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

Phase 2

Completed

• Conditions: Chronic Heart Failure With Reduced Ejection Fraction
• Interventions: Drug: IONIS-AGT-LRx; Drug: Placebo

• Registration Number: NCT04836182
• Lead Sponsor: Ionis Pharmaceuticals, Inc.

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.

Study Timeline

• Study First Submitted: 2021-04-05
• Study First Submitted QC: 2021-04-05
• Study First Posted: 2021-04-08
• Study Start: 2021-06-08
• Primary Completion: 2022-10-19
• Study Completion: 2023-01-11
• Status Verified: 2023-09
• Disposition First Submitted: 2023-09-06
• Last Update Submitted: 2023-09-06
• Disposition First Posted: 2023-09-11
• Last Update Posted: 2023-09-11

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 72

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
IONIS-AGT-LRx	IONIS-AGT-LRx	IONIS-AGT-LRX by subcutaneous injection once-weekly
Placebo	Placebo	Matching placebo by subcutaneous injection once-weekly

Primary Outcome Measures

Name	Time	Method
Percent Change in Plasma AGT Concentration From Baseline to Study Day 85	Baseline to Day 85

Secondary Outcome Measures

Name	Time	Method
Change in Plasma AGT From Baseline to Each Scheduled, Post-Baseline Visit	Baseline to Day 169
Percent Change in Plasma AGT From Baseline to Each Scheduled, Post-Baseline Visit	Baseline to Day 169
Absolute Level of NT-proBNP	Baseline to Day 169
Percent Change from Baseline in NT-proBNP to Each Scheduled, Post-Baseline Visit	Baseline to Day 169
Absolute Level of Plasma AGT	Baseline to Day 169
Change in NT-proBNP From Baseline to Each Scheduled, Post-Baseline Visit	Baseline to Day 169

Trial Locations

Locations (19)

Indywidualna Specjalistyczna Praktyka Lekarska; 🇵🇱 Lodz, Poland

Semmelweis Egyetem - Varosmajori Sziv es Ergyogyaszati Klinika; 🇭🇺 Budapest, Hungary

Arkansas Cardiology; 🇺🇸 Little Rock, Arkansas, United States

New Generation of Medical Research; 🇺🇸 Hialeah, Florida, United States

The Lindner Center for Research and Education at The Christ Hospital; 🇺🇸 Cincinnati, Ohio, United States

Newton Clinical Research; 🇺🇸 Oklahoma City, Oklahoma, United States

South Oklahoma Heart Research; 🇺🇸 Oklahoma City, Oklahoma, United States

Specjalistyczna Praktyka Lekarska; 🇵🇱 Kraków, Poland

NZOZ Pro Cordis Sopockie Centrum Badan Kardiologicznych; 🇵🇱 Sopot, Poland

Nature Coast Clinical Research - Crystal River; 🇺🇸 Crystal River, Florida, United States

Kardiologiai Maganrendeles es Klinikai Vizsgalohely; 🇭🇺 Orosháza, Hungary

Samodzielny Publiczny ZOZ Centralny Szpital Kliniczny Uniwersytetu Medycznego; 🇵🇱 Łódź, Poland

St. Louis Heart and Vascular Cardiology; 🇺🇸 Saint Louis, Missouri, United States

York Clinical Research LLC; 🇺🇸 Norfolk, Virginia, United States

North Texas Research Associates; 🇺🇸 Allen, Texas, United States

Michigan Heart; 🇺🇸 Ypsilanti, Michigan, United States

AKA-MED Centrum Spólka z Ograniczona Odpowiedzialnoscia; 🇵🇱 Ruda Slaska, Poland

4 Wojskowy Szpital Kliniczny z Poliklinika Samodzielny Publiczny ZOZ we Wroclawiu; 🇵🇱 Wroclaw, Poland

Centrum Chorob Serca w USK; 🇵🇱 Wrocław, Poland