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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Olmesartan
* Drug: Amlodipine
* Drug: Indapamide
* Drug: Placebo
* Drug: Zilebesiran


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Office SBP at Screening as follows: ≥155 mmHg and ≤180 mmHg for patients with untreated hypertension ≥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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zilebesiran (Add-on to Olmesartan)<br>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. | Drug: Olmesartan<br>* Olmesartan administered orally<br>Drug: Zilebesiran<br>* Zilebesiran administered by SC injection<br>* Other names: ALN-AGT01;|
| Experimental: Placebo (Add-on to Olmesartan)<br>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. | Drug: Olmesartan<br>* Olmesartan administered orally<br>Drug: Placebo<br>* Placebo administered by subcutaneous (SC) injection<br>Drug: Zilebesiran<br>* Zilebesiran administered by SC injection<br>* Other names: ALN-AGT01;|
| Experimental: Zilebesiran (Add-on to Amlodipine)<br>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. | Drug: Amlodipine<br>* Amlodipine administered orally<br>Drug: Zilebesiran<br>* Zilebesiran administered by SC injection<br>* Other names: ALN-AGT01;|
| Placebo Comparator: Placebo (Add-on to Amlodipine)<br>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. | Drug: Amlodipine<br>* Amlodipine administered orally<br>Drug: Placebo<br>* Placebo administered by subcutaneous (SC) injection<br>Drug: Zilebesiran<br>* Zilebesiran administered by SC injection<br>* Other names: ALN-AGT01;|
| Placebo Comparator: Zilebesiran (Add-on to Indapamide)<br>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. | Drug: Indapamide<br>* Indapamide administered orally<br>Drug: Zilebesiran<br>* Zilebesiran administered by SC injection<br>* Other names: ALN-AGT01;|
| Placebo Comparator: Placebo (Add-on to Indapamide)<br>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. | Drug: Indapamide<br>* Indapamide administered orally<br>Drug: Placebo<br>* Placebo administered by subcutaneous (SC) injection<br>Drug: Zilebesiran<br>* Zilebesiran administered by SC injection<br>* Other names: ALN-AGT01;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline at Month 3 in 24-Hour Mean Systolic Blood Pressure (SBP) Assessed by Ambulatory Blood Pressure Monitoring (ABPM) |  | Baseline and Month 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline at Month 3 in Office SBP |  | Baseline and Month 3 | 
| Time-adjusted Change from Baseline through Month 6 in Office SBP 24-hour Mean SBP, Assessed by ABPM |  | 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 |  | Baseline and Month 6 | 
| Change in 24-hour Mean SBP and DBP, Assessed by ABPM |  | Baseline and Month 6 | 
| Change in Office SBP and DBP |  | Baseline and Month 6 | 
| Change in Daytime and Nighttime Mean SBP and DBP, Assessed by ABPM | Daytime is defined as 6 am to 9:59 pm and nighttime is defined as 10 pm to 5:59 am. | Baseline and Month 6 | 
| Change from Baseline in Serum Angiotensinogen (AGT) |  | Baseline through Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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siRNA, High blood pressure, Hypertension, Hypertensive, Angiotensinogen, AGT