Pulse Reduction On Beta-blocker and Ivabradine Therapy



Status:Recruiting
Conditions:Cardiology, Cardiology, Cardiology
Therapuetic Areas:Cardiology / Vascular Diseases
Healthy:No
Age Range:18 - Any
Updated:5/27/2018
Start Date:November 2016
End Date:July 2020
Contact:Natasha Altman, MD
Email:Natasha.Altman@ucdenver.edu
Phone:303-724-2091

Use our guide to learn which trials are right for you!

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.

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.

Inclusion Criteria:

1. Age ≥ 18 years.

2. History of non-ischemic (confirmed by coronary angiogram), non-valvular dilated
cardiomyopathy considered to be idiopathic, HFrEF NYHA Class I, II, or III.

3. Must have experienced a sign or symptom of clinical heart failure at some time within
the preceding 12 months.

4. In sinus rhythm at Screening Visit.

5. Resting HR ≥ 70 bpm at the Screening Visit.

6. 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.

7. May have ICD or CRT device as indicated.

8. 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.

9. 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.

10. 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.

11. 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.

12. Must be competent to understand the information given in the Institutional Review
Board (IRB) informed consent form (ICF).

13. Echocardiographic parasternal window adequate for measuring LV volumes by 3D-echo.

14. Must sign the ICF prior to the initiation of any study procedure and not withdraw
consent prior to the Randomization Visit.

Exclusion Criteria:

1. NYHA Class IV symptoms at the Randomization Visit.

2. History of HF due to or associated with uncorrected primary valvular disease or
history of ischemic heart disease.

3. Any history of atrial fibrillation (even if in sinus rhythm at present).

4. Systolic blood pressure < 90/50 mmHg at the Screening Visit.

5. Significant fluid overload at the Randomization Visit, in the opinion of the
Investigator.

Evidence of significant fluid overload may include:

1. Mean jugular venous pressure above the clavicle at 90°.

2. Liver congestion.

3. Moist pulmonary rales post-cough.

4. Peripheral edema beyond 1+ pedal not explained by local factors.

6. History of untreated symptomatic bradycardia or if symptomatic bradycardia is likely
on full dose of study drug in the opinion of the Investigator.

7. 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.

8. Untreated thyroid disease, in the opinion of the Investigator, at the Randomization
Visit.

9. Serum potassium < 3.5 mmol/L at the Screening Visit.

a. Lab value will be assessed by the central lab at the Screening Visit and any
exclusionary results must be corrected prior to randomization as documented by either
the central or local lab.

10. Renal failure requiring dialysis, serum creatinine > 2.5 mg/dL, or an estimated
creatinine clearance < 30 mL/min (Cockcroft-Gault) at the Screening Visit.

a. Lab values will be assessed by the central lab at the Screening Visit and any
exclusionary results must be corrected prior to randomization as documented by either
the central or local lab.

11. Significant intrinsic liver disease or a total bilirubin > 2.5 mg/dL at the Screening
Visit.

a. Lab value will be assessed by the central lab at the Screening Visit and any
exclusionary results must be corrected prior to randomization as documented by either
the central or local lab.

12. Participation in a clinical study or treatment with an investigational drug or device
within 30 days of the Screening Visit (or 5 half-lives of the investigational agent,
whichever is longer).

13. Comorbid condition or illness which, in the opinion of the Investigator, may limit
life expectancy to less than 5 years.

14. Serious or active medical or psychiatric condition which, in the opinion of the
Investigator, may interfere with treatment, assessment, or compliance with the
protocol.

15. History of alcohol, drug, or chemical abuse that, in the opinion of the Investigator,
could impair or limit the patient's full participation in the study.
We found this trial at
2
sites
13001 E 17th Pl
Aurora, Colorado 80045
(303) 724-5000
Principal Investigator: Michael R Bristow, MD PhD
Phone: 303-724-2091
University of Colorado Anschutz Medical Campus Located in the Denver metro area near the Rocky...
?
mi
from
Aurora, CO
Click here to add this to my saved trials
410 W 10th Ave
Columbus, Ohio 43210
(614) 293-8652
Principal Investigator: William T Abraham, MD
Phone: 614-292-9560
The Ohio State University, Wexner Medical Center Located in Columbus, The Ohio State University Wexner...
?
mi
from
Columbus, OH
Click here to add this to my saved trials