This study involves patients with hypertension, which means high blood pressure, who also have either established cardiovascular disease or are at high risk for developing heart and blood vessel problems. Cardiovascular disease includes conditions affecting the heart and blood vessels, such as problems with the arteries that supply blood to the heart, brain, or legs. The study will test a medication called zilebesiran, which may also be referred to by its code name ALN-AGT01. This medication is given as an injection under the skin and works by targeting a specific substance in the liver that affects blood pressure. Participants will receive either zilebesiran or placebo in addition to their current blood pressure medications, which must include a type of water pill called a diuretic along with at least one other blood pressure medication.
The purpose of this study is to find out whether zilebesiran can reduce the risk of serious heart-related problems compared to placebo when added to standard blood pressure treatment. The study will look at whether the medication can prevent major events such as death from heart problems, heart attacks, strokes, or episodes of heart failure that require urgent medical attention or hospital admission. Heart failure is a condition where the heart cannot pump blood effectively enough to meet the body’s needs.
During the study, participants will receive injections of either zilebesiran or placebo while continuing their regular blood pressure medications. The study will measure blood pressure readings at regular visits and will track any heart-related health events that occur over time. Participants will be followed for several years to determine whether the treatment helps prevent serious cardiovascular problems. The study will also monitor how well the medication lowers blood pressure and whether it affects the risk of different types of heart and blood vessel complications.
1Initial enrollment and baseline assessment
Your blood pressure will be measured using an automated device while you are seated. This measurement must show a systolic blood pressure (the top number) between 140 and 180 mmHg on the day you join the study.
Blood and urine samples will be collected to assess your kidney function and other health markers.
Your current blood pressure medications will be reviewed. You should be taking a diuretic (a medication that helps your body remove excess fluid) and at least one other blood pressure medication. These medications must remain unchanged for at least 30 days before this visit.
2Random assignment to treatment group
You will be randomly assigned to receive either zilebesiran or placebo (an inactive substance that looks like the study medication but contains no active ingredient).
Neither you nor your doctor will know which treatment you are receiving. This is called a double-blind study design.
You will continue taking your regular blood pressure medications throughout the study.
3Study medication administration
You will receive injections of either zilebesiran or placebo under the skin (subcutaneous injection).
The study medication will be given at scheduled visits throughout the study period.
The exact dosage and frequency of injections will be determined by the study protocol.
4Month 6 assessment
At the 6-month visit, your blood pressure will be measured again while you are seated using an automated device.
This measurement will be compared to your initial blood pressure reading to assess how well the treatment is working.
Additional blood and urine tests may be performed to monitor your health and kidney function.
5Ongoing monitoring visits
You will attend regular follow-up visits throughout the study to monitor your health and safety.
At each visit, your blood pressure will be measured and you will be asked about any new symptoms or health changes.
Your doctor will monitor for any major heart-related events, including heart attack (damage to the heart muscle due to blocked blood flow), stroke (damage to the brain due to interrupted blood flow), or heart failure events (when the heart cannot pump blood effectively, requiring urgent medical attention or hospitalization).
Any side effects or changes in your health will be recorded.
6Long-term follow-up
The study will continue for several years to assess long-term outcomes.
Your participation will involve regular visits where your health status and any cardiovascular events will be documented.
You will continue taking your standard blood pressure medications as prescribed by your doctor throughout the entire study.
7End of study
The study is expected to conclude in October 2030.
A final assessment will be conducted, including blood pressure measurements and evaluation of your overall health.
Your doctor will discuss next steps for your ongoing blood pressure management after the study ends.
Who Can Join the Study?
You must be at least 18 years old if you have established cardiovascular disease (a condition affecting the heart and blood vessels), or at least 55 years old if you have a high risk for cardiovascular disease.
You must have either established cardiovascular disease (which includes coronary artery disease affecting the arteries of the heart, cerebrovascular disease affecting blood vessels in the brain, or peripheral arterial disease affecting blood vessels in the limbs) OR you must have high risk for cardiovascular disease, which means having at least 2 of the following: being 70 years or older, having reduced kidney function with an eGFR (a measure of how well your kidneys are working) below 60, having high levels of protein in your urine, being a current smoker, having atrial fibrillation (an irregular heart rhythm) and taking medication for it, having a high calcium score in your heart arteries above 100, having elevated NT-proBNP (a blood marker for heart stress) above 125, or having type 1 or 2 diabetes (a condition where blood sugar is too high) or having a BMI (body mass index, a measure of body fat based on height and weight) of 30 or higher, or 27 or higher if you are of East Asian, Southeast Asian, or South Asian descent.
