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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)

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ClinicalTrials.gov Identifier: NCT04836182
Recruitment Status : Completed
First Posted : April 8, 2021
Last Update Posted : September 11, 2023
Sponsor:
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

Study Description
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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).

Condition or disease Intervention/treatment Phase
Chronic Heart Failure With Reduced Ejection Fraction Drug: IONIS-AGT-LRx Drug: Placebo Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : June 8, 2021
Actual Primary Completion Date : October 19, 2022
Actual Study Completion Date : January 11, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arms and Interventions
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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 Name: 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.


Outcome Measures
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Primary Outcome Measures :
  1. Percent Change in Plasma AGT Concentration From Baseline to Study Day 85 [ Time Frame: Baseline to Day 85 ]

Secondary Outcome Measures :
  1. Absolute Level of Plasma AGT [ Time Frame: Baseline to Day 169 ]
  2. Change in Plasma AGT From Baseline to Each Scheduled, Post-Baseline Visit [ Time Frame: Baseline to Day 169 ]
  3. Percent Change in Plasma AGT From Baseline to Each Scheduled, Post-Baseline Visit [ Time Frame: Baseline to Day 169 ]
  4. Absolute Level of NT-proBNP [ Time Frame: Baseline to Day 169 ]
  5. Change in NT-proBNP From Baseline to Each Scheduled, Post-Baseline Visit [ Time Frame: Baseline to Day 169 ]
  6. Percent Change from Baseline in NT-proBNP to Each Scheduled, Post-Baseline Visit [ Time Frame: Baseline to Day 169 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04836182


Locations
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Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.
More Information
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Responsible Party: Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT04836182    
Other Study ID Numbers: ISIS 757456-CS5
2020-005878-10 ( EudraCT Number )
First Posted: April 8, 2021    Key Record Dates
Last Update Posted: September 11, 2023
Last Verified: September 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ionis Pharmaceuticals, Inc.:
Heart Failure
AGT
NT-proBNP
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases