A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Participants With Chronic Heart Failure With Reduced Ejection Fraction

NCT ID: NCT04836182

Last Updated: 2023-09-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 72 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-06-08
• Study Completion Date: 2023-01-11

Brief Summary

The purpose of this study is to evaluate the effect of IONIS-AGT-LRX weekly subcutaneous (SC) injection on plasma angiotensinogen (AGT) concentration from Baseline to Study Day 85 (Week 13) and to evaluate the effect of IONIS-AGT-LRx weekly SC injection on plasma AGT concentration and N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) levels at each scheduled visit in chronic heart failure participants with reduced ejection fraction (HFrEF).

Detailed Description

This study will be a Phase 2, double-blind, randomized, placebo-controlled study in up to 72 participants. Participants will be randomized in a 2:1 ratio to either IONIS-AGT-LRX or matching placebo and receive a once-weekly SC treatment. The length of participation in the study will be approximately 35 weeks, which includes an up to 10-week screening period, a 12-week treatment period, and a 13-week post-treatment period.

Conditions

Chronic Heart Failure With Reduced Ejection Fraction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

IONIS-AGT-LRx

IONIS-AGT-LRX by subcutaneous injection once-weekly

Group Type: EXPERIMENTAL

IONIS-AGT-LRx

Intervention Type: DRUG

Multiple doses of IONIS-AGT-LRx will be administered by SC injection.

Placebo

Matching placebo by subcutaneous injection once-weekly

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

IONIS-AGT-LRx-matching placebo will be administered by SC injection.

Interventions

IONIS-AGT-LRx

Multiple doses of IONIS-AGT-LRx will be administered by SC injection.

Intervention Type: DRUG

Placebo

IONIS-AGT-LRx-matching placebo will be administered by SC injection.

Intervention Type: DRUG

Other Intervention Names

ISIS 757456

Eligibility Criteria

Inclusion Criteria

1. Females must be non-pregnant and non-lactating and of non- childbearing potential.

2. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential (WOCBP), she must be willing to use a highly effective contraceptive method

3. Screening NT-proBNP ≥ 600 picograms per milliliter (pg/mL) and less than (<) 8500 pg/mL

4. Established diagnosis of heart failure (HF) with reduced systolic function for at least 6 months prior to the screening visit (left ventricular ejection fraction, [LVEF] ≤ 40%

5. New York Heart Association class I-III

Participants should receive background standard of care for HFrEF. Therapy should have been individually optimized and stable for ≥ 4 weeks before randomization and include:

1. An angiotensin-converting-enzyme inhibitor (ACEi), or angiotensin II receptor blockers (ARBs) or sacubitril/valsartan (mandatory)

2. A beta-blocker (unless contraindicated or not tolerated)

3. A mineralocorticoid receptor antagonist (MRA, unless contraindicated or not tolerated)

Exclusion Criteria

1. HF due to restrictive cardiomyopathy, active myocarditis, chemotherapy, hypertrophic cardiomyopathy, primary cardiac valve disease, non-compaction cardiomyopathy, or takotsubo cardiomyopathy.

2. Acute decompensated HF requiring intravenous (IV) diuretics, IV inotropes or IV vasodilators with discharge date within 30 days of screening or acute mechanical support (e.g., intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular assist device) with discharge date within 90 days of screening.

3. Symptomatic hypotension or systolic blood pressure (SBP) ≤ 90 millimeters of mercury (mmHg) at screening.

4. Uncontrolled hypertension (HTN) (SBP > 160 mmHg or diastolic blood pressure (BP) > 100 mmHg) prior to screening.

5. Heart transplant, and/or Left Ventricular Assist Device (LVAD) prior to screening or anticipated heart transplant or LVAD during the study.

6. Implantation of a cardiac resynchronization therapy device (CRT) within 3 months prior screening or intent to implant a CRT within 3 months after screening.

7. Acute coronary syndrome, unstable angina, stroke, transient ischemic attack (TIA), coronary revascularization, cardiac device implantation, cardiac valve repair, carotid or other major surgery within 3 months of screening.

8. Coronary, valve or carotid artery disease likely to require surgical or percutaneous intervention within the 3 months after screening.

9. Severe pulmonary disease with any of the following:

1. Requirement of continuous (home) oxygen or

2. Known diagnosis of severe chronic obstructive pulmonary disease (as defined by the American Thoracic Society/European Respiratory Society) or severe restrictive lung disease, in the opinion of the investigator.

10. Screening laboratory results as follows, or any other clinically significant abnormalities in screening laboratory values that would render a participant unsuitable for inclusion in the opinion of the investigator.

1. Alanine aminotransferase/aspartate aminotransferase (ALT/AST) > 2.0 × upper limit of normal (ULN).

2. Total bilirubin ≥ 1.5 × ULN (participants with total bilirubin ≥ 1.5 × ULN may be allowed on study if indirect bilirubin only is elevated, ALT/AST is not greater than the ULN, and known to have Gilbert's disease).

3. Platelets < 100,000/millimeter^3 (mm^3).

4. Urine protein creatinine ratio (UPCR) ≥ 500 milligrams per gram (mg/g).

5. Hemoglobin A1c (HbA1c) > 9.5% or uncontrolled diabetes per investigator judgement.

6. Estimated glomerular filtration rate (eGFR) < 30 milliliters/ minute /1.73 m^2 (mL/min/1.73 meter^2) at screening.

7. Abnormal thyroid function tests with clinical significance per investigator judgement.

8. Serum potassium > 5.1 millimoles per liter (mmol/L) at screening.

11. Requirement of treatment with both ACEi and ARBs.

12. Previous history of intolerance to ACEi or ARBs or history of hyperkalemia.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ionis Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Arkansas Cardiology

Little Rock, Arkansas, United States

Nature Coast Clinical Research - Crystal River

Crystal River, Florida, United States

New Generation of Medical Research

Hialeah, Florida, United States

Michigan Heart

Ypsilanti, Michigan, United States

St. Louis Heart and Vascular Cardiology

St Louis, Missouri, United States

The Lindner Center for Research and Education at The Christ Hospital

Cincinnati, Ohio, United States

South Oklahoma Heart Research

Oklahoma City, Oklahoma, United States

Newton Clinical Research

Oklahoma City, Oklahoma, United States

North Texas Research Associates

Allen, Texas, United States

York Clinical Research LLC

Norfolk, Virginia, United States

Semmelweis Egyetem - Varosmajori Sziv es Ergyogyaszati Klinika

Budapest, , Hungary

Kardiologiai Maganrendeles es Klinikai Vizsgalohely

Orosháza, , Hungary

Specjalistyczna Praktyka Lekarska

Krakow, , Poland

Samodzielny Publiczny ZOZ Centralny Szpital Kliniczny Uniwersytetu Medycznego

Lodz, , Poland

Indywidualna Specjalistyczna Praktyka Lekarska

Lodz, , Poland

AKA-MED Centrum Spólka z Ograniczona Odpowiedzialnoscia

Ruda Śląska, , Poland

NZOZ Pro Cordis Sopockie Centrum Badan Kardiologicznych

Sopot, , Poland

Centrum Chorob Serca w USK

Wroclaw, , Poland

4 Wojskowy Szpital Kliniczny z Poliklinika Samodzielny Publiczny ZOZ we Wroclawiu

Wroclaw, , Poland

Countries

United States; Hungary; Poland

Other Identifiers

2020-005878-10

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

ISIS 757456-CS5

Identifier Type: -

Identifier Source: org_study_id