Ignite Creation Date:
2024-05-06 @ 9:23 AM
Last Modification Date:
2024-10-26 @ 12:14 PM
Study NCT ID:
NCT02973594
Status:
COMPLETED
Last Update Posted:
2023-12-20
First Post:
2016-11-22
Brief Title:
Pulse Reduction On Beta-blocker and Ivabradine Therapy
Sponsor:
University of Colorado Denver
Organization:
University of Colorado Denver
Study Overview
Official Title:
Pulse Reduction On Beta-blocker and Ivabradine Therapy
Status:
COMPLETED
Status Verified Date:
2023-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PROBE-IT
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 35in 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
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 35in 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
Detailed Description:
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 HFrEFIDC 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 21 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 ie 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 25 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
Eligible patients will be randomized 21 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 ie 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 25 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None