Effect of Ivabradine on Exercise Capacity After Heart Transplantation (VANISH-CAV)

• ClinicalTrials.gov Identifier: NCT03405831
• Recruitment Status: Unknown
• First Posted: January 23, 2018
• Last Update Posted: March 5, 2019
• Sponsor: Finn Gustafsson
• Collaborators: Danish Heart Foundation; Rigshospitalet, Denmark
• Information provided by (Responsible Party): Finn Gustafsson, Rigshospitalet, Denmark

Study Description

Brief Summary:

This study evaluates whether treatment with ivabradine compared to placebo can improve exercise capacity in long-term heart transplant recipients with cardiac allograft vasculopathy and elevated heart rate at rest.

Patients will receive treatment with either ivabradin or placebo for a period of 12 weeks.

Condition or disease	Intervention/treatment	Phase
Cardiac Allograft Vasculopathy; Transplanted Heart Complication	Drug: Ivabradine; Drug: Placebo	Phase 4

Detailed Description:

Elevated resting heart rate (HR) is a normal finding after successful heart transplantation (HTx) due to parasympathetic denervation at the operation.

Elevated resting HR is generally acknowledged as a negative predictor of outcome in heart disease. The impact in heart transplant recipients is not fully understood, however, it has been associated with increased risk of developing cardiac allograft vasculopathy (CAV) or death.

Cardiac allograft vasculopathy is a diffuse vascular disease affecting the entire coronary tree. It is the leading cause of death in patients more than 5 years after HTx and it is well known that patients with CAV have markedly reduced exercise capacity.

The association between elevated HR and CAV raises the question whether an intervention to specifically lower HR could improve symptoms and prognosis in heart transplant recipients with CAV and elevated resting HR.

Small studies have shown that HR reduction using the If channel blocker ivabradine after HTx is safe. However, none of these studies were randomized or blinded, and as such proof of any efficacy (beyond HR reduction) after HTx is non-existing. Clearly, there is a need to determine if such treatment could improve exercise capacity, graft function and prognosis after HTx.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 35 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention Model Description

This is a prospective single-center, double-blinded, placebo controlled, randomized study in long-term heart transplant recipients.

Patients who meet the eligibility criteria will be randomized 1:1 at inclusion for one of two treatment groups: (i) treatment with ivabradine 5 mg bid or (ii) treatment with placebo bid for a period of 12 weeks. 35 participants will be enrolled.

• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effect of Ivabradine Treatment on Exercise Capacity in Patients With Cardiac Allograft Vasculopathy After Heart Transplantation
• Actual Study Start Date: April 17, 2018
• Estimated Primary Completion Date: December 2019
• Estimated Study Completion Date: December 2019

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Ivabradine; Study participants in this arm will receive ivabradin 5 mg bid for a period of 12 weeks.	Drug: Ivabradine; Ivabradine, oral tablets, 5 mg, coated in gelatine capsules to ensure blinding, 1 capsule twice a day, for a period of 12 weeks; Other Name: Procoralan
Placebo Comparator: Placebo; Study participants in this arm will receive placebo bid for a period of 12 weeks.	Drug: Placebo; Placebo, gelatine capsules to ensure blinding, 1 capsule twice daily, for a period of 12 weeks

Outcome Measures

Primary Outcome Measures :

1. ΔVO2max [ Time Frame: The VO2max is assessed at baseline and 12 weeks follow-up. ]
   The change in VO2max (ΔVO2max) (mL/kg/min) from baseline to 12 weeks follow-up. The peak oxygen uptake (VO2max) reflects the maximal ability of a person to take in, transport and use oxygen, and it defines the functional aerobic capacity. It is used to provide an overall assessment of exercise capacity.

Secondary Outcome Measures :

