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Pulse Reduction on Beta Blocker and Ivabradine Therapy (PROBE-IT)

Study category: Heart and Blood Conditions

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Description

The goals of this study are (1) to test the hypothesis that HR reduction is an important underlying antecedent for reverse remodeling, and (2) to identify components of the beta1-GSN responsible for reverse remodeling caused by HR reduction using ivabradine, which could allow for better drug targeting. This study will also yield hypothesis-generating data on whether ivabradine might be useful in earlier stage HFrEF patients than the current indication.

Details
Age

Adult

Eligibility

1. Age &#8805; 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, with an LVEF < 0.45. 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 &#8805; 70 bpm at the Screening Visit. 6. Receiving guideline-indicated oral renin-angiotensin-aldosterone 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 &#8805; 6 months and target doses for &#8805; 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. Patients unable to tolerate any dose of beta-blockers, defined as at least two attempts to institute therapy at low dose, will be eligible for the study if they otherwise qualify. Patients with a contraindication to beta-blockade, such as beta2 agonist dependent bronchial asthma, will also qualify for enrollment. 9. Evidence of stable or declining LVEF, defined as no increase by &#8805; 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 &#8805; 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. Women who are breastfeeding and wish to be in this study will be required to discontinue breastfeeding during treatment and for an additional 2 weeks after stopping study medication. 14. Echocardiographic parasternal window adequate for measuring LV volumes by 3D-echo. 15. Must sign the ICF prior to the initiation of any study procedure and not withdraw consent prior to the Randomization Visit.

Detailed Eligibility: 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, with an LVEF < 0.45. 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-aldosterone 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. Patients unable to tolerate any dose of beta-blockers, defined as at least two attempts to institute therapy at low dose, will be eligible for the study if they otherwise qualify. Patients with a contraindication to beta-blockade, such as beta2 agonist dependent bronchial asthma, will also qualify for enrollment. 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. Women who are breastfeeding and wish to be in this study will be required to discontinue breastfeeding during treatment and for an additional 2 weeks after stopping study medication. 14. Echocardiographic parasternal window adequate for measuring LV volumes by 3D-echo. 15. Must sign the ICF prior to the initiation of any study procedure and not withdraw consent prior to the Randomization Visit.

Phase

Not Applicable - Describes studies without FDA-defined phases, including studies of devices or behavioral interventions.

Type of Study

Treatment

Location

University of Colorado Hospital

Principal Investigator
Natasha Altman,  MD

Natasha Altman, MD

Study ID

Protocol Number: 16-1363

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