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

NCT05103332 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: ALN-AGT01-0032021-003776-13
• Study Type: interventional
• Target: 663
• Locations: 8 countries
• Sites: 110

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.

Conditions

Hypertension

Keywords

High blood pressure; Hypertension; Hypertensive; siRNA; Angiotensinogen; AGT

Outcome Measures

Primary Outcomes (3)

• Indapamide: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data

  24-hour ABPM device was programmed to take readings every 20 minutes during day (6 am- 9:59 pm) and every 30 minutes during night (10 pm-5:59 am). ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33; 2. the number of successful nighttime readings were ≥11; 3. no more than 3 hours are not represented (i.e.,3 sections of 60 minutes where 0 valid readings were obtained). To summarize 24-hour ABPM, the hourly adjusted mean was calculated. Hourly adjusted mean was the average BP for each hour of the day. The 24-hour mean was the average of the hourly means. Least squares (LS) mean and standard error (SE) were calculated using a mixed model repeated measures (MMRM) approach. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for SBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.

  Baseline and Month 3

• Amlodipine: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data

  24-hour ABPM device was programmed to take readings every 20 minutes during day (6 am- 9:59 pm) and every 30 minutes during night (10 pm-5:59 am). ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33; 2. the number of successful nighttime readings were ≥11; 3. no more than 3 hours are not represented (i.e.,3 sections of 60 minutes where 0 valid readings were obtained). To summarize 24-hour ABPM, the hourly adjusted mean was calculated. Hourly adjusted mean was the average BP for each hour of the day. The 24-hour mean was the average of the hourly means. LS mean and SE were calculated using a MMRM approach. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for SBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.

  Baseline and Month 3

• Olmesartan: Change From Baseline at Month 3 in 24-hour Mean SBP Assessed by ABPM - Censored Data

  24-hour ABPM device was programmed to take readings every 20 minutes during day (6 am- 9:59 pm) and every 30 minutes during night (10 pm-5:59 am). ABPM was considered adequate if: 1. the number of successful daytime readings were ≥33; 2. the number of successful nighttime readings were ≥11; 3. no more than 3 hours are not represented (i.e.,3 sections of 60 minutes where 0 valid readings were obtained). To summarize 24-hour ABPM, the hourly adjusted mean was calculated. Hourly adjusted mean was the average BP for each hour of the day. The 24-hour mean was average of the hourly means. LS mean and SE were calculated using a MMRM approach. Hypothetical strategy was used for the intercurrent event of using antihypertensive escape medication, i.e., data for SBP assessed using ABPM, while participants were on and within 2 weeks after stopping any escape medication were censored for this endpoint.

  Baseline and Month 3

Secondary Outcomes (42)

• Indapamide: Change From Baseline at Month 3 in Office SBP - Censored Data

  Baseline and Month 3

• Indapamide: Time-adjusted Change From Baseline Through Month 6 in 24-hour Mean SBP, Assessed by ABPM - All Collected Data

  Baseline through Month 6

• Indapamide: Time-adjusted Change From Baseline Through Month 6 in Office SBP - All Collected Data

  Baseline through Month 6

• Indapamide: Percentage of Participants With 24-hour Mean SBP <130 mmHg and/or Reduction From Baseline ≥20 mmHg Assessed by ABPM Without Escape Antihypertensive Medications at Month 6

  Month 6

• Indapamide: Change From Baseline at Month 3 in 24-hour Mean Diastolic Blood Pressure (DBP), Assessed by ABPM - Censored Data

  Baseline and Month 3

Study Arms (6)

Placebo (Add-on to Indapamide)

PLACEBO COMPARATOR

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.

Drug: Indapamide; Drug: Placebo; Drug: Zilebesiran

Zilebesiran (Add-on to Indapamide)

EXPERIMENTAL

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.

Drug: Indapamide; Drug: Zilebesiran

Placebo (Add-on to Amlodipine)

PLACEBO COMPARATOR

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.

Drug: Amlodipine; Drug: Placebo; Drug: Zilebesiran

Zilebesiran (Add-on to Amlodipine)

EXPERIMENTAL

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.

Drug: Amlodipine; Drug: Zilebesiran

Placebo (Add-on to Olmesartan)

PLACEBO COMPARATOR

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.

Drug: Olmesartan; Drug: Placebo; Drug: Zilebesiran

Zilebesiran (Add-on to Olmesartan)

EXPERIMENTAL

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.

Drug: Olmesartan; Drug: Zilebesiran

Interventions

Indapamide DRUG

Indapamide administered orally

Placebo (Add-on to Indapamide); Zilebesiran (Add-on to Indapamide)

Amlodipine DRUG

Amlodipine administered orally

Placebo (Add-on to Amlodipine); Zilebesiran (Add-on to Amlodipine)

Olmesartan DRUG

Olmesartan administered orally

Placebo (Add-on to Olmesartan); Zilebesiran (Add-on to Olmesartan)

Placebo DRUG

Placebo administered by SC injection

Placebo (Add-on to Amlodipine); Placebo (Add-on to Indapamide); Placebo (Add-on to Olmesartan)

Zilebesiran DRUG

Zilebesiran administered by SC injection

Also known as: ALN-AGT01

Placebo (Add-on to Amlodipine); Placebo (Add-on to Indapamide); Placebo (Add-on to Olmesartan); Zilebesiran (Add-on to Amlodipine); Zilebesiran (Add-on to Indapamide); Zilebesiran (Add-on to Olmesartan)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• hour mean SBP ≥130 mmHg and ≤160 mmHg by ABPM after at least 4 weeks of run-in

You may not qualify if:

• 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)

Sponsors & Collaborators

• Alnylam Pharmaceuticals: lead

Study Sites (110)