1. ΔHRrest [ Time Frame: 12 weeks ]
   Change in resting HR (beats/min) from baseline to 12 weeks follow-up
2. ΔHRreserve [ Time Frame: 12 weeks ]
   Change in HR reserve (beats/min) from baseline to 12 weeks follow-up
3. ΔLVmass [ Time Frame: 12 weeks ]
   Change in left ventricular (LV) mass (g) evaluated by cardiac MRI from baseline to 12 weeks follow-up
4. ΔLVEF [ Time Frame: 12 weeks ]
   Change in left ventricular ejection fraction (LVEF) (%) evaluated by cardiac MRI from baseline to 12 weeks follow-up
5. Δmitral deceleration time [ Time Frame: 12 weeks ]
   Change in mitral decelaration time (ms) evaluated by echocardiography from baseline to 12 weeks follow-up
6. ΔE/é [ Time Frame: 12 weeks ]
   Change in E/é evaluated by echocardiography from baseline to 12 weeks follow-up
7. ΔE/A ratio [ Time Frame: 12 weeks ]
   Change in E/A ratio evaluated by echocardiography from baseline to 12 weeks follow-up
8. Δisovolumetric relaxation time [ Time Frame: 12 weeks ]
   Change in isovolumetric relaxation time (ms) evaluated by echocardiography from baseline to 12 weeks follow-up
9. Δtransmitral flow rate [ Time Frame: 12 weeks ]
   Change in transmitral flow rate (volume/min) evaluated by cardiac MRI from baseline to 12 weeks follow-up
10. Δpulmonary venous flow [ Time Frame: 12 weeks ]
    Change in pulmonary venous flow (volume/min) evaluated by cardiac MRI from baseline to 12 weeks follow-up
11. ΔLVEDV [ Time Frame: 12 weeks ]
    Change in LVEDV (left ventricular end diastolic volume) (ml) evaluated by cardiac MRI from baseline to 12 weeks follow-up
12. ΔLVESV [ Time Frame: 12 weeks ]
    Change in LVESV (left ventricular end systolic volume) (ml) evaluated by cardiac MRI from baseline to 12 weeks follow-up
13. ΔLV peak filling rate [ Time Frame: 12 weeks ]
    Change in left ventricular (LV) peak filling rate (volume/min) evaluated by cardiac MRI from baseline to 12 weeks follow-up
14. Δtime to peak filling [ Time Frame: 12 weeks ]
    Change in time to peak filling (sec) evaluated by cardiac MRI from baseline to 12 weeks follow-up
15. ΔQOL KCCQ [ Time Frame: 12 weeks ]
    Change in QOL score evaluated by Kansas City Cardiomyopathy Questionnaire from baseline to 12 weeks follow-up
16. ΔQOL EQ-5D-5L [ Time Frame: 12 weeks ]
    Change in QOL score evaluated by EQ-5D-5L questionnaire from baseline to 12 weeks follow-up

Other Outcome Measures:

1. Coronary vessel characterization [ Time Frame: Substudy objective is only evaluated at baseline ]
   Substudy objective: To characterize coronary vessels in CAV using new imaging modalities and relating them to functional parameters of cardiac function. Modalities performed at baseline: Intravascular ultrasound (IVUS)/Near-infrared spectroscopy (NIRS), optical coherence tomography (OCT), 82-Rubudium positron emission tomography (PET) scan

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 100 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patients > 1 year post heart transplantation
• CAV verified by coronary angiography or intravascular ultrasound
• Resting HR > 80 bpm
• Age > 18 years
• Signed informed consent

Women, who have not yet entered menopause (defined as no menstrual bleeding in the last 12 months), will be required to provide a negative urine human chorionic gonadotropin (hCG) before entering the study and must use a safe birth control method in the total study period.

Exclusion Criteria:

• Rejection (>H1R) < 3 months
• Severe renal failure (estimated glomerular filtration rate (GFR) < 30 mL/min/1.73 m2)
• Inability or contraindication to perform a VO2 max test
• Presence of any condition that might per se influence exercise performance
• Known contraindication for treatment with ivabradine
• Hypersensitivity to the active substance or to any of the excipients of either study drug

Contacts and Locations

Contacts

Contact: Finn Gustafsson, MD PhD DMSc; +45 35459743; finng@dadlnet.dk

Contact: Lærke Nelson, MD; +45 35459549; laerke.marie.nelson@regionh.dk

Locations

Denmark

Department of Cardiology, Copenhagen University Hospital, Rigshospitalet; Recruiting

Copenhagen, Denmark, DK-2100

Contact: Finn Gustafsson, MD PhD DMSc +45 3545 9743 finng@dadlnet.dk

Contact: Lærke Nelson, MD +45 3545 9549 laerke.marie.nelson@regionh.dk

Principal Investigator: Lærke Nelson, MD

Sponsors and Collaborators

Finn Gustafsson

Danish Heart Foundation

Rigshospitalet, Denmark

Investigators

• Principal Investigator: Lærke Nelson, MD; Rigshospitalet, Denmark

More Information

• Responsible Party: Finn Gustafsson, MD, PhD, DMSci; Professor of Cardiology; Team Leader Advanced Heart Failure, Transplantation and Mechanical Circulatory Support; Department of Cardiology; The Heart Center; Copenhagen University Hospital; Rigshospitalet, Rigshospitalet, Denmark
• ClinicalTrials.gov Identifier: NCT03405831
• Other Study ID Numbers: RH-HJE-LN-01
• First Posted: January 23, 2018
• Last Update Posted: March 5, 2019
• Last Verified: March 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Finn Gustafsson, Rigshospitalet, Denmark:

Heart transplantation; Exercise capacity; Heart rate; Cardiac allograft vasculopathy

Additional relevant MeSH terms:

Vascular Diseases; Cardiovascular Diseases