Pulse Reduction On Beta-blocker and Ivabradine Therapy (PROBE-IT)
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|ClinicalTrials.gov Identifier: NCT02973594|
Recruitment Status : Recruiting
First Posted : November 25, 2016
Last Update Posted : June 13, 2019
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.
|Condition or disease||Intervention/treatment||Phase|
|Dilated Cardiomyopathies, Idiopathic Heart Failure, Systolic Ventricular Remodeling Electrical Remodeling||Drug: Ivabradine Drug: Placebo||Phase 4|
The Pulse Reduction on Beta-blocker and Ivabradine Therapy (PROBE-IT) Study is a double-blind, randomized, two-arm parallel group, placebo-controlled design that compares the effect of heart rate reduction on ventricular reverse remodeling (assessed by LVEF change at 24 weeks) and on the beta1-gene signaling network in NYHA Class I-III HFrEF patients with an idiopathic dilated cardiomyopathy etiology (HFrEF/IDC), who are in sinus rhythm and whose heart rates remain ≥ 70 bpm on target or maximally tolerated doses of beta-blockers to which they have evidence of non-response by LVEF (< 5 absolute percentage points).
Eligible patients will be randomized (2:1) to blinded treatment with ivabradine or matching placebo and will be initiated as per Corlanor® prescribing information over 4 weeks. The dose at 4 weeks post randomization will be considered the intention-to-treat end of titration dose, but further dose adjustment can be made based on clinical factors.
The primary endpoint, i.e., effect of heart rate reduction on reverse remodeling (LVEF), will be assessed after 24 weeks. LV phenotyping by 3D-echocardiography, endomyocardial biopsy and coronary sinus sampling for cardiac norepinephrine levels will be performed at baseline and at 24 weeks. Exercise testing at baseline will be performed to assess level of beta blockade. Upon completion of the study, gene expression in endomyocardial biopsy tissue samples for each patient will be quantified using RNA-seq and quantified with respect to phenotypic measurements including LVEF and heart rate changes.
After the Week 24 Visit, patients will return for an End-of-Study Visit and be offered open label ivabradine with dose initiation accomplished by stopping study drug and starting Corlanor at 5 mg BID or 2.5 mg BID if the patient is taking that dose of study drug. Investigators and patients will not be informed of the blinded study drug assignment at the time of study completion.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||36 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Primary Purpose:||Basic Science|
|Official Title:||Pulse Reduction On Beta-blocker and Ivabradine Therapy|
|Study Start Date :||November 2016|
|Estimated Primary Completion Date :||July 2020|
|Estimated Study Completion Date :||July 2020|
Active Comparator: Ivabradine
Patients will receive ivabradine 2.5-7.5 mg PO bid in addition to baseline maximum-tolerated beta-blocker therapy.
Other Name: Corlanor
Placebo Comparator: Placebo
Patients will receive placebo bid in addition to baseline maximum-tolerated beta-blocker therapy.
- Left ventricular reverse remodeling according to heart rate response [ Time Frame: 24 weeks ]Improvement in left ventricular ejection fraction (LVEF) of ≥ 5 absolute percentage points in patients above vs. below median HR reduction for all subjects.
- Comparison of gene expression abundances by heart rate response [ Time Frame: 24 weeks ]Quantification of changes in mRNA and microRNA abundance based on response above and below median for all subjects.
- Left ventricular reverse remodeling by treatment group (ivabradine vs. placebo) [ Time Frame: 24 weeks ]Comparison of change (absolute LVEF percentage points) in subjects randomized to ivabradine vs. placebo.
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): NCT02973594
|Contact: Natasha Altman, MD||303-724-2091||Natasha.Altman@ucdenver.edu|
|Contact: David P Kao, MD||303-724-8308||David.Kao@ucdenver.edu|
|United States, Colorado|
|University of Colorado Anschutz Medical Campus||Recruiting|
|Aurora, Colorado, United States, 80045|
|Contact: Natasha Altman, MD 303-724-2091 Natasha.Altman@ucdenver.edu|
|Contact: Leslie Meyer 720-848-6530 Leslie.Meyer@ucdenver.edu|
|Principal Investigator: Michael R Bristow, MD PhD|
|United States, Ohio|
|The Ohio State University Wexner Medical Center||Recruiting|
|Columbus, Ohio, United States, 43210|
|Contact: William T Abraham, MD 614-292-9560 email@example.com|
|Principal Investigator: William T Abraham, MD|
|Principal Investigator:||Michael R Bristow, MD PhD||University of Colorado, Denver|