Clinical Trial Site

Mesa, Arizona, 85213, United States

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Tempe, Arizona, 85281, United States

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Tempe, Arizona, 85282, United States

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Bell Gardens, California, 90201, United States

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Beverly Hills, California, 90211, United States

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Canoga Park, California, 91304, United States

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Carlsbad, California, 92008, United States

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Encinitas, California, 92024, United States

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Garden Grove, California, 92844, United States

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Hollywood, California, 91606, United States

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Huntington Beach, California, 92647, United States

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Irvine, California, 92614, United States

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Long Beach, California, 90805, United States

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Los Angeles, California, 90057, United States

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Mission Hills, California, 91345, United States

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Oceanside, California, 92056, United States

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Panorama City, California, 91402, United States

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San Diego, California, 92103, United States

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Santa Clarita, California, 91355, United States

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South Gate, California, 90280, United States

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Tustin, California, 92780, United States

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Upland, California, 91786, United States

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Washington D.C., District of Columbia, 20011, United States

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Clearwater, Florida, 33756, United States

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Coconut Creek, Florida, 33073, United States

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Coral Gables, Florida, 33134, United States

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Hollywood, Florida, 33021, United States

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Hollywood, Florida, 33024, United States

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Inverness, Florida, 34452, United States

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Jacksonville, Florida, 32256, United States

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Miami, Florida, 33032, United States

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Miami, Florida, 33125, United States

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Miami, Florida, 33135, United States

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Miami, Florida, 33144, United States

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Miami, Florida, 33176, United States

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Naples, Florida, 34105, United States

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Orlando, Florida, 32162, United States

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Orlando, Florida, 32801, United States

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Pembroke Pines, Florida, 33027, United States

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Tampa, Florida, 33603, United States

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Winter Haven, Florida, 33880, United States

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Winter Park, Florida, 32789, United States

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Acworth, Georgia, 30101, United States

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Canton, Georgia, 30114, United States

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Columbus, Georgia, 31904, United States

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Savannah, Georgia, 31406, United States

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Louisville, Kentucky, 40202, United States

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New Orleans, Louisiana, 70769, United States

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Southgate, Michigan, 48195, United States

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Jackson, Mississippi, 39209, United States

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Hazelwood, Missouri, 63042, United States

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Jefferson City, Missouri, 65109, United States

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New York, New York, 10036, United States

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Greensboro, North Carolina, 27403, United States

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Greensboro, North Carolina, 27410, United States

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Monroe, North Carolina, 28112, United States

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Winston-Salem, North Carolina, 27157, United States

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Norman, Oklahoma, 73072, United States

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Little River, South Carolina, 29566, United States

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Memphis, Tennessee, 38119, United States

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Amarillo, Texas, 79109, United States

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Coppell, Texas, 75019, United States

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Dallas, Texas, 75251, United States

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Houston, Texas, 77074, United States

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Houston, Texas, 77081, United States

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Lake Jackson, Texas, 77566, United States

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Plano, Texas, 75024, United States

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Sherman, Texas, 75092, United States

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Splendora, Texas, 77372, United States

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Stephenville, Texas, 76401, United States

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Tomball, Texas, 77375, United States

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Waco, Texas, 76708, United States

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Burke, Virginia, 22015, United States

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Kenosha, Wisconsin, 53142, United States

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Brampton, Ontario, Canada

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Concord, Ontario, Canada

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London, Ontario, N5W 6A2, Canada

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Toronto, Ontario, Canada

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Winnipeg, Ontario, Canada

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Chicoutimi, Quebec, Canada

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Lévis, Quebec, Canada

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Pointe-Claire, Quebec, Canada

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Québec, Quebec, Canada

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Sherbrooke, Quebec, Canada

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Trois-Rivières, Quebec, Canada

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Québec, Canada

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Tartu, Estonia

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Frankfurt, Germany

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Riga, Latvia

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Kaunas, Lithuania

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Vilnius, Lithuania

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Częstochowa, Poland

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Gdansk, Poland

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Katowice, Poland

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Staszów, Poland

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Warsaw, Poland

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Wroclaw, Poland

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Bellshill, Lanarkshire, ML4 3NJ, United Kingdom

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Carshalton, United Kingdom

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Edinburgh, United Kingdom

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Fowey, United Kingdom

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Glasgow, United Kingdom

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Lancashire Preston, United Kingdom

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Liskeard, United Kingdom

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London, United Kingdom

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Manchester, United Kingdom

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Newquay, United Kingdom

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Plymouth, United Kingdom

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Sheffield, United Kingdom

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Torpoint, United Kingdom

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Related Publications (1)

• Desai AS, Karns AD, Badariene J, Aswad A, Neutel JM, Kazi F, Park W, Stiglitz D, Makarova N, Havasi A, Zappe DH, Saxena M; KARDIA-2 Study Group. Add-On Treatment With Zilebesiran for Inadequately Controlled Hypertension: The KARDIA-2 Randomized Clinical Trial. JAMA. 2025 Jul 1;334(1):46-55. doi: 10.1001/jama.2025.6681.

  PMID: 40434761 DERIVED

MeSH Terms

Conditions

Hypertension

Interventions

Indapamide; Amlodipine; olmesartan

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Alnylam Pharmaceuticals

clinicaltrials@alnylam.com

866-330-0326

Study Officials

• Medical Director

  Alnylam Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 22, 2021
• First Posted: November 2, 2021
• Study Start: November 5, 2021
• Primary Completion: December 11, 2023
• Study Completion: September 13, 2024
• Last Updated: November 3, 2025
• Results First Posted: July 9, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will share

Locations

PL (6); LI (2); LA (1); CA (12); DE (1); US (74); ES (1); GB (13)