What side effects are associated with this type of intervention?

Common treatments for high blood pressure, such as ACE inhibitors and ARBs, can have several side effects. ACE inhibitors may cause a persistent dry cough, elevated blood potassium levels, low blood pressure, dizziness, and, in rare cases, angioedema (swelling of deeper layers of the skin). ARBs, which are often used as an alternative to ACE inhibitors, generally have fewer side effects but can still cause dizziness, elevated blood potassium levels, and, less commonly, angioedema. Both classes of drugs are generally well-tolerated but require monitoring for these potential adverse effects.

What prior FDA approvals exist?

The FDA has approved several classes of drugs for the treatment of high blood pressure that target the renin-angiotensin system. These include angiotensin-converting enzyme (ACE) inhibitors like enalapril and benazepril, and angiotensin II receptor blockers (ARBs) such as valsartan and olmesartan. These medications work by inhibiting different components of the renin-angiotensin system to lower blood pressure. Zilebesiran, currently under study, represents a novel approach by using RNA interference to target angiotensinogen, potentially offering a new mechanism for blood pressure control.

What other types of research exist?

Promising novel alternatives to Zilebesiran for high blood pressure treatment in 2024 include: 1) Aliskiren, a direct renin inhibitor, which has shown efficacy in managing hypertension. 2) PCSK9 inhibitors, primarily used for cholesterol management, have potential benefits in cardiovascular health, including blood pressure reduction. 3) Dapagliflozin, an SGLT2 inhibitor, has demonstrated positive effects on blood pressure in patients with chronic kidney disease. 4) Inclisiran, an RNA interference therapeutic targeting PCSK9, which may offer cardiovascular benefits including blood pressure control.

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Zilebesiran for High Blood Pressure (KARDIA-2 Trial)

Phase 2

Waitlist Available

Research Sponsored by Alnylam Pharmaceuticals

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

24-hour mean SBP >130 mmHg and ≤160 mmHg by ABPM after at least 4 weeks of run-in on protocol-specified background antihypertensive medication

≥145 mmHg and ≤180 mmHg for patients on antihypertensive medications

Must not have

Estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73m^2

Type 1 diabetes mellitus, poorly controlled Type 2 diabetes mellitus, newly diagnosed Type 2 diabetes mellitus

Timeline

Screening 3 weeks

Treatment Varies

Follow Up baseline and month 6

Summary

This trial is testing zilebesiran, a medication that may help lower blood pressure, in patients who need extra help managing their high blood pressure. It works by influencing body processes that regulate blood pressure.

Who is the study for?

This trial is for adults with high blood pressure not well-controlled by standard medications. Eligible participants have a 24-hour average systolic blood pressure between >130 and ≤160 mmHg, and office readings of ≥145 to ≤180 mmHg if on meds or ≥155 to ≤180 mmHg if untreated. They can't join if they've used investigational drugs recently, have very low kidney function, unmanaged diabetes, recent heart issues, or certain other conditions.

What is being tested?

The study tests Zilebesiran's ability to lower blood pressure when added to common antihypertensive drugs like Amlodipine, Indapamide, or Olmesartan. Participants will be randomly assigned either Zilebesiran or a placebo as an add-on therapy while continuing their usual hypertension medication.

What are the potential side effects?

Potential side effects of Zilebesiran may include reactions at the injection site since it's given under the skin (SC), possible changes in kidney function which will be monitored due to its effect on blood pressure regulation mechanisms.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My average blood pressure is between 130 and 160 mmHg after 4 weeks on certain blood pressure meds.

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My blood pressure is between 145 and 180 mmHg while on medication.

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My blood pressure is between 155 and 180 mmHg and I haven't treated it yet.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My kidney function is severely reduced.

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I have Type 1 diabetes or my Type 2 diabetes is either poorly controlled or newly diagnosed.

