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: Placebo; Drug: Indapamide; Drug: Zilebesiran; 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: 663 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 <lower limit of normal (LLN) range or >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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663 participants in 6 patient groups, including a placebo group

Placebo (Add-on to Indapamide)

Placebo Comparator group

Description:

Following a 4-week run-in treatment on indapamide, 2.5 milligrams (mg), orally, once daily (QD), eligible participants were randomized to receive placebo matched to zilebesiran as a subcutaneous (SC) injection on Day 1 of 6-month double-blind (DB) treatment period as add-on therapy to indapamide. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran once every 6 months (Q6M) during the open-label extension (OLE) period. Upon implementation of Amendment 3, the OLE period was closed.

Treatment:

Drug: Zilebesiran

Drug: Indapamide

Drug: Placebo

Zilebesiran (Add-on to Indapamide)

Experimental group

Description:

Following a 4-week run-in treatment on indapamide, 2.5 mg, orally, QD, eligible participants were randomized to receive zilebesiran 600 mg, as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to indapamide. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran, Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed.

Treatment:

Drug: Zilebesiran

Drug: Indapamide

Placebo (Add-on to Amlodipine)

Placebo Comparator group

Description:

Following a 4-week run-in treatment on amlodipine, 5 mg, orally, QD, eligible participants were randomized to receive placebo matched to zilebesiran as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to amlodipine. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed.

Treatment:

Drug: Amlodipine

Drug: Zilebesiran

Drug: Placebo

Zilebesiran (Add-on to Amlodipine)

Experimental group

Description:

Following a 4-week run-in treatment on amlodipine, 5 mg, orally, QD, eligible participants were randomized to receive zilebesiran 600 mg, as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to amlodipine. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran, Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed.

Treatment:

Drug: Amlodipine

Drug: Zilebesiran

Placebo (Add-on to Olmesartan)

Placebo Comparator group

Description:

Following a 4-week run-in treatment on olmesartan, 40 mg, orally, QD, (or 20 mg, orally, QD for participants with creatinine clearance ≤60 milliliters per minute \[mL/min\] at screening enrolled at sites outside of the United States \[US\] consistent with local labeling), eligible participants were randomized to receive placebo matched to zilebesiran as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to olmesartan. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed.

Treatment:

Drug: Olmesartan

Drug: Zilebesiran

Drug: Placebo

Zilebesiran (Add-on to Olmesartan)

Experimental group

Description:

Following a 4-week run-in treatment on olmesartan, 40 mg, orally, QD, (or 20 mg, orally, QD for participants with creatinine clearance ≤60 mL/min at screening enrolled at sites outside of the US consistent with local labeling), eligible participants were randomized to receive zilebesiran 600 mg, as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to olmesartan. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran, Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed.

Treatment:

Drug: Olmesartan

Drug: Zilebesiran