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

Overview

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.

Full Title of Study: “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”

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Primary Purpose: Treatment
  • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Study Primary Completion Date: September 18, 2023

Interventions

• 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

Arms, Groups and Cohorts

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Clinical Trial Outcome Measures

Primary Measures

• 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 Measures

• 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 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 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

Participating in This Clinical Trial

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, newly diagnosed Type 2 diabetes mellitus – History of any cardiovascular event within 6 months prior to randomization – History of intolerance to SC injection(s)

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: No

Investigator Details

• Lead Sponsor
  • Alnylam Pharmaceuticals
• Provider of Information About this Clinical Study
  • Sponsor
• Overall Official(s)
  • Medical Director, Study Director, Alnylam Pharmaceuticals