A Phase 1, Randomized, Double-Blind, Placebo-Controlled Single Dose and Active Comparator-Controlled Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneously Administered ALN-AGT01 in Patients With Hypertension
Overview
- Phase
- Phase 1
- Intervention
- ALN-AGT01
- Conditions
- Hypertension
- Sponsor
- Alnylam Pharmaceuticals
- Enrollment
- 124
- Locations
- 1
- Primary Endpoint
- Number of Participants with Adverse Events (AEs)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) effects of subcutaneous (SC) ALN-AGT01 (zilebesiran) in participants with hypertension. The study will be conducted in 4 parts: Part A will be a single ascending dose (SAD) phase in hypertensive participants, Part B will be a single dose (SD) phase in hypertensive participants with controlled salt intake, Part D will be a MD phase in hypertensive participants who are obese, and Part E will be an open-label SD phase with co-administration of irbesartan in hypertensive patients.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Has mild to moderate hypertension with mean sitting systolic blood pressure (SBP) of \>130 and ≤165 mmHg without hypertensive medication for Parts A, B and D, and \>135 and ≤165 mmHg without hypertensive medication for Part E
- •Parts A and B: Has body mass index (BMI) ≥18 and ≤35 kg/m\^2; Part D: Has BMI \>35 and ≤50 kg/m\^2; Part E: Has BMI ≥18 kg/m\^2 and ≤50 kg/m\^2
- •Has a normal 12-lead electrocardiogram (ECG)
- •Is a nonsmoker
Exclusion Criteria
- •Has secondary hypertension
- •Has orthostatic hypotension
- •Has estimated glomerular filtration rate (eGFR) of \<60 mL/min/1.73m\^2
- •Recently received an investigational agent
- •Has diabetes mellitus
- •Has history of any cardiovascular event
- •Has history of intolerance to SC injection(s)
Arms & Interventions
Part A: SAD: ALN-AGT01
Participants will be administered a single dose of ALN-AGT01.
Intervention: ALN-AGT01
Part A: SAD: ALN-AGT01-Matching Placebo
Participants will be administered a single dose of ALN-AGT01-matching placebo.
Intervention: ALN-AGT01-Matching Placebo
Part B: SD: ALN-AGT01
Participants with controlled salt intake will be administered a single dose of ALN-AGT01.
Intervention: ALN-AGT01
Part B: SD: ALN-AGT01-Matching Placebo
Participants with controlled salt intake will be administered a single dose of ALN-AGT01-matching placebo.
Intervention: ALN-AGT01-Matching Placebo
Part D: MD: ALN-AGT01 + Irbesartan-Matching Placebo
Participants, who are obese, will be administered multiple doses of ALN-AGT01 and irbesartan-matching placebo.
Intervention: ALN-AGT01
Part D: MD: ALN-AGT01 + Irbesartan-Matching Placebo
Participants, who are obese, will be administered multiple doses of ALN-AGT01 and irbesartan-matching placebo.
Intervention: Irbesartan-Matching Placebo
Part D: MD: ALN-AGT01-Matching Placebo + Irbesartan
Participants, who are obese, will be administered multiple doses of ALN-AGT01-matching placebo and irbesartan.
Intervention: ALN-AGT01-Matching Placebo
Part D: MD: ALN-AGT01-Matching Placebo + Irbesartan
Participants, who are obese, will be administered multiple doses of ALN-AGT01-matching placebo and irbesartan.
Intervention: Irbesartan
Part E: Open Label: ALN-AGT01 + Irbesartan
Participants will be administered a single dose of ALN-AGT01 and multiple doses of irbesartan.
Intervention: ALN-AGT01
Part E: Open Label: ALN-AGT01 + Irbesartan
Participants will be administered a single dose of ALN-AGT01 and multiple doses of irbesartan.
Intervention: Irbesartan
Outcomes
Primary Outcomes
Number of Participants with Adverse Events (AEs)
Time Frame: Parts A, B and E: each up to approximately 12 months; Part D: up to approximately 18 months
Secondary Outcomes
- Area Under the Concentration-time Curve (AUC) of ALN-AGT01 and of Potential Metabolites(Parts A, B and E: Up to Day 15; Part D: Up to Day 99)
- Change from Baseline in Blood Angiotensinogen (AGT) Level(Parts A, B and E: each up to approximately 12 months; Part D: up to approximately 18 months)
- Maximum Observed Plasma Concentration (Cmax) of ALN-AGT01 and of Potential Metabolites(Parts A, B and E: Up to Day 15; Part D: Up to Day 99)