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

A Double-Blind, Placebo-Controlled, Randomized, Multicenter, Phase 2 Study Assessing the Safety, Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor of Angiotensinogen Production, Administered Subcutaneously Over 12 Weeks in Patients With Chronic Heart Failure With Reduced Ejection Fraction

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).

Study Overview

• Status: Completed
• Conditions: Chronic Heart Failure With Reduced Ejection Fraction
• Intervention / Treatment: Drug: IONIS-AGT-LRx; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 2

Contacts and Locations

Study Locations

• Hungary
  • Budapest, Hungary, H-1122
    • Semmelweis Egyetem - Varosmajori Sziv es Ergyogyaszati Klinika
  • Orosháza, Hungary, 5900
    • Kardiologiai Maganrendeles es Klinikai Vizsgalohely
• Poland
  • Kraków, Poland, 30-082
    • Specjalistyczna Praktyka Lekarska
  • Lodz, Poland, 94-255
    • Indywidualna Specjalistyczna Praktyka Lekarska
  • Ruda Slaska, Poland, 41-710
    • Aka-Med Centrum Spólka Z Ograniczona Odpowiedzialnoscia
  • Sopot, Poland, 81-717
    • NZOZ PRO CORDIS Sopockie Centrum Badan Kardiologicznych
  • Wroclaw, Poland, 50-981
    • 4 Wojskowy Szpital Kliniczny z Poliklinika Samodzielny Publiczny ZOZ we Wroclawiu
  • Wrocław, Poland, 50-556
    • Centrum Chorob Serca w USK
  • Łódź, Poland, 92-213
    • Samodzielny Publiczny ZOZ Centralny Szpital Kliniczny Uniwersytetu Medycznego
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cardiology
  • Florida
    • Crystal River, Florida, United States, 34429
      • Nature Coast Clinical Research - Crystal River
    • Hialeah, Florida, United States, 33016
      • New Generation of Medical Research
  • Michigan
    • Ypsilanti, Michigan, United States, 48197
      • Michigan Heart
  • Missouri
    • Saint Louis, Missouri, United States, 63136
      • St. Louis Heart and Vascular Cardiology
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Center for Research and Education at The Christ Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73135
      • South Oklahoma Heart Research
    • Oklahoma City, Oklahoma, United States, 73159
      • Newton Clinical Research
  • Texas
    • Allen, Texas, United States, 75013
      • North Texas Research Associates
  • Virginia
    • Norfolk, Virginia, United States, 23510
      • York Clinical Research LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IONIS-AGT-LRx; IONIS-AGT-LRX by subcutaneous injection once-weekly	Drug: IONIS-AGT-LRx; Multiple doses of IONIS-AGT-LRx will be administered by SC injection.; Other Names: ISIS 757456
Placebo Comparator: Placebo; Matching placebo by subcutaneous injection once-weekly	Drug: Placebo; IONIS-AGT-LRx-matching placebo will be administered by SC injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent Change in Plasma AGT Concentration From Baseline to Study Day 85	Baseline to Day 85

Secondary Outcome Measures

Outcome Measure	Time Frame
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
Percent Change from Baseline in NT-proBNP to Each Scheduled, Post-Baseline Visit	Baseline to Day 169

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 8, 2021
• Primary Completion (Actual): October 19, 2022
• Study Completion (Actual): January 11, 2023

Study Registration Dates

• First Submitted: April 5, 2021
• First Submitted That Met QC Criteria: April 5, 2021
• First Posted (Actual): April 8, 2021

Study Record Updates

• Last Update Posted (Actual): September 11, 2023
• Last Update Submitted That Met QC Criteria: September 6, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Heart Failure; NT-proBNP; AGT
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: ISIS 757456-CS5; 2020-005878-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No