Clinical trial NCT04836182: A Study to Assess the Safety, Tolerability and Efficacy of IONIS-AGT-LRx in Participants With Chronic Heart Failure With Reduced Ejection Fraction
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Heart Failure With Reduced Ejection Fraction
Keywords: Heart Failure
AGT
NT-proBNP
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2021-04-08
Enrollment: 72
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Eligibility 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.

Primary outcomes:
measure: Percent Change in Plasma AGT Concentration From Baseline to Study Day 85
timeFrame: Baseline to Day 85
Secondary outcomes:
measure: Absolute Level of Plasma AGT
timeFrame: Baseline to Day 169
measure: Change in Plasma AGT From Baseline to Each Scheduled, Post-Baseline Visit
timeFrame: Baseline to Day 169
measure: Percent Change in Plasma AGT From Baseline to Each Scheduled, Post-Baseline Visit
timeFrame: Baseline to Day 169
measure: Absolute Level of NT-proBNP
timeFrame: Baseline to Day 169
measure: Change in NT-proBNP From Baseline to Each Scheduled, Post-Baseline Visit
timeFrame: Baseline to Day 169
measure: Percent Change from Baseline in NT-proBNP to Each Scheduled, Post-Baseline Visit
timeFrame: Baseline to Day 169
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Arkansas Cardiology
state: Arkansas
city: Crystal River
country: United States
facility: Nature Coast Clinical Research - Crystal River
state: Florida
city: Hialeah
country: United States
facility: New Generation of Medical Research
state: Florida
city: Ypsilanti
country: United States
facility: Michigan Heart
state: Michigan
city: Saint Louis
country: United States
facility: St. Louis Heart and Vascular Cardiology
state: Missouri
city: Cincinnati
country: United States
facility: The Lindner Center for Research and Education at The Christ Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: South Oklahoma Heart Research
state: Oklahoma
city: Oklahoma City
country: United States
facility: Newton Clinical Research
state: Oklahoma
city: Allen
country: United States
facility: North Texas Research Associates
state: Texas
city: Norfolk
country: United States
facility: York Clinical Research LLC
state: Virginia
city: Budapest
country: Hungary
facility: Semmelweis Egyetem - Varosmajori Sziv es Ergyogyaszati Klinika
city: Orosháza
country: Hungary
facility: Kardiologiai Maganrendeles es Klinikai Vizsgalohely
city: Kraków
country: Poland
facility: Specjalistyczna Praktyka Lekarska
city: Lodz
country: Poland
facility: Indywidualna Specjalistyczna Praktyka Lekarska
city: Ruda Slaska
country: Poland
facility: AKA-MED Centrum Spólka z Ograniczona Odpowiedzialnoscia
city: Sopot
country: Poland
facility: NZOZ Pro Cordis Sopockie Centrum Badan Kardiologicznych
city: Wroclaw
country: Poland
facility: 4 Wojskowy Szpital Kliniczny z Poliklinika Samodzielny Publiczny ZOZ we Wroclawiu
city: Wrocław
country: Poland
facility: Centrum Chorob Serca w USK
city: Łódź
country: Poland
facility: Samodzielny Publiczny ZOZ Centralny Szpital Kliniczny Uniwersytetu Medycznego
Study officials:
References: