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

Alnylam Pharmaceuticals

Status and phase: Completed; Phase 2

Conditions: Hypertension

Treatments: Drug: Indapamide; Drug: Zilebesiran; Drug: Placebo; Drug: Olmesartan; Drug: Amlodipine

Study type: Interventional

Funder types: Industry

Identifiers

NCT05103332

ALN-AGT01-003

2021-003776-13 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 672 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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672 participants in 6 patient groups, including a placebo group

Zilebesiran (Add-on to Olmesartan)

Experimental group

Description:

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.

Treatment:

Drug: Olmesartan

Drug: Zilebesiran

Placebo (Add-on to Olmesartan)

Experimental group

Description:

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.

Treatment:

Drug: Olmesartan

Drug: Placebo

Drug: Zilebesiran

Zilebesiran (Add-on to Amlodipine)

Experimental group

Description:

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.

Treatment:

Drug: Amlodipine

Drug: Zilebesiran

Placebo (Add-on to Amlodipine)

Placebo Comparator group

Description:

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.

Treatment:

Drug: Amlodipine

Drug: Placebo

Drug: Zilebesiran

Zilebesiran (Add-on to Indapamide)

Placebo Comparator group

Description:

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.

Treatment:

Drug: Zilebesiran

Drug: Indapamide

Placebo (Add-on to Indapamide)

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

Drug: Zilebesiran

Drug: Indapamide