ZILEBESIRAN for Hypertension | Cardiovascular disease | High cardiovascular risk

Inclusion criteria

• {"criterion_text":"- 01. Age at the time of initial informed consent as follows: a. 18 years or older for patients with established CVD b. 55 years or older for patients with high risk for CVD."}
• {"criterion_text":"- 02. Established CVD or high risk for CVD: a. Established CVD defined as 1 or more of the following: Coronary artery disease, Cerebrovascular disease, Peripheral arterial disease OR b. High risk for CVD, defined by the presence of 2 or more of the following CV risk factors: i. Age ≥70 years at the time of initial informed consent ii. eGFR <60 mL/min/1.73m2 during screening iii. Urine albumin:creatinine ratio >300 mg/g during screening iv. Current smoker v. Atrial fibrillation on medical therapy (eg, anticoagulation or rate control) vi. Documented history of CAC with most recent CAC score >100 Agatston Units vii. NT-proBNP >125 pg/mL (15 pmol/L) during screening viii. Presence of 1 or both of the following (multiple events are counted as 1 total CV risk factor): • Type 1 or 2 diabetes mellitus • BMI ≥30 kg/m2 or ≥27 kg/m2 if the patient is of East Asian, Southeast Asian, or South Asian descent (eg, Chinese, Japanese, Korean, Indian, Pakistani, Thai)"}
• {"criterion_text":"- 03. Treated hypertension on stable therapy with a thiazide, thiazide-like, or loop diuretic and at least 1 other standard of care antihypertensive medication from the classes below. Fixed-dose combination medications will be considered as multiple medications based on their individual components. Stable therapy is defined as having no change in the prescription of antihypertensive medications or dosing regimens within 30 days prior to screening and during the Screening period. Antihypertensive medications must be prescribed consistent with guideline recommendations and/or local standards. If clinically appropriate, per Investigator discretion, patients not receiving a diuretic at the time of the Prescreening visit may have a thiazide or thiazide-like diuretic added before screening; patients must maintain this new antihypertensive regimen for at least 30 days prior to screening and during the Screening period to establish stability and should intend to continue this medication through the study period. a. ACE inhibitor or ARB b. CCB c. Beta blocker d. MRA e. Vasodilator (eg, hydralazine, minoxidil, alpha blocker) f. Centrally acting antihypertensive medication (eg, clonidine)"}
• {"criterion_text":"- 04. Seated automated mean office SBP ≥145 mmHg and <180 mmHg during the Screening period and ≥140 mmHg and <180 mmHg on Day 1 (before randomization) with measurements taken at least 7 days apart."}
• {"criterion_text":"- 05. Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent."}

