A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Hypertensive Participants With Uncontrolled Blood Pressure

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of IONIS-AGT-LRx compared to placebo on seated automated office systolic blood pressure (SBP) from baseline to Study Day 85 in uncontrolled hypertensive participants on ≥ 3 antihypertensive medications and to evaluate the effect of IONIS-AGT-LRx on ambulatory blood pressure, seated automated office SBP, seated automated office diastolic blood pressure (DBP), and plasma angiotensinogen (AGT) at each scheduled visit in uncontrolled hypertensive participants on ≥ 3 antihypertensive medications.

Detailed Description
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This study will be a Phase 2, double-blind, randomized, placebo-controlled study in up to 150 participants. Participants will be randomized in a 2:1 ratio and will receive a once-weekly subcutaneous (SC) treatment with either IONIS-AGT-LRx or matching placebo. The length of participation in the study will be approximately 31 weeks, which includes an up to 6-week screening period, a 12-week treatment period, and a 13-week post-treatment period.

Official Title
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A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor of Angiotensinogen Production Administered Subcutaneously for 12 Weeks to Hypertensive Patients With Uncontrolled Blood Pressure

Conditions
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Hypertension

Intervention / Treatment
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* Drug: IONIS-AGT-LRx
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females aged 18-80 inclusive and weighing ≥ 50 kilograms (kg) at the time of informed consent Females: must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal Males must be abstinent, surgically sterile or if engaged in sexual relations with a woman of childbearing potential (WOCBP), a highly effective contraceptive method must be used Body mass index (BMI) ≤ 45.0 kilograms per square meter (kg/m^2) At screening, the participant must have been on a stable, maximally tolerated regimen (per Investigator judgement) of 3 or more antihypertensive medications for at least 1 month prior to screening and will be required to maintain this regimen throughout the study. The combination of antihypertensive medications must be in the following categories: a) angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB), b) beta blocker: c) calcium channel blocker d) diuretic, e) alpha-1 blocker f) centrally acting sympatholytic agent or g) direct acting vasodilators (e.g. hydralazine) Exclusion Criteria: Clinically significant abnormalities in screening laboratory results, medical history according to Investigator judgment History of secondary hypertension (HTN) including, but not limited to any of the following: renovascular HTN (unilateral or bilateral renal artery stenosis), coarctation of the aorta, primary hyperaldosteronism, Cushing's disease, pheochromocytoma, polycystic kidney disease, and drug-induced HTN The use of the following at time of screening and during the course of the study: Other medications for the treatment of HTN (e.g., minoxidil, diazoxide, renin inhibitors) Medications that may cause hyperkalemia unless on a stable dose at least 1 month prior to the screening visit and no known history of hyperkalemia per Investigator judgement Use of oral anticoagulants, unless stable for 4 weeks prior to the first dose of study drug and regular monitoring must be performed per clinical practice during the study unless the participant is receiving vitamin K agonists. If the participant is receiving vitamin K antagonists (e.g., warfarin) international normalized ratio (INR) should be in therapeutic range, as established by the Investigator, for 4 weeks prior to the first dose Chronic administration of NSAIDs or COX-2 inhibitors (except aspirin for cardiovascular disease provided the total daily dose does not exceed 325 mg) History of bleeding diathesis, coagulopathy, immune thrombocytopenic purpura (ITP), thrombotic cytopenic purpura (TTP), or any qualitative or quantitative platelet defect Unstable/underlying known cardiovascular disease defined as: Any history of congestive heart failure (New York Heart Association [NYHA] Class III-IV) Any history of previous myocardial infarction, coronary revascularization, unstable or stable angina pectoris ˂ 1 year prior to screening Any hemodynamically unstable atrial or ventricular arrhythmias Significant uncorrected valvular heart disease Any history of stroke or transient ischemic attack < 1 year prior to screening A cardiac valve repair, cardiac device implantation, and/or a hospitalization for heart failure within 3 months of screening Participant works nighttime shifts (e.g., 11 PM to 7 AM)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IONIS-AGT-LRx<br>Multiple doses of IONIS-AGT-LRx will be administered subcutaneously once-weekly for 12 weeks. | Drug: IONIS-AGT-LRx<br>* Multiple doses of IONIS-AGT-LRx will be administered by SC injection.<br>* Other names: ISIS 757456;|
| Placebo Comparator: Placebo<br>IONIS-AGT-LRx-matching placebo will be administered subcutaneously once-weekly for 12 weeks. | Drug: Placebo<br>* IONIS-AGT-LRx-matching placebo will be administered by SC injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Seated Automated Office Systolic Blood Pressure (SBP) from Baseline to Study Day 85 |  | Baseline to Day 85 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in plasma AGT to each scheduled, post-baseline visit |  | Baseline up to Day 169 | 
| Change from Baseline to Study Day 85 in 24-hour mean SBP measured by ambulatory blood pressure monitoring (ABPM) |  | Baseline to Day 85 | 
| Change from Baseline to Study Day 85 in 24-hour mean Diastolic Blood Pressure (DBP) measured by ABPM |  | Baseline up to Day 85 | 
| Percentage of participants reaching the goals of seated automated office seated SBP ≤ 140 mmHg, DBP ≤ 90 mmHg, and both during the study (excluding participants with a baseline SBP of ≤ 140 mmHg) |  | Up to Day 169 | 
| Percentage of participants reaching the goals of automated office seated SBP ≤ 130 mmHg, DBP ≤ 80 mmHg, and both during the study |  | Baseline up to Day 169 | 
| Change from Baseline on seated automated office SBP to each scheduled, post-Baseline visit |  | Baseline up to Day 169 | 
| Change from Baseline on seated automated office DBP to each scheduled, post-Baseline visit |  | Baseline up to Day 169 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension, Hypertensive, AGT, Angiotensinogen, Blood Pressure