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

• ClinicalTrials.gov Identifier: NCT05103332
• Recruitment Status: Active, not recruiting
• First Posted: November 2, 2021
• Last Update Posted: May 10, 2024
• Sponsor: Alnylam Pharmaceuticals
• Information provided by (Responsible Party): Alnylam Pharmaceuticals

Tracking Information

• First Submitted Date: October 22, 2021
• First Posted Date: November 2, 2021
• Last Update Posted Date: May 10, 2024
• Actual Study Start Date: November 5, 2021
• Actual Primary Completion Date: September 18, 2023 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: May 26, 2022): 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 ]
• Original Primary Outcome Measures (submitted: October 22, 2021): Change in 24-Hour Mean Systolic Blood Pressure (SBP) from Baseline to Month 3, Assessed by Ambulatory Blood Pressure Monitoring (ABPM) [ Time Frame: Baseline to Month 3 ]

Current Secondary Outcome Measures (submitted: May 9, 2024)

• Change from Baseline at Month 3 in Office SBP [ Time Frame: Baseline and Month 3 ]
• 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 ]
• 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 ]
• Change in 24-hour Mean SBP and Diastolic Blood Pressure (DBP), Assessed by ABPM [ Time Frame: Baseline and Month 6 ]
• Change in Office SBP and DBP [ Time Frame: Baseline and Month 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.
• Change from Baseline in Serum Angiotensinogen (AGT) [ Time Frame: Baseline through Month 6 ]

Original Secondary Outcome Measures (submitted: October 22, 2021)

• Change in Office SBP from Baseline to Month 3 [ Time Frame: Baseline to Month 3 ]
• Change in 24-Hour Mean SBP from Baseline to Month 6, Assessed by ABPM [ Time Frame: Baseline to Month 6 ]
• Change in Office SBP from Baseline to Month 6 [ Time Frame: Baseline to Month 6 ]
• Change in 24-Hour Mean Diastolic Blood Pressure (DBP) from Baseline to Months 3 and 6, Assessed by ABPM [ Time Frame: Baseline to Months 3 and 6 ]
• Change in Office DBP from Baseline to Months 3 and 6 [ Time Frame: Baseline to Months 3 and 6 ]
• Change in Daytime and Nighttime Mean SBP and DBP from Baseline to Month 3 and Month 6, assessed by ABPM [ Time Frame: Baseline to Months 3 and 6 ]
• Change in Serum Angiotensinogen (AGT) from Baseline through Month 6 [ Time Frame: Baseline through Month 6 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Zilebesiran as Add-on Therapy in Patients With Hypertension Not Adequately Controlled by a Standard of Care Antihypertensive Medication (KARDIA-2)
• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Hypertension

Intervention

• Drug: Olmesartan
  Olmesartan administered orally
• Drug: Amlodipine
  Amlodipine administered orally
• Drug: Indapamide
  Indapamide administered orally
• Drug: Placebo
  Placebo administered by subcutaneous (SC) injection
• Drug: Zilebesiran
  Zilebesiran administered by SC injection
  Other Name: ALN-AGT01

Study Arms

• 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 open-label extension (OLE) period will be closed and participants will not receive any further treatment with zilebesiran in the OLE period.
  Interventions:

  • Drug: Olmesartan
  • Drug: Zilebesiran
• 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.
  Interventions:

  • Drug: Olmesartan
  • Drug: Placebo
  • Drug: Zilebesiran
• 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.
  Interventions:

  • Drug: Amlodipine
  • Drug: Zilebesiran
• 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.
  Interventions:

  • Drug: Amlodipine
  • Drug: Placebo
  • Drug: Zilebesiran
• 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.
  Interventions:

  • Drug: Indapamide
  • Drug: Zilebesiran
• 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.
  Interventions:

  • Drug: Indapamide
  • Drug: Placebo
  • Drug: Zilebesiran

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: August 16, 2023): 672
• Original Estimated Enrollment (submitted: October 22, 2021): 800
• Estimated Study Completion Date: December 31, 2025
• Actual Primary Completion Date: September 18, 2023 (Final data collection date for primary outcome measure)

Eligibility 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 milliequivalents per liter (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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Estonia, Germany, Latvia, Lithuania, Poland, Puerto Rico, United Kingdom, United States

Administrative Information

• NCT Number: NCT05103332
• Other Study ID Numbers: ALN-AGT01-003; 2021-003776-13 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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 United States (US) and/or the European Union (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.

• Current Responsible Party: Alnylam Pharmaceuticals
• Original Responsible Party: Same as current
• Current Study Sponsor: Alnylam Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Alnylam Pharmaceuticals

• PRS Account: Alnylam Pharmaceuticals
• Verification Date: May 2024