An Interventional Study to Evaluate the Effect of Ivabradine on Exercise Capacity in Heart Transplant Recipients

A Phase 3, Open-label, Multicenter Study to Evaluate the Effect of Ivabradine on Exercise Capacity in Heart Transplant Recipients With Elevated Resting Heart Rate

The hypothesis is that the treatment with ivabradine will increase pVO2 after 16 weeks of treatment compared to baseline in the heart transplant recipient population with elevated resting HR.

Study Overview

• Status: Withdrawn
• Conditions: Heart Transplantation, Elevated Resting Heart Rate
• Intervention / Treatment: Drug: Ivabradine

Detailed Description

The primary goal of this study is to assess the impact of ivabradine on cardiopulmonary exercise capacity in heart transplant recipients with elevated resting heart rate (HR).

Exercise capacity will be assessed by the determination of the peak oxygen consumption (pVO2) during standard cardiopulmonary exercise test before and after the treatment period with ivabradine. The secondary goal is to determine HR reduction with ivabradine in the patient population.

• Study Type: Interventional
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subject has provided informed consent/assent prior to initiation of any study-specific activities/procedures
• Male or female, ≥ 18 to ≤ 70 years of age at signing of informed consent
• History of heart transplantation within 1 to 4 years from screening
• Sinus rhythm and elevated resting HR > 95 bpm at screening (ECG)
• Able to perform exercise testing as required per protocol, per the investigator, at time of screening
• Peak VO2 < 70% of the predicted normal value for age and gender with respiratory exchange ratio (RER) ≥ 1.05, from a CPET conducted during screening

Exclusion Criteria:

• Participation in a cardiac rehabilitation program during the study period
• Treatment for heart transplant rejection within the previous 3 months before screening
• Severe allograft vasculopathy limiting the tolerance of CPET at time of screening
• During CPET at screening, significant adverse finding (eg, exercise-induced early ischemic changes, abnormal blood pressure response, unexpected arrhythmia or other serious finding) that precludes safe participation in the study, per investigator
• Sick sinus syndrome, sinoatrial block and/or third degree atrioventricular block, unless a functioning demand pacemaker is present, or pacemaker dependency at screening
• Resting systolic blood pressure >160 mmHg or <100 mmHg, or diastolic blood pressure >90 mmHg at screening
• History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
• Presence of clinically meaningful acute or chronic infection, per investigator, at screening
• Major medical event or procedure (as determined by investigator) within 3 months prior to screening
• Previously received ivabradine after heart transplantation (prior to the participation in this study)
• Subjects taking QT prolonging medicinal products for cardiovascular (eg, but not limited to, quinidine, disopyramide, bepridil, sotalol, ibutilide) or non-cardiovascular disease (eg, but not limited to, pimozide, ziprasidone, sertindole, mefloquine, halofantrine, pentamidine, cisapride, intravenous (IV) erythromycin)
• Subjects should not be receiving beta-blockers, diltiazem, or verapamil for at least 7 days before screening
• Subjects exposed to a strong Cytochrome P450 3A4 (CYP3A4) inhibitor (examples of strong CYP3A4 inhibitors include; azole antifungals [eg, itraconazole], macrolide antibiotics [eg, clarithromycin, telithromycin], human immunodeficiency virus protease inhibitors, [eg, nelfinavir], and nefazodone]) within 14 days prior to screening, or to a strong CYP3A4 inducer (examples of CYP3A4 inducers include; St. John's wort, rifampicin, barbiturates, and phenytoin) within 28 days prior to screening
• Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded.
• Hemoglobin < 8 g/dL at screening (or within 3 months prior to screening if no clinically meaningful event, as determined by the investigator, has occurred in that period) and not expected to receive blood transfusion during the study
• Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 (by the Modification of Diet in Renal Disease [MDRD] equation) at screening (or within 3 months prior to screening)
• Subject has known sensitivity to any of the products to be administered during dosing
• Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 2 weeks after the last dose of investigational product
• Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 2 weeks after the last dose of investigational product. Refer to Section 12.5 for additional contraceptive information
• Female subjects of childbearing potential with a positive pregnancy test assessed at screening by a serum pregnancy test

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single Arm; Study Product	Drug: Ivabradine; Ivabradine will be provided in bottles (60 tablets per bottle) labeled ivabradine 5 mg and ivabradine 7.5 mg. The 2.5 mg dose of ivabradine will be achieved by subjects splitting the 5 mg tablets into equal halves.; Other Names: Corlanor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
pVO2	To evaluate the effect of treatment with ivabradine on exercise capacity as measured by peak oxygen consumption (pVO2)	Week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resting Heart Rate	To evaluate the effect of treatment with ivabradine on resting heart rate (HR)	Week 16

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Anticipated): November 2, 2018
• Primary Completion (Anticipated): February 19, 2020
• Study Completion (Anticipated): February 19, 2020

Study Registration Dates

• First Submitted: August 2, 2018
• First Submitted That Met QC Criteria: August 2, 2018
• First Posted (Actual): August 7, 2018

Study Record Updates

• Last Update Posted (Actual): November 19, 2018
• Last Update Submitted That Met QC Criteria: November 15, 2018
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Other Study ID Numbers: 20180037

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No