Pulse Reduction On Beta-blocker and Ivabradine Therapy

NCT02973594 | Completed Phase 4 DMC

• 1 other identifier: 16-1363
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 2

Brief Summary

Heart failure with reduced left ventricular ejection fraction (HFrEF) is the most common form of chronic heart failure in subjects ≤ 75 years of age. Beta-blocker therapy greatly reduces mortality and improves ventricular function in HFrEF patients, but 30-40% of patients do not show improvement in ventricular function with beta blockade. An extensive gene signaling network downstream from the beta1-adrenergic receptor, the primary target of beta-blocker therapy is likely important for development and progression HFrEF. Pathologic changes in this gene signaling network are only reversed towards normal levels when ventricular function improves. One potential mechanism for failure to improve ventricular function in HFrEF patients unresponsive to beta blocker therapy is a lack of heart rate reduction. Ivabradine is an FDA-approved medication believed to have therapeutic benefit in HFrEF patients through reduction in heart rate independent of beta-blockade. Ivabradine has been shown to reduce the risk of hospitalization for worsening HF in patients with stable, symptomatic chronic heart failure with reduced EF (≤ 35%)in sinus rhythm with resting heart rate ≥ 70 bpm and who are on maximally tolerated doses of beta blockers or who have a contraindication to beta blockers. Given the high rate of mortality and hospitalization of HFrEF patients even with current therapies, there is a large unmet need for improving HFrEF therapy. The goals of this study are to test the hypothesis that heart rate reduction is an important antecedent for improvement in ventricular function, and to identify components of the beta1-adrenergic receptor gene signaling network responsible for improvement in ventricular function caused by heart rate reduction.

Conditions

Dilated Cardiomyopathies, Idiopathic; Heart Failure, Systolic; Ventricular Remodeling; Electrical Remodeling

Keywords

left ventricular reverse remodeling; beta-1 adrenergic receptor signaling; idiopathic dilated cardiomyopathy; HCN4 inhibition; beta-1 adrenergic receptor blocker; gene expression

Outcome Measures

Primary Outcomes (1)

• Left ventricular reverse remodeling according to heart rate response

  Improvement in left ventricular ejection fraction (LVEF) of ≥ 5 absolute percentage points in patients above vs. below median HR reduction for all subjects.

  24 weeks

Secondary Outcomes (2)

• Comparison of gene expression abundances by heart rate response

  24 weeks

• Left ventricular reverse remodeling by treatment group (ivabradine vs. placebo)

  24 weeks

Study Arms (2)

Ivabradine

ACTIVE COMPARATOR

Patients will receive ivabradine 2.5-7.5 mg PO bid in addition to baseline maximum-tolerated beta-blocker therapy.

Drug: Ivabradine

Placebo

PLACEBO COMPARATOR

Patients will receive placebo bid in addition to baseline maximum-tolerated beta-blocker therapy.

Drug: Placebo

Interventions

Ivabradine DRUG

Also known as: Corlanor

Ivabradine

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years.
• History of non-ischemic (confirmed by coronary angiogram), non-valvular dilated cardiomyopathy considered to be idiopathic, HFrEF NYHA Class I, II, or III.
• Must have experienced a sign or symptom of clinical heart failure at some time within the preceding 12 months.
• In sinus rhythm at Screening Visit.
• Resting HR ≥ 70 bpm at the Screening Visit.
• Receiving guideline-indicated oral renin-angiotensin-adosterone system (RAAS) inhibitor therapy at the Randomization Visit, i.e., an ACE inhibitor, angiotensin receptor blocker, or sacubitril/valsartan plus a mineralocorticoid receptor antagonist as tolerated.
• May have ICD or CRT device as indicated.
• Receiving beta-blocker therapy for ≥ 6 months and target doses for ≥ 3 months prior to Baseline Visit.
• Target dose of carvedilol is 25 mg BID, and metoprolol succinate, 150 mg/day. Patients who are not receiving doses that are at least at these target levels will have their heart failure beta-blocker up-titrated to target and an LVEF re-measured in 3 months, at which time they could be eligible for enrollment. Patients on \< target doses who are intolerant to higher than target doses may be enrolled.
• Evidence of stable or declining LVEF, defined as no increase by ≥ 5 % on a measurement done within 6 months of screening compared to the most recent historical measurement performed within 36 months of the index measure. Must have been on a dose of ≥ 50% of target during the period that documented the lack of a reverse remodeling response. Prior LVEF measurements could have been performed by any imaging technique, e.g., echocardiography, radionuclide methods, MRI, or contrast ventriculography.
• Women of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Baseline and Randomization Visits.
• a. Women who are surgically sterile or post-menopausal for at least 12 months are not considered to be of childbearing potential.
• Women of childbearing potential must agree to use a highly effective contraception for the duration of the trial and for at least 30 days following the last dose of study drug.
• Must be competent to understand the information given in the Institutional Review Board (IRB) informed consent form (ICF).
• Echocardiographic parasternal window adequate for measuring LV volumes by 3D-echo.

