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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
First received
Last updated
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
Health authority
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.

Study Design


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
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