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

Ionis Pharmaceuticals

Status and phase: Completed; Phase 2

Conditions: Hypertension

Treatments: Drug: IONIS-AGT-LRx; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT04714320

ISIS 757456-CS4

Details and patient eligibility

About

The purpose of this study was 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.

Full description

This was a phase 2, double-blind, randomized, placebo-controlled study in up to 160 participants. Participants were randomized in a 2:1 ratio and received a once-weekly subcutaneous (SC) treatment with either IONIS-AGT-LRx or matching placebo. The length of participation in the study was approximately 31 weeks, which included an up to 6-week screening period, a 12-week treatment period, and a 13-week post-treatment period.

Enrollment: 160 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

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 non-steroidal anti-inflammatory drugs (NSAIDs) or cyclooxygenase 2 (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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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160 participants in 3 patient groups, including a placebo group

Pooled Placebo

Placebo Comparator group

Description:

Participants received ISIS 757456 matching placebo subcutaneously once weekly for 12 weeks.

Treatment:

Drug: Placebo

IONIS-AGT-LRx 80 mg

Experimental group

Description:

Participants received ISIS 757456 80 milligrams (mg), subcutaneous (SC) injection, once weekly for 12 weeks.

Treatment:

Drug: IONIS-AGT-LRx

IONIS-AGT-LRx 120 mg

Experimental group

Description:

Participants received ISIS 757456 120 mg, SC injection, once weekly for 12 weeks.

Treatment:

Drug: IONIS-AGT-LRx