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ZENITH: Zilebesiran in Patients with Hypertension Not Adequately Controlled and With Either Established Cardiovascular Disease or High Risk for Cardiovascular Disease
EU CTIS ID: 2025-522960-34-00
What this study is testing
01. To evaluate whether zilebesiran compared to placebo reduces the risk of CV death, nonfatal MI, nonfatal stroke, or HF event (hospitalization for HF or urgent HF visit)
- Therapeutic confirmatory (Phase III)
A plain-language read of the study's public EU CTIS listing. The study team confirms the details.
Who can take part
You may be able to join if
- 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.
- 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)
- 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)
- 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.
- 05. Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent.
You likely can't join if
- 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.
- 10. Hemoglobin A1c (HbA1c) >10% within 60 days before screening or during the Screening period.
- 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.
- 12. Hospitalization for HF within 60 days before screening or during the Screening period.
- 13. History of clinically significant CV event (eg, MI, stroke, revascularization procedure) within 60 days before screening or during the Screening period.
- 14. Known history of left ventricular ejection fraction <40% on most recent echocardiogram or equivalent imaging.
See the full eligibility criteria
Who can join
- 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.
- 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)
- 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)
- 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.
- 05. Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent.
What rules you out
- 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.
- 10. Hemoglobin A1c (HbA1c) >10% within 60 days before screening or during the Screening period.
- 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.
- 12. Hospitalization for HF within 60 days before screening or during the Screening period.
- 13. History of clinically significant CV event (eg, MI, stroke, revascularization procedure) within 60 days before screening or during the Screening period.
- 14. Known history of left ventricular ejection fraction <40% on most recent echocardiogram or equivalent imaging.
- 15. Severe aortic stenosis.
- 16. Has undergone major organ transplantation or is anticipated to undergo transplantation during the study.
- 17. Known medical history or evidence of liver cirrhosis.
- 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).
- 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).
- 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.
- 20. Is not willing to comply with the contraceptive requirements during the study, as described in Section 5.10.1 of the Protocol.
- 21. Female patient is pregnant, planning a pregnancy, or breast-feeding.
- 22. Known history of alcohol use disorder or other substance abuse, within the last 12 months before screening, in the opinion of the Investigator
- 23. Blood pressure cannot be accurately assessed (eg, due to cuff size limitations).
- 24. Placed in an institution on the basis of an official or court order.
- 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)
- 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.
- 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.
- 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).
- 07. Use of a potassium binder for the treatment of hyperkalemia within 3 months before screening and during the Screening period.
- 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.
- 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.
The study team makes the final eligibility decision.
Where it's taking place
- Brazil
- Canada
- Argentina
- Japan
- New Zealand
- United States
- United Kingdom
- India
- China
- Mexico
- Korea, Republic of
- South Africa
- Serbia
- Turkey
- Chile
- Australia
- Colombia
- Taiwan
Questions & answers
Do participants get paid in this trial?
This listing doesn't specify compensation. Many trials still reimburse travel or offer a stipend, so it's worth asking the study team when you connect.
Is it free to join, and do I need insurance?
Searching and applying through BridgeMD is free. In clinical trials the study-related treatment and visits are generally provided at no cost to you. You usually don't need insurance to take part - confirm specifics with the study team.
How long does this study last?
The listing doesn't state an exact length. The study team walks you through the schedule and number of visits before you decide to enroll.
Who can join this trial?
This study is enrolling all sexes, 65+ years, 18-64 years. The study team makes the final eligibility decision.
Where is this trial taking place?
Study sites include Brazil; Canada; Argentina; Japan; New Zealand; United States and 12 more location(s). Enter your location above to see the nearest site and check your eligibility.
Explore other conditions
BridgeMD is an information and trial-matching tool - not medical advice, and not the study sponsor. Details come from EU CTIS; the study team decides eligibility.