Observed Plasma Concentration (Cmax) of Rel2-vlk mRNA |  | Day 1 (within 60 minutes predose) up to Day 183 | 
| Area Under the Curve From Time 0 to Time t (AUC0-t) of Rel2-vlk mRNA |  | Day 1 (within 60 minutes predose) up to Day 183 | 
| Serum Concentrations of Relaxin-2-variable Light Chain Kappa (Rel2- vlk) Protein |  | Day 1 (within 60 minutes predose) up to Day 183 | 
| Maximum Observed Effect (Emax) of Rel2- vlk Protein |  | Day 1 (within 60 minutes predose) up to Day 183 | 
| Area Under the Effect-Time Curve (AUEC) of Rel2-vlk Protein |  | Day 1 (within 60 minutes predose) up to Day 183 | 
| Number of Participants With Anti-polyethylene glycol (PEG) Antibodies |  | Baseline up to Day 183 | 
| Number of Participants With anti-Rel2-vlk Protein Antibodies |  | Baseline up to Day 183 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple ascending dose, mRNA-0184, Heart failure, Single ascending dose