A Study to Evaluate Efficacy and Safety of ALN-AGT01 in Patients With Mild To-Moderate Hypertension

Phase 2

Completed

Conditions: Hypertension

Interventions: Drug: Placebo
Drug: ALN-AGT01

Registration Number: NCT04936035

Lead Sponsor: Alnylam Pharmaceuticals

Brief Summary: The purpose of this study is to evaluate the effect of ALN-AGT01 on systolic and diastolic blood pressure and to characterize the pharmacodynamic (PD) effects and safety of ALN-AGT01.

Detailed Description: Participants will receive ALN-AGT01 or placebo for the first 6 months of the 12-month double-blind (DB) treatment period. Participants randomized to placebo will be re-randomized at Month 6 to 1 of the 4 initial ALN-AGT01 regimens until the end of the 12-month DB treatment period. Participants randomized to ALN-AGT01 regimens will remain on their originally assigned regimens through remainder of the study.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 394

Inclusion Criteria

Daytime mean SBP ≥135 mmHg and ≤160 mmHg by ABPM, without antihypertensive medication

Exclusion Criteria

Secondary hypertension, orthostatic hypotension
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2× upper limit of normal (ULN)
Elevated potassium >5 mEq/L
Estimated glomerular filtration rate (eGFR) of ≤30 mL/min/1.73m^2
Received an investigational agent within the last 30 days
Type 1 diabetes mellitus, poorly controlled Type 2 diabetes mellitus, newly diagnosed Type 2 diabetes mellitus
History of any cardiovascular event within 6 months prior to randomization
History of intolerance to SC injection(s)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Zilebesiran 150 Milligrams (mg) Once Every 6 Months (Q6M)	ALN-AGT01	Participants receive zilebesiran, 150 mg, SC injection, Q6M, during the 12-month DB period. Participants will continue receiving the same zilebesiran regimen for up to 24 additional months in the DB Extension period. Participants in this arm will receive a placebo during those dosing visits when they do not receive zilebesiran to maintain the blind. Upon implementation of Amendment 6, the DB Extension period was closed.
Zilebesiran 300 mg Q6M	ALN-AGT01	Participants receive zilebesiran, 300 mg, SC injection, Q6M, during the 12-month DB period. Participants will continue receiving the same zilebesiran regimen for up to 24 additional months in the DB Extension period. Participants in this arm will receive a placebo during those dosing visits when they do not receive zilebesiran to maintain the blind. Upon implementation of Amendment 6, the DB Extension period was closed.
Zilebesiran 150 Milligrams (mg) Once Every 6 Months (Q6M)	Placebo	Participants receive zilebesiran, 150 mg, SC injection, Q6M, during the 12-month DB period. Participants will continue receiving the same zilebesiran regimen for up to 24 additional months in the DB Extension period. Participants in this arm will receive a placebo during those dosing visits when they do not receive zilebesiran to maintain the blind. Upon implementation of Amendment 6, the DB Extension period was closed.
Zilebesiran 300 mg Q6M	Placebo	Participants receive zilebesiran, 300 mg, SC injection, Q6M, during the 12-month DB period. Participants will continue receiving the same zilebesiran regimen for up to 24 additional months in the DB Extension period. Participants in this arm will receive a placebo during those dosing visits when they do not receive zilebesiran to maintain the blind. Upon implementation of Amendment 6, the DB Extension period was closed.
Zilebesiran 300 mg Q3M	ALN-AGT01	Participants receive zilebesiran, 300 mg, SC injection, Q3M, during the 12-month DB period. Participants continue receiving the same zilebesiran regimen for up to 24 additional months in the DB Extension period. Upon implementation of Amendment 6, the DB Extension period was closed.
Placebo	Placebo	Participants received zilebesiran matching placebo, subcutaneous (SC) injection, once every 3 months (Q3M), with re-randomization at Month 6 to 1 of the initial 4 zilebesiran regimens. Participants will continue their respective zilebesiran regimen up to Month 12 in the DB period and up to 24 additional months in the DB Extension period. Upon implementation of Amendment 6, the DB Extension period was closed.
Placebo	ALN-AGT01	Participants received zilebesiran matching placebo, subcutaneous (SC) injection, once every 3 months (Q3M), with re-randomization at Month 6 to 1 of the initial 4 zilebesiran regimens. Participants will continue their respective zilebesiran regimen up to Month 12 in the DB period and up to 24 additional months in the DB Extension period. Upon implementation of Amendment 6, the DB Extension period was closed.
Zilebesiran 600 mg Q6M	Placebo	Participants receive zilebesiran, 600 mg, SC injection, Q6M, during the 12-month DB period. Participants will continue receiving the same zilebesiran regimen for up to 24 additional months in the DB Extension period. Participants in this arm will receive a placebo during those dosing visits when they do not receive zilebesiran to maintain the blind. Upon implementation of Amendment 6, the DB Extension period was closed.
Zilebesiran 600 mg Q6M	ALN-AGT01	Participants receive zilebesiran, 600 mg, SC injection, Q6M, during the 12-month DB period. Participants will continue receiving the same zilebesiran regimen for up to 24 additional months in the DB Extension period. Participants in this arm will receive a placebo during those dosing visits when they do not receive zilebesiran to maintain the blind. Upon implementation of Amendment 6, the DB Extension period was closed.

