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

NCT04836182 | Completed Phase 2 FDA Drug

• 2 other identifiers: ISIS 757456-CS52020-005878-10
• Study Type: interventional
• Target: 72
• Locations: 3 countries
• Sites: 19

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).

Conditions

Chronic Heart Failure With Reduced Ejection Fraction

Keywords

Heart Failure; AGT; NT-proBNP

Outcome Measures

Primary Outcomes (1)

• Percent Change in Plasma AGT Concentration From Baseline to Study Day 85

  Baseline to Day 85

Secondary Outcomes (6)

• Absolute Level of Plasma AGT

  Baseline to Day 169

• 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

• Change in NT-proBNP From Baseline to Each Scheduled, Post-Baseline Visit

  Baseline to Day 169

Study Arms (2)

IONIS-AGT-LRx

EXPERIMENTAL

IONIS-AGT-LRX by subcutaneous injection once-weekly

Drug: IONIS-AGT-LRx

Placebo

PLACEBO COMPARATOR

Matching placebo by subcutaneous injection once-weekly

Drug: Placebo

Interventions

IONIS-AGT-LRx DRUG

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

Also known as: ISIS 757456

IONIS-AGT-LRx

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Females must be non-pregnant and non-lactating and of non- childbearing potential.
• 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
• Screening NT-proBNP ≥ 600 picograms per milliliter (pg/mL) and less than (\<) 8500 pg/mL
• 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%
• 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:
• An angiotensin-converting-enzyme inhibitor (ACEi), or angiotensin II receptor blockers (ARBs) or sacubitril/valsartan (mandatory)
• A beta-blocker (unless contraindicated or not tolerated)
• A mineralocorticoid receptor antagonist (MRA, unless contraindicated or not tolerated)

You may not qualify if:

• HF due to restrictive cardiomyopathy, active myocarditis, chemotherapy, hypertrophic cardiomyopathy, primary cardiac valve disease, non-compaction cardiomyopathy, or takotsubo cardiomyopathy.
• 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.
• Symptomatic hypotension or systolic blood pressure (SBP) ≤ 90 millimeters of mercury (mmHg) at screening.
• Uncontrolled hypertension (HTN) (SBP \> 160 mmHg or diastolic blood pressure (BP) \> 100 mmHg) prior to screening.
• Heart transplant, and/or Left Ventricular Assist Device (LVAD) prior to screening or anticipated heart transplant or LVAD during the study.
• Implantation of a cardiac resynchronization therapy device (CRT) within 3 months prior screening or intent to implant a CRT within 3 months after screening.
• 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.
• Coronary, valve or carotid artery disease likely to require surgical or percutaneous intervention within the 3 months after screening.
• Severe pulmonary disease with any of the following:
• Requirement of continuous (home) oxygen or
• 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.
• Alanine aminotransferase/aspartate aminotransferase (ALT/AST) \> 2.0 × upper limit of normal (ULN).
• 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).
• Platelets \< 100,000/millimeter\^3 (mm\^3).
• Urine protein creatinine ratio (UPCR) ≥ 500 milligrams per gram (mg/g).

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead

Study Sites (19)

Arkansas Cardiology

Little Rock, Arkansas, 72205, United States

Location

Nature Coast Clinical Research - Crystal River

Crystal River, Florida, 34429, United States

Location

New Generation of Medical Research

Hialeah, Florida, 33016, United States

Location

Michigan Heart

Ypsilanti, Michigan, 48197, United States

Location

St. Louis Heart and Vascular Cardiology

St Louis, Missouri, 63136, United States

Location

The Lindner Center for Research and Education at The Christ Hospital

Cincinnati, Ohio, 45219, United States

Location

South Oklahoma Heart Research

Oklahoma City, Oklahoma, 73135, United States

Location

Newton Clinical Research

Oklahoma City, Oklahoma, 73159, United States

Location

North Texas Research Associates

Allen, Texas, 75013, United States

Location

York Clinical Research LLC

Norfolk, Virginia, 23510, United States

Location

Semmelweis Egyetem - Varosmajori Sziv es Ergyogyaszati Klinika

Budapest, H-1122, Hungary

Location

Kardiologiai Maganrendeles es Klinikai Vizsgalohely

Orosháza, 5900, Hungary

Location

Specjalistyczna Praktyka Lekarska

Krakow, 30-082, Poland

Location

Samodzielny Publiczny ZOZ Centralny Szpital Kliniczny Uniwersytetu Medycznego

Lodz, 92-213, Poland

Location

Indywidualna Specjalistyczna Praktyka Lekarska

Lodz, 94-255, Poland

Location

AKA-MED Centrum Spólka z Ograniczona Odpowiedzialnoscia

Ruda Śląska, 41-710, Poland

Location

NZOZ Pro Cordis Sopockie Centrum Badan Kardiologicznych

Sopot, 81-717, Poland

Location

Centrum Chorob Serca w USK

Wroclaw, 50-556, Poland

Location

4 Wojskowy Szpital Kliniczny z Poliklinika Samodzielny Publiczny ZOZ we Wroclawiu

Wroclaw, 50-981, Poland

Location

MeSH Terms

Conditions

Heart Failure

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 5, 2021
• First Posted: April 8, 2021
• Study Start: June 8, 2021
• Primary Completion: October 19, 2022
• Study Completion: January 11, 2023
• Last Updated: September 11, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (10); HU (2); PL (7)