Exclusion criteria

• {"criterion_text":"- 01. Known history of secondary hypertension (including, but not limited to, due to known history of renovascular hypertension, primary aldosteronism, pheochromocytoma, Cushing syndrome, or aortic coarctation). Hypertension secondary to CKD is not a criterion for exclusion."}
• {"criterion_text":"- 10. Hemoglobin A1c (HbA1c) >10% within 60 days before screening or during the Screening period."}
• {"criterion_text":"- 11. Known weight loss >10% in the 3 months before screening. Patients receiving drugs that have the potential to cause significant weight loss (eg, glucagon-like peptide-1 agonists) should be on a stable dose for at least 3 months before screening."}
• {"criterion_text":"- 12. Hospitalization for HF within 60 days before screening or during the Screening period."}
• {"criterion_text":"- 13. History of clinically significant CV event (eg, MI, stroke, revascularization procedure) within 60 days before screening or during the Screening period."}
• {"criterion_text":"- 14. Known history of left ventricular ejection fraction <40% on most recent echocardiogram or equivalent imaging."}
• {"criterion_text":"- 15. Severe aortic stenosis."}
• {"criterion_text":"- 16. Has undergone major organ transplantation or is anticipated to undergo transplantation during the study."}
• {"criterion_text":"- 17. Known medical history or evidence of liver cirrhosis."}
• {"criterion_text":"- 18. Medical history that might limit the individual’s ability participate for the duration of the study (eg, severe respiratory disease; NYHA Class IV heart failure; cancer or evidence of spread within approximately the last 5 years, other than non-melanoma skin cancer)."}
• {"criterion_text":"- 19. For whatever reason, the Investigator believes the patient is not likely to be able to follow the protocol (eg, intolerance to SC injections or any excipient of the study drug) or the risk is likely greater than benefit from a persistent inhibitor of the RAS (eg, a patient with bilateral renal artery stenosis who developed renal failure following treatment with a RAS inhibitor)."}
• {"criterion_text":"- 02. Symptomatic orthostatic hypotension, defined as a fall of ≥20 mmHg SBP or ≥10 mmHg diastolic blood pressure (DBP) within approximately 1 to 3 minutes of standing up from a seated position by office blood pressure that is accompanied by symptoms (eg, dizziness, weakness, lightheadedness, or syncope) during screening."}
• {"criterion_text":"- 20. Is not willing to comply with the contraceptive requirements during the study, as described in Section 5.10.1 of the Protocol."}
• {"criterion_text":"- 21. Female patient is pregnant, planning a pregnancy, or breast-feeding."}
• {"criterion_text":"- 22. Known history of alcohol use disorder or other substance abuse, within the last 12 months before screening, in the opinion of the Investigator"}
• {"criterion_text":"- 23. Blood pressure cannot be accurately assessed (eg, due to cuff size limitations)."}
• {"criterion_text":"- 24. Placed in an institution on the basis of an official or court order."}
• {"criterion_text":"- 03. Has any of the following laboratory parameter assessments at screening: a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3×upper limit of normal (ULN). b. Total serum bilirubin >1.5×ULN. Patients with elevated total bilirubin that is secondary to documented Gilbert’s syndrome are eligible if the total bilirubin is <2×ULN. c. International normalized ratio (INR) >1.5 (patients on warfarin with an elevated INR will be allowed). d. Serum potassium >4.8 mEq/L (most recent value prior to randomization will be used for eligibility). e. eGFR <30 mL/min/1.73m2 (calculation will be based on the CKD Epidemiology Collaboration [CKD-EPI] equation)"}
• {"criterion_text":"- 04. Has known active human immunodeficiency virus (HIV) infection. Patients on antiretroviral therapy who are clinically stable and compliant with treatment for 6 months before screening per Investigator judgement are eligible for inclusion if they meet all of the inclusion criteria and none of the exclusion criteria."}
• {"criterion_text":"- 05. Received an investigational agent within the last 30 days or 5 half-lives, whichever is longer, before the first dose of study drug. Any agent that has received health agency authorization (including for emergency use) by local or regional regulatory authorities is not considered investigational."}
• {"criterion_text":"- 06. Currently taking both an ARB and an ACE inhibitor (either as single medications or part of combination medications such as ACE inhibitor/diuretic combinations or ARNIs that include an ARB)."}
• {"criterion_text":"- 07. Use of a potassium binder for the treatment of hyperkalemia within 3 months before screening and during the Screening period."}
• {"criterion_text":"- 08. Currently taking, taken within 6 months before screening and during the Screening period, or anticipated to receive any therapeutic agent that targets AGT (approved or investigational) during the study Note: Patients who were in other zilebesiran clinical studies are eligible if it is known that they did not receive zilebesiran and they have completed their participation in the study."}
• {"criterion_text":"- 09. Current or prior known history of severe intolerance to an ARB or ACE inhibitor other than cough (eg, angioedema, recurrent hyperkalemia, recurrent acute kidney injury), per Investigator judgement."}

Primary endpoints

• {"endpoint_text":"- 01. Time to first occurrence of a composite endpoint of CV death, nonfatal MI, nonfatal stroke, or HF event (hospitalization for HF or urgent HF visit).","definition_or_measurement_approach":"Time-to-event: time to first occurrence of the composite of cardiovascular (CV) death, nonfatal myocardial infarction (MI), nonfatal stroke, or heart failure (HF) event (hospitalization for HF or urgent HF visit)."}

Secondary endpoints

• {"endpoint_text":"- 01. Change from baseline in mean seated office SBP at Month 6","definition_or_measurement_approach":"Change from baseline in mean seated office systolic blood pressure (SBP) measured in clinic at Month 6."}
• {"endpoint_text":"- 02. Time to first occurrence of a composite endpoint of CV death, nonfatal MI, or nonfatal stroke","definition_or_measurement_approach":"Time-to-event: time to first occurrence of composite of CV death, nonfatal MI or nonfatal stroke."}
• {"endpoint_text":"- 03. Composite endpoint of CV death and total (first and subsequent) HF events (hospitalization for HF or urgent HF visit)","definition_or_measurement_approach":"Composite of CV death and total heart failure events (first and subsequent HF hospitalizations or urgent HF visits)."}
• {"endpoint_text":"- 04. Time to first occurrence of composite endpoint of CV death, nonfatal MI, nonfatal stroke, or coronary revascularization","definition_or_measurement_approach":"Time-to-event: time to first occurrence of CV death, nonfatal MI, nonfatal stroke, or coronary revascularization."}
• {"endpoint_text":"- 05. Time to all-cause death","definition_or_measurement_approach":"Time-to-event: time from randomization to death from any cause."}

Methods

• Patient brochures / recruitment brochures / recruitment flyers / recruitment posters — country-specific print materials provided (examples present for Austria, Belgium, Czechia, Denmark, France, Germany, Hungary, Italy, Poland, Portugal, Romania, Spain, Sweden and others).
• Online outreach / social media / paid-search campaigns / website landing pages / digital banners — country-specific online outreach materials and social media ads listed (e.g. 'Online-Outreach-Campaign', 'Social-Media-Ads', 'Paid-Search-Ad' documents for multiple countries).
• GP / primary care engagement and GP letters — country-specific GP/primary-care outreach (e.g. GP letter and site outreach materials in Italy, Austria and other countries).
• Participant portal and electronic engagement materials — participant portal and study guide / registration postcards (noted in Czech materials).
• Email campaigns and Trialmed HBP patient email outreach — email templates and patient engagement emails (documents present in Czech and other country packs).
• Site-based recruitment (posters/flyers displayed at clinical sites) — local site recruitment materials and study guides for clinic distribution.

