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Zilebesiran for uncontrolled high blood pressure in people with or at high risk for cardiovascular disease

ZENITH: A Phase 3 Global, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Zilebesiran in Addition to Standard of Care in Reducing Major Adverse Cardiovascular Events in Adult Patients With Hypertension Not Adequately Controlled and With Either Established Cardiovascular Disease or High Risk for Cardiovascular Disease

Phase 3 Interventional Alnylam Pharmaceuticals · NCT07181109

This will test whether zilebesiran versus placebo reduces the chance of heart attack, stroke, heart-failure events, or cardiovascular death in adults whose high blood pressure isn’t controlled and who have or are at high risk for cardiovascular disease.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment11000 (estimated)
Ages18 Years and up
SexAll
SponsorAlnylam Pharmaceuticals Industry-sponsored
Locations597 sites (Birmingham, Alabama and 596 other locations)
Trial IDNCT07181109 on ClinicalTrials.gov

What this trial studies

This phase 3, randomized, placebo-controlled, event-driven trial compares zilebesiran with placebo in adults with treated but inadequately controlled hypertension who either have established cardiovascular disease or are at high cardiovascular risk. Participants must be on stable therapy with at least two standard antihypertensive medications, including a thiazide/thiazide-like or loop diuretic. The primary outcome is a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure events, and the study will continue until a prespecified number of adjudicated events have occurred. Dosing and follow-up are managed at participating clinical sites with blinded outcome adjudication.

Who should consider this trial

Good fit: Adults with treated but inadequately controlled hypertension who either are 18+ with established cardiovascular disease or are 55+ with high cardiovascular risk and who are on at least two antihypertensive medicines including a thiazide/thiazide-like or loop diuretic are the intended participants.

Not a fit: Patients with secondary hypertension, symptomatic orthostatic hypotension, significant liver or kidney dysfunction, high potassium, or other listed lab exclusions are not eligible and therefore unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, zilebesiran could lower the rate of major cardiovascular events and deaths in patients with uncontrolled hypertension and high cardiovascular risk.

How similar studies have performed: Early-phase studies of AGT-targeting siRNA drugs including zilebesiran showed notable blood-pressure lowering, but large event-driven outcome benefits have not yet been proven.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

* Is 18 years or older for patients with established cardiovascular disease (CVD)
* Is 55 years or older for patients with high risk for CVD
* Has established CVD (defined as coronary, cerebrovascular, or peripheral artery disease) or high risk for CVD
* Has treated hypertension on stable therapy with at least 2 standard of care antihypertensive medications, one of which must be a thiazide, thiazide-like, or loop diuretic

Exclusion Criteria:

* Has known history of secondary hypertension
* Has symptomatic orthostatic hypotension
* Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3×upper limit of normal (ULN)
* Has total serum bilirubin \>1.5×ULN
* Has international normalized ratio (INR) \>1.5
* Has serum potassium \>4.8 mEq/L
* Has estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73m\^2

Where this trial is running

Birmingham, Alabama and 596 other locations

+547 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions High Risk Cardiovascular DiseaseHypertensionHigh Cardiovascular RiskHigh blood pressuresiRNAAngiotensinogenAGTCardiovascular disease
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.