A Study to Evaluate Efficacy and Safety of ALN-AGT01 in Patients With Mild To-Moderate Hypertension (KARDIA-1)

A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Multicenter Study to Evaluate the Efficacy and Safety of ALN-AGT01 in Patients With Mild-to-Moderate Hypertension

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.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Placebo; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 394
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Red Deer, Alberta, Canada
      • Clinical Trial Site
  • Nova Scotia
    • New Minas, Nova Scotia, Canada
      • Clinical Trial Site
  • Ontario
    • Brampton, Ontario, Canada
      • Clinical Trial Site
    • Toronto, Ontario, Canada
      • Clinical Trial Site
  • Quebec
    • Chicoutimi, Quebec, Canada
      • Clinical Trial Site
    • Mirabel, Quebec, Canada
      • Clinical Trial Site
    • Montreal, Quebec, Canada
      • Clinical Trial Site
    • Québec, Quebec, Canada
      • Clinical Trial Site
    • Trois-Rivières, Quebec, Canada
      • Clinical Trial Site
    • Victoriaville, Quebec, Canada
      • Clinical Trial Site
• Puerto Rico
  • Bayamón, Puerto Rico, 00961
    • Clinical Trial Site
  • Ponce, Puerto Rico, 00716
    • Clinical Trial Site
  • San Juan, Puerto Rico
    • Clinical Trial Site
• Ukraine
  • Ivano-Frankivsk, Ukraine
    • Clinical Trial Site
  • Kharkiv, Ukraine
    • Clinical Trial Site
  • Odesa, Ukraine
    • Clinical Trial Site
  • Uzhhorod, Ukraine
    • Clinical Trial Site
• United Kingdom
  • Glasgow, United Kingdom
    • Clinical Trial Site
  • Hexham, United Kingdom
    • Clinical Trial Site
  • London, United Kingdom
    • Clinical Trial Site
  • Manchester, United Kingdom
    • Clinical Trial Site
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Clinical Trial Site
  • Arizona
    • Tempe, Arizona, United States, 85281
      • Clinical Trial Site
    • Tempe, Arizona, United States, 85282
      • Clinical Trial Site
  • California
    • Beverly Hills, California, United States, 90211
      • Clinical Trial Site
    • La Mesa, California, United States, 91942
      • Clinical Trial Site
    • Los Angeles, California, United States, 90057
      • Clinical Trial Site
    • San Diego, California, United States, 92103
      • Clinical Trial Site
    • South Gate, California, United States, 90280
      • Clinical Trial Site
    • Vista, California, United States, 92083
      • Clinical Trial Site
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20011
      • Clinical Trial Site
  • Florida
    • Clearwater, Florida, United States, 33756
      • Clinical Trial Site
    • Coral Gables, Florida, United States, 33134
      • Clinical Trial Site
    • Fleming Island, Florida, United States, 32003
      • Clinical Trial Site
    • Hollywood, Florida, United States, 33021
      • Clinical Trial Site
    • Hollywood, Florida, United States, 33024
      • Clinical Trial Site
    • Inverness, Florida, United States, 34452
      • Clinical Trial Site
    • Jacksonville, Florida, United States, 32216
      • Clinical Trial Site
    • Jacksonville, Florida, United States, 32256
      • Clinical Trial Site
    • Jacksonville, Florida, United States, 32204
      • Clinical Trial Site
    • Miami, Florida, United States, 33126
      • Clinical Trial Site
    • Miami, Florida, United States, 33135
      • Clinical Trial Site
    • Naples, Florida, United States, 34102
      • Clinical Trial Site
    • Orlando, Florida, United States, 32801
      • Clinical Trial Site
  • Georgia
    • Acworth, Georgia, United States, 30101
      • Clinical Trial Site
    • Columbus, Georgia, United States, 31904
      • Clinical Trial Site
    • Fayetteville, Georgia, United States, 30214
      • Clinical Trial Site
    • Macon, Georgia, United States, 31210
      • Clinical Trial Site
  • Illinois
    • Champaign, Illinois, United States, 61822
      • Clinical Trial Site
  • Indiana
    • Valparaiso, Indiana, United States, 46383
      • Clinical Trial Site
  • Iowa
    • West Des Moines, Iowa, United States, 50266
      • Clinical Trial Site
  • Louisiana
    • Lake Charles, Louisiana, United States, 70601
      • Clinical Trial Site
    • New Orleans, Louisiana, United States, 70124
      • Clinical Trial Site
    • Prairieville, Louisiana, United States, 70769
      • Clinical Trial Site
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • Clinical Trial Site
  • Mississippi
    • Jackson, Mississippi, United States, 39209
      • Clinical Trial Site
  • Missouri
    • Jefferson City, Missouri, United States, 65109
      • Clinical Trial Site
  • Nevada
    • Las Vegas, Nevada, United States, 89119
      • Clinical Trial Site
  • New York
    • New York, New York, United States, 10036
      • Clinical Trial Site
    • The Bronx, New York, United States, 10456
      • Clinical Trial Site
  • North Carolina
    • Greensboro, North Carolina, United States, 27408
      • Clinical Trial Site
    • Greensboro, North Carolina, United States, 27410
      • Clinical Trial Site
  • Oregon
    • Medford, Oregon, United States, 97504
      • Clinical Trial Site
  • South Carolina
    • Greenville, South Carolina, United States, 29607
      • Clinical Trial Site
  • Tennessee
    • Memphis, Tennessee, United States, 38119
      • Clinical Trial Site
  • Texas
    • Cedar Park, Texas, United States, 78613
      • Clinical Trial Site
    • Houston, Texas, United States, 77074
      • Clinical Trial Site
    • Houston, Texas, United States, 77081
      • Clinical Trial Site
    • Magnolia, Texas, United States, 77355
      • Clinical Trial Site
    • Pearland, Texas, United States, 77584
      • Clinical Trial Site
    • San Antonio, Texas, United States, 78229
      • Clinical Trial Site
    • Stephenville, Texas, United States, 76401
      • Clinical Trial Site
    • Tomball, Texas, United States, 77375
      • Clinical Trial Site
    • Waco, Texas, United States, 76708
      • Clinical Trial Site
  • Virginia
    • Burke, Virginia, United States, 22015
      • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 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.	Drug: Placebo; Placebo administered by SC injection; Drug: ALN-AGT01; ALN-AGT01 administered by SC injection; Other Names: Zilebesiran
Experimental: Zilebesiran 150 Milligrams (mg) Once Every 6 Months (Q6M); 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.	Drug: Placebo; Placebo administered by SC injection; Drug: ALN-AGT01; ALN-AGT01 administered by SC injection; Other Names: Zilebesiran
Experimental: Zilebesiran 300 mg Q6M; 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.	Drug: Placebo; Placebo administered by SC injection; Drug: ALN-AGT01; ALN-AGT01 administered by SC injection; Other Names: Zilebesiran
Experimental: Zilebesiran 300 mg Q3M; 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.	Drug: ALN-AGT01; ALN-AGT01 administered by SC injection; Other Names: Zilebesiran
Experimental: Zilebesiran 600 mg Q6M; 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.	Drug: Placebo; Placebo administered by SC injection; Drug: ALN-AGT01; ALN-AGT01 administered by SC injection; Other Names: Zilebesiran