Netherlands

Earliest CTIS Part Ii Submission Date

19-01-2026

Latest Decision Or Authorization Date

04-02-2026

Processing Time Days

16

Number Of Participants

102

Slovakia

Earliest CTIS Part Ii Submission Date

19-12-2025

Latest Decision Or Authorization Date

03-02-2026

Processing Time Days

46

Number Of Participants

126

Austria

Earliest CTIS Part Ii Submission Date

21-01-2026

Latest Decision Or Authorization Date

07-02-2026

Processing Time Days

17

Number Of Participants

144

Belgium

Earliest CTIS Part Ii Submission Date

13-10-2025

Latest Decision Or Authorization Date

04-02-2026

Processing Time Days

114

Number Of Participants

146

Bulgaria

Earliest CTIS Part Ii Submission Date

13-10-2025

Latest Decision Or Authorization Date

09-02-2026

Processing Time Days

119

Number Of Participants

439

Czechia

Earliest CTIS Part Ii Submission Date

07-11-2025

Latest Decision Or Authorization Date

03-02-2026

Processing Time Days

88

Number Of Participants

292

Denmark

Earliest CTIS Part Ii Submission Date

06-01-2026

Latest Decision Or Authorization Date

03-02-2026

Processing Time Days

28

Number Of Participants

66

France

Earliest CTIS Part Ii Submission Date

13-10-2025

Latest Decision Or Authorization Date

04-02-2026

Processing Time Days

114

Number Of Participants

78

Germany

Earliest CTIS Part Ii Submission Date

13-10-2025

Latest Decision Or Authorization Date

04-02-2026

Processing Time Days

114

Number Of Participants

380

Greece

Earliest CTIS Part Ii Submission Date

13-10-2025

Latest Decision Or Authorization Date

05-02-2026

Processing Time Days

115

Number Of Participants

140

Hungary

Earliest CTIS Part Ii Submission Date

14-11-2025

Latest Decision Or Authorization Date

05-02-2026

Processing Time Days

83

Number Of Participants

185

Italy

Earliest CTIS Part Ii Submission Date

13-10-2025

Latest Decision Or Authorization Date

06-02-2026

Processing Time Days

116

Number Of Participants

193

Poland

Earliest CTIS Part Ii Submission Date

12-12-2025

Latest Decision Or Authorization Date

08-02-2026

Processing Time Days

58

Number Of Participants

810

Portugal

Earliest CTIS Part Ii Submission Date

27-11-2025

Latest Decision Or Authorization Date

05-02-2026

Processing Time Days

70

Number Of Participants

133

Romania

Earliest CTIS Part Ii Submission Date

23-12-2025

Latest Decision Or Authorization Date

09-02-2026

Processing Time Days

48

Number Of Participants

292

Spain

Earliest CTIS Part Ii Submission Date

13-10-2025

Latest Decision Or Authorization Date

09-02-2026

Processing Time Days

119

Number Of Participants

418

Sweden

Earliest CTIS Part Ii Submission Date

13-10-2025

Latest Decision Or Authorization Date

04-02-2026

Processing Time Days

114

Number Of Participants

38

Primary sponsor

Full Name

Alnylam Pharmaceuticals Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Fisher Clinical Services GmbH

Name

Arup Laboratories Inc.

Name

Syneos Health Inc.

Name

PPD Development LP

Responsibilities

Preparation and submission of applications to CA and ECs (and other trial operations responsibilities as listed)

Name

PPD Denmark Filial Af PPD Scandinavia AB Sverige

Responsibilities

Project management duties or monitoring/regulatory

Name

PPD Global Central Labs

Name

Propharma Group The Netherlands B.V.

Third parties

• {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Arup Laboratories Inc.","duties_or_roles":"","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Syneos Health Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"University Of Wisconsin","duties_or_roles":"","organisation_type":"Educational Institution"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Denmark","full_name":"PPD Denmark Filial Af PPD Scandinavia AB Sverige","duties_or_roles":"Project management duties or monitoring/regulatory","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"PPD Global Central Labs","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Propharma Group The Netherlands B.V.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Greece","full_name":"PPD Global Ltd.","duties_or_roles":"Project management duties or monitoring/regulatory","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"Preparation and submission of applications to CA and ECs (and multiple trial support duties listed)","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"Greece","full_name":"PPD Global Ltd.","duties_or_roles":"Project management duties or monitoring/regulatory","organisation_type":"Pharmaceutical company"}