You must be taking medication for hypertension (high blood pressure) that includes a diuretic (a medication that helps remove excess water from the body, also called a water pill) and at least one other blood pressure medication such as an ACE inhibitor, ARB, calcium channel blocker, beta blocker, or other types of blood pressure medications. Your medication doses must have been stable for at least 30 days before joining the study.
Your systolic blood pressure (the top number in a blood pressure reading) when measured while sitting must be between 145 and 180 during the screening period, and between 140 and 180 on the first day of the study, with measurements taken at least 7 days apart.
You must be able to understand the study requirements, be willing and able to follow them, and provide written consent to participate.
Who Cannot Join the Study?
The specific exclusion criteria (reasons why you cannot participate) have not been provided in the available study information
Generally, clinical trials have specific requirements about who can and cannot participate to ensure patient safety
Common reasons people may not be able to join heart and blood pressure studies include having certain other medical conditions, taking specific medications, or having recent serious health events
You will need to discuss with the study team to learn the complete list of reasons that would prevent participation in this particular trial
Zilebesiran is an investigational medication being studied for the treatment of high blood pressure (hypertension) in patients who have not achieved adequate blood pressure control with their current medications. This medication is being tested to see if it can help reduce serious heart-related problems such as heart attacks, strokes, death from heart disease, or hospitalizations due to heart failure when added to the patient’s existing blood pressure treatments.
Placebo is an inactive substance that looks like the study medication but contains no active medicine. It is used in this trial to compare the effects of zilebesiran against no additional treatment, helping researchers determine if zilebesiran truly provides benefits beyond standard care.
Cardiovascular Disease – Cardiovascular disease refers to a group of disorders affecting the heart and blood vessels. It develops when the blood vessels become narrowed or blocked, often due to the buildup of fatty deposits on the vessel walls. This process can reduce blood flow to the heart, brain, or other parts of the body. Over time, the condition may progress and affect the heart’s ability to pump blood effectively. The disease can manifest in various forms, including problems with heart rhythm, blood vessel function, or heart muscle strength. Many people with cardiovascular disease experience a gradual worsening of symptoms as the condition advances.
Hypertension – Hypertension, commonly known as high blood pressure, is a condition where the force of blood against the artery walls is consistently too high. The condition often develops gradually over many years without causing noticeable symptoms. As blood pressure remains elevated, it puts extra strain on the blood vessels and the heart. The blood vessels may become less elastic and more narrow over time. This ongoing pressure can affect various organs in the body, particularly the heart, brain, and kidneys. Most cases of hypertension have no identifiable cause and are considered primary or essential hypertension.
Myocardial Infarction – Myocardial infarction, commonly called a heart attack, occurs when blood flow to a part of the heart muscle is blocked. This blockage is usually caused by a blood clot that forms in a coronary artery narrowed by fatty deposits. Without adequate blood supply, the affected heart muscle begins to suffer damage within minutes. The longer the blockage persists, the more heart muscle tissue is affected. The damaged area of the heart muscle may form scar tissue after the event. The extent of heart muscle damage influences how well the heart can pump blood afterward.
Stroke – Stroke occurs when blood supply to part of the brain is interrupted or reduced, preventing brain tissue from receiving oxygen and nutrients. The most common type happens when a blood clot blocks an artery leading to the brain. Within minutes of being deprived of blood, brain cells begin to die. The location and extent of the affected brain area determine which body functions are impaired. Some strokes are caused by bleeding in or around the brain rather than blockage. The effects of stroke depend on how quickly blood flow is restored and how much brain tissue is damaged.
Heart Failure – Heart failure is a condition where the heart cannot pump blood efficiently enough to meet the body’s needs. It typically develops gradually as the heart muscle becomes weaker or stiffer over time. The condition often results from other heart problems that have damaged or overworked the heart muscle. As heart failure progresses, the heart tries to compensate by enlarging, developing more muscle mass, or pumping faster. Fluid may accumulate in the lungs and other parts of the body because blood flow slows and backs up. Despite its name, heart failure does not mean the heart has stopped working, but rather that it is not working as well as it should.
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