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

Chronic Heart Failure With Reduced Ejection Fraction Clinical Trial

— ASTRAAS-HF  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04836182
• Other study ID #: ISIS 757456-CS5
• Secondary ID: 2020-005878-10
• Status: Completed
• Phase: Phase 2
• Start date: June 8, 2021
• Est. completion date: January 11, 2023

Study information

• Verified date: September 2023
• Source: Ionis Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 72
• Est. completion date: January 11, 2023
• Est. primary completion date: October 19, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Heart Failure With Reduced Ejection Fraction
• Heart Failure

Intervention

Drug:
• IONIS-AGT-LRx
Multiple doses of IONIS-AGT-LRx will be administered by SC injection.
• Placebo
IONIS-AGT-LRx-matching placebo will be administered by SC injection.

Locations

Country	Name	City	State
Hungary	Semmelweis Egyetem - Varosmajori Sziv es Ergyogyaszati Klinika	Budapest
Hungary	Kardiologiai Maganrendeles es Klinikai Vizsgalohely	Orosháza
Poland	Specjalistyczna Praktyka Lekarska	Kraków
Poland	Indywidualna Specjalistyczna Praktyka Lekarska	Lodz
Poland	Samodzielny Publiczny ZOZ Centralny Szpital Kliniczny Uniwersytetu Medycznego	Lódz
Poland	AKA-MED Centrum Spólka z Ograniczona Odpowiedzialnoscia	Ruda Slaska
Poland	NZOZ Pro Cordis Sopockie Centrum Badan Kardiologicznych	Sopot
Poland	4 Wojskowy Szpital Kliniczny z Poliklinika Samodzielny Publiczny ZOZ we Wroclawiu	Wroclaw
Poland	Centrum Chorob Serca w USK	Wroclaw
United States	North Texas Research Associates	Allen	Texas
United States	The Lindner Center for Research and Education at The Christ Hospital	Cincinnati	Ohio
United States	Nature Coast Clinical Research - Crystal River	Crystal River	Florida
United States	New Generation of Medical Research	Hialeah	Florida
United States	Arkansas Cardiology	Little Rock	Arkansas
United States	York Clinical Research LLC	Norfolk	Virginia
United States	Newton Clinical Research	Oklahoma City	Oklahoma
United States	South Oklahoma Heart Research	Oklahoma City	Oklahoma
United States	St. Louis Heart and Vascular Cardiology	Saint Louis	Missouri
United States	Michigan Heart	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Ionis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Hungary,  Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change in Plasma AGT Concentration From Baseline to Study Day 85		Baseline to Day 85
Secondary	Absolute Level of Plasma AGT		Baseline to Day 169
Secondary	Change in Plasma AGT From Baseline to Each Scheduled, Post-Baseline Visit		Baseline to Day 169
Secondary	Percent Change in Plasma AGT From Baseline to Each Scheduled, Post-Baseline Visit		Baseline to Day 169
Secondary	Absolute Level of NT-proBNP		Baseline to Day 169
Secondary	Change in NT-proBNP From Baseline to Each Scheduled, Post-Baseline Visit		Baseline to Day 169
Secondary	Percent Change from Baseline in NT-proBNP to Each Scheduled, Post-Baseline Visit		Baseline to Day 169