Pulse Reduction On Beta-blocker and Ivabradine Therapy

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.