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM	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.	Baseline and Month 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline at Month 3 in Mean Sitting Office SBP	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.	Baseline and Month 3
Change From Baseline at Month 6 in 24-hour Mean SBP Assessed by ABPM	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.	Baseline and Month 6
Change From Baseline at Month 6 in Mean Sitting Office SBP	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.	Baseline and Month 6
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	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.	Month 6
Change From Baseline at Month 3 in 24-hour Mean DBP Assessed by ABPM	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.	Baseline and Month 3
Change From Baseline at Month 6 in 24-hour Mean DBP Assessed by ABPM	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	Baseline and Month 6
Change From Baseline at Month 3 in Mean Sitting Office DBP	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.	Baseline and Month 3
Time Adjusted Change From Baseline Through Month 3 in Mean Sitting Office SBP and DBP	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.	Baseline and Month 3
Change From Baseline at Month 6 in Mean Sitting Office DBP	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.	Baseline and Month 6
Time Adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP and DBP Assessed by ABPM	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.	Baseline and Month 6
Time Adjusted Change From Baseline Through Month 6 in Mean Sitting Office SBP and DBP	Time adjusted change is the AUC between Month 1 and 6 visits divided by the duration of time period.	Baseline and Month 6
Change From Baseline in Daytime/Nighttime Mean SBP and DBP Assessed by ABPM at Each Visit	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.	Baseline, and Months 1, 3 and 6
Percentage Change From Baseline in Serum Angiotensinogen (AGT) Through Month 6		Baseline, Week 2 and Months 1, 2, 3, 4, 5 and 6

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: Medical Director, Alnylam Pharmaceuticals

Publications and helpful links

General Publications

• Bakris GL, Saxena M, Gupta A, Chalhoub F, Lee J, Stiglitz D, Makarova N, Goyal N, Guo W, Zappe D, Desai AS; KARDIA-1 Study Group. RNA Interference With Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial. JAMA. 2024 Mar 5;331(9):740-749. doi: 10.1001/jama.2024.0728.

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2021
• Primary Completion (Actual): April 4, 2023
• Study Completion (Actual): December 5, 2024

Study Registration Dates

• First Submitted: June 14, 2021
• First Submitted That Met QC Criteria: June 14, 2021
• First Posted (Actual): June 23, 2021

Study Record Updates

• Last Update Posted (Estimated): December 23, 2025
• Last Update Submitted That Met QC Criteria: December 5, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Hypertension; Hypertensive; siRNA; High blood pressure; AGT; Angiotensinogen
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Hypertension
• Other Study ID Numbers: ALN-AGT01-002; 2021-001248-82 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Access to Anonymized individual participant data that support these results is made available 12 months after study completion and not less than 12 months after the product and indication have been approved in the US and/or the EU.

Data will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Requests for access to data can be submitted via the website www.vivli.org.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No