You may not qualify if:

• NYHA Class IV symptoms at the Randomization Visit.
• History of HF due to or associated with uncorrected primary valvular disease or history of ischemic heart disease.
• Any history of atrial fibrillation (even if in sinus rhythm at present).
• Systolic blood pressure \< 90/50 mmHg at the Screening Visit.
• Significant fluid overload at the Randomization Visit, in the opinion of the Investigator.
• Evidence of significant fluid overload may include:
• Mean jugular venous pressure above the clavicle at 90°.
• Liver congestion.
• Moist pulmonary rales post-cough.
• Peripheral edema beyond 1+ pedal not explained by local factors.
• History of untreated symptomatic bradycardia or if symptomatic bradycardia is likely on full dose of study drug in the opinion of the Investigator.
• Moderate to severe asthma or other obstructive lung disease requiring chronic use (\> 2 days/week) of an inhaled β2-selective adrenergic agonist \< 7 days of the Randomization Visit.
• Untreated thyroid disease, in the opinion of the Investigator, at the Randomization Visit.
• Serum potassium \< 3.5 mmol/L at the Screening Visit.
• Renal failure requiring dialysis, serum creatinine \> 2.5 mg/dL, or an estimated creatinine clearance \< 30 mL/min (Cockcroft-Gault) at the Screening Visit.

Sponsors & Collaborators

• University of Colorado, Denver: lead
• American Heart Association: collaborator
• Ohio State University: collaborator

Study Sites (2)

University of Colorado Anschutz Medical Campus

Aurora, Colorado, 80045, United States

Location

The Ohio State University Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

Related Publications (7)

• Kao DP, Lowes BD, Gilbert EM, Minobe W, Epperson LE, Meyer LK, Ferguson DA, Volkman AK, Zolty R, Borg CD, Quaife RA, Bristow MR. Therapeutic Molecular Phenotype of beta-Blocker-Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy. Circ Cardiovasc Genet. 2015 Apr;8(2):270-83. doi: 10.1161/CIRCGENETICS.114.000767. Epub 2015 Jan 30.

  PMID: 25637602 BACKGROUND

• Lowes BD, Zolty R, Minobe WA, Robertson AD, Leach S, Hunter L, Bristow MR. Serial gene expression profiling in the intact human heart. J Heart Lung Transplant. 2006 May;25(5):579-88. doi: 10.1016/j.healun.2006.01.006. Epub 2006 Apr 11.

  PMID: 16678038 BACKGROUND

• Lowes BD, Gilbert EM, Abraham WT, Minobe WA, Larrabee P, Ferguson D, Wolfel EE, Lindenfeld J, Tsvetkova T, Robertson AD, Quaife RA, Bristow MR. Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents. N Engl J Med. 2002 May 2;346(18):1357-65. doi: 10.1056/NEJMoa012630.

  PMID: 11986409 BACKGROUND

• Tardif JC, O'Meara E, Komajda M, Bohm M, Borer JS, Ford I, Tavazzi L, Swedberg K; SHIFT Investigators. Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and function: results from the SHIFT echocardiography substudy. Eur Heart J. 2011 Oct;32(20):2507-15. doi: 10.1093/eurheartj/ehr311. Epub 2011 Aug 29.

  PMID: 21875858 BACKGROUND

• Bohm M, Swedberg K, Komajda M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010 Sep 11;376(9744):886-94. doi: 10.1016/S0140-6736(10)61259-7.

  PMID: 20801495 BACKGROUND

• Bristow MR. Treatment of chronic heart failure with beta-adrenergic receptor antagonists: a convergence of receptor pharmacology and clinical cardiology. Circ Res. 2011 Oct 28;109(10):1176-94. doi: 10.1161/CIRCRESAHA.111.245092.

  PMID: 22034480 BACKGROUND

• Altman NL, Gill EA, Kahwash R, Meyer LK, Wagner JA, Karimpour-Fard A, Berning AA, Minobe WA, Carroll IA, Jonas ER, Slavov D, Emani S, Abraham WT, Gollah AR, Ellis SL, Taylor MRG, Graw SL, Mestroni L, McKinsey TA, Buttrick PM, Kao DP, Bristow MR. Heart Rate Reduction Is Associated With Reverse Left Ventricular Remodeling and Mechanism-Specific Molecular Phenotypes in Dilated Cardiomyopathy. Circ Heart Fail. 2025 Apr;18(4):e012484. doi: 10.1161/CIRCHEARTFAILURE.124.012484. Epub 2025 Mar 7.

  PMID: 40052260 DERIVED

MeSH Terms

Conditions

Cardiomyopathy, Dilated; Heart Failure, Systolic; Ventricular Remodeling; Atrial Remodeling

Interventions

Ivabradine

Condition Hierarchy (Ancestors)

Cardiomegaly; Heart Diseases; Cardiovascular Diseases; Cardiomyopathies; Laminopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Heart Failure; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Pathologic Processes

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Michael R Bristow, MD PhD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 22, 2016
• First Posted: November 25, 2016
• Study Start: November 1, 2016
• Primary Completion: December 1, 2022
• Study Completion: June 30, 2023
• Last Updated: December 20, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share

Locations

US (2)