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I have high blood pressure due to another condition or experience significant drops in blood pressure upon standing.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ baseline and month 6

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~baseline and month 6

This trial's timeline: 3 weeks for screening, Varies for treatment, and baseline and month 6 for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Secondary study objectives

Change in Daytime and Nighttime Mean SBP and DBP, Assessed by ABPM

Trial Design

6Treatment groups

Experimental Treatment

Placebo Group

Group I: Zilebesiran (Add-on to Olmesartan)Experimental Treatment2 Interventions

Following a run-in on olmesartan, eligible participants will receive zilebesiran on Day 1 of a 6-month double-blind treatment period as add-on to olmesartan. Thereafter, participants will receive zilebesiran once every 6 months during the open-label extension period. Upon implementation of Amendment 3, the open-label extension (OLE) period will be closed and participants will not receive any further treatment with zilebesiran in the OLE period.

Group II: Zilebesiran (Add-on to Amlodipine)Experimental Treatment2 Interventions

Following a run-in on amlodipine, eligible participants will receive zilebesiran on Day 1 of a 6-month double-blind treatment period as add-on to amlodipine. Thereafter, participants will receive zilebesiran once every 6 months during the open-label extension period. Upon implementation of Amendment 3, the OLE period will be closed and participants will not receive any further treatment with zilebesiran in the OLE period.

Group III: Placebo (Add-on to Olmesartan)Experimental Treatment3 Interventions

Following a run-in on olmesartan, eligible participants will receive placebo on Day 1 of a 6-month double-blind treatment period as add-on to olmesartan. Thereafter, participants will receive zilebesiran once every 6 months during the open-label extension period. Upon implementation of Amendment 3, the OLE period will be closed and participants will not receive any further treatment with zilebesiran in the OLE period.

Group IV: Placebo (Add-on to Amlodipine)Placebo Group3 Interventions

Following a run-in on amlodipine, eligible participants will receive placebo on Day 1 of a 6-month double-blind treatment period as add-on to amlodipine. Thereafter, participants will receive zilebesiran once every 6 months during the open-label extension period. Upon implementation of Amendment 3, the OLE period will be closed and participants will not receive any further treatment with zilebesiran in the OLE period.

Group V: Placebo (Add-on to Indapamide)Placebo Group3 Interventions

Following a run-in on indapamide, eligible participants will receive placebo on Day 1 of a 6-month double-blind treatment period as add-on to indapamide. Thereafter, participants will receive zilebesiran once every 6 months during the open-label extension period. Upon implementation of Amendment 3, the OLE period will be closed and participants will not receive any further treatment with zilebesiran in the OLE period.

Group VI: Zilebesiran (Add-on to Indapamide)Placebo Group2 Interventions

Following a run-in on indapamide, eligible participants will receive zilebesiran on Day 1 of a 6-month double-blind treatment period as add-on to indapamide. Thereafter, participants will receive zilebesiran once every 6 months during the open-label extension period. Upon implementation of Amendment 3, the OLE period will be closed and participants will not receive any further treatment with zilebesiran in the OLE period.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Amlodipine

2004

Completed Phase 4

~40680

Olmesartan

2021

Completed Phase 4

~9300

Zilebesiran

2021

Completed Phase 2

~680

Placebo

1995

Completed Phase 3

~2670

0 / 6Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for high blood pressure include ACE inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers, diuretics, and beta-blockers. ACE inhibitors and ARBs work by inhibiting the renin-angiotensin-aldosterone system (RAAS), which reduces blood vessel constriction and lowers blood pressure. Calcium channel blockers prevent calcium from entering heart and blood vessel cells, leading to relaxed blood vessels. Diuretics help the kidneys remove excess sodium and water, reducing blood volume and pressure. Beta-blockers decrease heart rate and output. Treatments like zilebesiran, which use RNA interference to target angiotensinogen, offer a novel approach by directly reducing the production of components involved in RAAS, potentially providing more precise control of blood pressure. These mechanisms are crucial for managing high blood pressure, as they help prevent complications such as heart disease, stroke, and kidney damage.

Multicenter clinical trials. Potential influence of consumer education.Novel therapeutic strategies in the management of arterial hypertension.Impact of telmisartan on cardiovascular outcome in hypertensive patients at high risk: a Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease subanalysis.