Primary Outcome Measures

Name	Time	Method
Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM	Baseline and Month 3	24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of BP by each hour of the day. The 24-hour mean was the average of the hourly means. Least squares (LS) mean and standard error (SE) were calculated using a mixed model repeated measures (MMRM) approach.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline at Month 3 in Mean Sitting Office SBP	Baseline and Month 3	The mean office BP in the sitting position was used for the analysis. Office BP in the sitting position was collected with a set of 4 replicates. The average of the last 3 replicates was calculated and used for analysis. LS mean and SE were calculated using a MMRM approach.
Change From Baseline at Month 6 in 24-hour Mean SBP Assessed by ABPM	Baseline and Month 6	24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of blood pressure (BP) by each hour of the day. The 24-hour mean was the average of the hourly means. LS mean and SE were calculated using a MMRM approach.
Change From Baseline at Month 6 in Mean Sitting Office SBP	Baseline and Month 6	The mean office BP in the sitting position was used for the analysis. Office BP in the sitting position was collected with a set of 4 replicates. The average of the last 3 replicates was calculated and used for analysis. LS mean and SE were calculated using a MMRM approach.
Percentage of Participants With 24-hour Mean SBP Assessed by ABPM <130 mmHg and/or Reduction of ≥20 mmHg From Baseline Without Additional Antihypertensive Medications at Month 6	Month 6	24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of blood pressure (BP) by each hour of the day. The 24-hour mean was the average of the hourly means.
Change From Baseline at Month 3 in 24-hour Mean DBP Assessed by ABPM	Baseline and Month 3	24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of blood pressure (BP) by each hour of the day. The 24-hour mean was the average of the hourly means. LS mean and SE were calculated using a MMRM approach.
Change From Baseline at Month 6 in 24-hour Mean DBP Assessed by ABPM	Baseline and Month 6	24-hour ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were≥11, 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). To summarize the 24-hour ABPM, the hourly adjusted mean was calculated. Hourly mean was the average of blood pressure (BP) by each hour of the day. The 24-hour mean was the average of the hourly means. LS mean and SE were calculated using a MMRM approach
Change From Baseline at Month 3 in Mean Sitting Office DBP	Baseline and Month 3	The mean office BP in the sitting position was used for the analysis. Office BP in the sitting position was collected with a set of 4 replicates. The average of the last 3 replicates was calculated and used for analysis. LS mean and SE were calculated using a MMRM approach.
Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP	Baseline and Month 3	Time adjusted change from baseline in mean sitting office SBP and DBP was the area under the curve (AUC) between Month 1 and 3 visits divided by the duration of time period.
Change From Baseline at Month 6 in Mean Sitting Office DBP	Baseline and Month 6	The mean office BP in the sitting position was used for the analysis. Office BP in the sitting position was collected with a set of 4 replicates. The average of the last 3 replicates was calculated and used for analysis. LS mean and SE were calculated using a MMRM approach.
Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM	Baseline and Month 6	Time adjusted change from baseline through Month 6 in 24-hour mean SBP and DBP was determined as the AUC between Month 1 and 6 visits divided by the duration of the time period.
Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP	Baseline and Month 6	Time adjusted change is the AUC between Month 1 and 6 visits divided by the duration of time period.
Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit	Baseline, and Months 1, 3 and 6	ABPM was programmed to take readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 5:59 am). An ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33, 2. the number of successful nighttime readings were ≥11, and 3. no more than 3 hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). Baseline was defined as the last assessment prior to receiving the first dose of study drug. LS mean and SE were calculated using a MMRM approach.
Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6	Baseline, Week 2 and Months 1, 2, 3, 4, 5 and 6