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Zilebesiran as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication (KARDIA-2) (KARDIA-2)

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ClinicalTrials.gov Identifier: NCT05103332
Recruitment Status : Active, not recruiting
First Posted : November 2, 2021
Last Update Posted : April 18, 2024
Sponsor:
Information provided by (Responsible Party):
Alnylam Pharmaceuticals

Study Description
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Brief Summary:
The purpose of this study is to evaluate the effect of zilebesiran on systolic and diastolic blood pressure and to characterize the pharmacodynamic (PD) effects and safety of zilebesiran as add-on therapy.

Condition or disease Intervention/treatment Phase
Hypertension Drug: Olmesartan Drug: Amlodipine Drug: Indapamide Drug: Placebo Drug: Zilebesiran Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 672 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of Zilebesiran Used as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication
Actual Study Start Date : November 5, 2021
Actual Primary Completion Date : September 18, 2023
Estimated Study Completion Date : December 31, 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Zilebesiran (Add-on to Olmesartan)
Following a run-in on olmesartan, eligible participants will receive zilebesiran on Day 1 of a 6-month double-blind treatment period as add-on to olmesartan. Thereafter, participants will receive zilebesiran once every 6 months during the open-label extension period. Upon implementation of Amendment 3, the OLE period will be closed and participants will not receive any further treatment with zilebesiran in the OLE period.
 Drug: Olmesartan
Olmesartan administered orally

Drug: Zilebesiran
Zilebesiran administered by SC injection
Other Name: ALN-AGT01
Experimental: Placebo (Add-on to Olmesartan)
Following a run-in on olmesartan, eligible participants will receive placebo on Day 1 of a 6-month double-blind treatment period as add-on to olmesartan. Thereafter, participants will receive zilebesiran once every 6 months during the open-label extension period. Upon implementation of Amendment 3, the OLE period will be closed and participants will not receive any further treatment with zilebesiran in the OLE period.
 Drug: Olmesartan
Olmesartan administered orally

Drug: Placebo
Placebo administered by subcutaneous (SC) injection

Drug: Zilebesiran
Zilebesiran administered by SC injection
Other Name: ALN-AGT01
Experimental: Zilebesiran (Add-on to Amlodipine)
Following a run-in on amlodipine, eligible participants will receive zilebesiran on Day 1 of a 6-month double-blind treatment period as add-on to amlodipine. Thereafter, participants will receive zilebesiran once every 6 months during the open-label extension period. Upon implementation of Amendment 3, the OLE period will be closed and participants will not receive any further treatment with zilebesiran in the OLE period.
 Drug: Amlodipine
Amlodipine administered orally

Drug: Zilebesiran
Zilebesiran administered by SC injection
Other Name: ALN-AGT01
Placebo Comparator: Placebo (Add-on to Amlodipine)
Following a run-in on amlodipine, eligible participants will receive placebo on Day 1 of a 6-month double-blind treatment period as add-on to amlodipine. Thereafter, participants will receive zilebesiran once every 6 months during the open-label extension period. Upon implementation of Amendment 3, the OLE period will be closed and participants will not receive any further treatment with zilebesiran in the OLE period.
 Drug: Amlodipine
Amlodipine administered orally

Drug: Placebo
Placebo administered by subcutaneous (SC) injection

Drug: Zilebesiran
Zilebesiran administered by SC injection
Other Name: ALN-AGT01
Placebo Comparator: Zilebesiran (Add-on to Indapamide)
Following a run-in on indapamide, eligible participants will receive zilebesiran on Day 1 of a 6-month double-blind treatment period as add-on to indapamide. Thereafter, participants will receive zilebesiran once every 6 months during the open-label extension period. Upon implementation of Amendment 3, the OLE period will be closed and participants will not receive any further treatment with zilebesiran in the OLE period.
 Drug: Indapamide
Indapamide administered orally

Drug: Zilebesiran
Zilebesiran administered by SC injection
Other Name: ALN-AGT01
Placebo Comparator: Placebo (Add-on to Indapamide)
Following a run-in on indapamide, eligible participants will receive placebo on Day 1 of a 6-month double-blind treatment period as add-on to indapamide. Thereafter, participants will receive zilebesiran once every 6 months during the open-label extension period. Upon implementation of Amendment 3, the OLE period will be closed and participants will not receive any further treatment with zilebesiran in the OLE period.
 Drug: Indapamide
Indapamide administered orally

Drug: Placebo
Placebo administered by subcutaneous (SC) injection

Drug: Zilebesiran
Zilebesiran administered by SC injection
Other Name: ALN-AGT01


Outcome Measures
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Primary Outcome Measures :
  1. Change from Baseline at Month 3 in 24-Hour Mean Systolic Blood Pressure (SBP) Assessed by Ambulatory Blood Pressure Monitoring (ABPM) [ Time Frame: Baseline and Month 3 ]

Secondary Outcome Measures :
  1. Change from Baseline at Month 3 in Office SBP [ Time Frame: Baseline and Month 3 ]
  2. Time-adjusted Change from Baseline through Month 6 in Office SBP and 24-hour Mean SBP, Assessed by ABPM [ Time Frame: Baseline through Month 6 ]
  3. Proportion of Patients with 24-hour Mean SBP Assessed by ABPM <130 mmHg and/or Reduction from Baseline ≥ 20 mmHg without Escape Antihypertensive Medication at Month 6 [ Time Frame: Baseline and Month 6 ]
  4. Change in 24-hour Mean SBP and DBP, Assessed by ABPM [ Time Frame: Baseline and Month 6 ]
  5. Change in Office SBP and DBP [ Time Frame: Baseline and Month 6 ]
  6. Change in Daytime and Nighttime Mean SBP and DBP, Assessed by ABPM [ Time Frame: Baseline and Month 6 ]
    Daytime is defined as 6 am to 9:59 pm and nighttime is defined as 10 pm to 5:59 am.

  7. Change from Baseline in Serum Angiotensinogen (AGT) [ Time Frame: Baseline through Month 6 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Office SBP at Screening as follows:

    1. ≥155 mmHg and ≤180 mmHg for patients with untreated hypertension
    2. ≥145 mmHg and ≤180 mmHg for patients on antihypertensive medications
  • 24-hour mean SBP ≥130 mmHg and ≤160 mmHg by ABPM after at least 4 weeks of run-in

Exclusion Criteria:

  • Secondary hypertension, orthostatic hypotension
  • 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, or laboratory evidence of diabetes during screening without known diagnosis of diabetes
  • History of any cardiovascular event within 6 months prior to randomization
  • History of intolerance to SC injection(s)
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05103332


Locations
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Sponsors and Collaborators
Alnylam Pharmaceuticals
Investigators
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Study Director: Medical Director Alnylam Pharmaceuticals
More Information
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Responsible Party: Alnylam Pharmaceuticals
ClinicalTrials.gov Identifier: NCT05103332    
Other Study ID Numbers: ALN-AGT01-003
2021-003776-13 ( EudraCT Number )
First Posted: November 2, 2021    Key Record Dates
Last Update Posted: April 18, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alnylam Pharmaceuticals:
High blood pressure
Hypertension
Hypertensive
 siRNA
Angiotensinogen
AGT
Additional relevant MeSH terms:
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Hypertension
Vascular Diseases
Cardiovascular Diseases
Amlodipine
Olmesartan
Indapamide
Antihypertensive Agents
Calcium Channel Blockers
Membrane Transport Modulators
 Molecular Mechanisms of Pharmacological Action
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Vasodilator Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Diuretics
Natriuretic Agents
Sodium Chloride Symporter Inhibitors