Nicotinamide Riboside and Prevention of Cancer Therapy Related Cardiac Dysfunction in Breast Cancer Patients

Study Overview
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Brief Summary
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Breast cancer is the most common form of cancer in women. Modern breast cancer treatments have led to increased survival, but at the same time, increased risk for cardiotoxicity and development of heart failure. In this study, the investigators want to evaluate whether nicotinamide riboside can prevent cancer-related cardiac dysfunction in metastatic breast cancer patients scheduled for anthracycline therapy. Further, the investigators will evaluate change in signs of skeletal muscle injury and functional capacity.

Detailed Description
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The trial is prospective, randomised, double-blind and placebo-controlled. The primary objective is change in left ventricular ejection fraction (LVEF), determined by cardiac MRI (CMR). Secondary objectives are change in circulating high-sensitivity cardiac troponin I and T (hs-TnI and hs-TnT), Creatine Kinase (CK) and myoglobin, and various measurements of change in left ventricular systolic function determined by CMR and echocardiography. Additional assessments are evaluation of the patient's functional capacity and the patients will be asked to fill out questionnaires to assess quality of life. 60 patients will be randomised in a 1:1 ratio. The duration of blinded therapy will depend on the duration of anthracycline therapy. All patients will be examined at baseline and 3 months, and if the patient is scheduled for extended anthracycline therapy, an additional examination will be performed at 6 months.

Official Title
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Effect of Nicotinamide Riboside on Myocardial and Skeletal Muscle Injury and Function in Patients With Metastatic Breast Cancer Receiving Anthracyclines

Conditions
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Breast Cancer, Metastatic Breast Cancer, Cancer Therapy-Related Cardiac Dysfunction, Cardiotoxicity, Heart Failure

Intervention / Treatment
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* Dietary Supplement: Nicotinamide Riboside
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women with metastatic breast cancer (stage IV breast cancer) scheduled for anthracycline-containing chemotherapy Eastern Cooperative Oncology Group performance status 0-2 Exclusion Criteria Age <18 years Acute myocardial infarction within the last three months Participation in another pharmaceutical clinical trial of an investigational medicinal product (IMP) less than 4 weeks prior to inclusion or use of other investigational drugs within 5 half-lives of enrollment, whichever is longer Conditions that would affect the participants to comply with the study protocol as psychiatric or mental disorders, alcohol abuse or other substance abuse, suspected poor drug compliance, language barriers Life expectancy < 6 months Known allergy to any of the components in the Nicotinamide Riboside (Niagen®) tablet Contraindications or inability to undergo CMR examination

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind, randomised, placebo-controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment Arm<br>The patients randomised into this arm of the trial will receive 500 mg Nicotinamide Riboside b.i.d. The duration of blinded therapy will depend on the duration of anthracycline therapy, and will for some patients last for 3 months, others for 6 months. | Dietary Supplement: Nicotinamide Riboside<br>* Nicotinamide Riboside 500mg b.i.d as long as the patient is receiving anthracycline therapy<br>* Other names: Niagen (serial number 85932490, registration number 4606519);|
| Placebo Comparator: Placebo Control Arm<br>The patients randomised into this arm of the trial will receive a matching placebo b.i.d. The duration of treatment is equivalent to the description in the treatment arm. | Dietary Supplement: Placebo<br>* Matching placebo b.i.d as long as the patient is receiving anthracycline therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Whether the administration of nicotinamide riboside can prevent the reduction in left ventricular systolic function measured by cardiovascular magnetic resonance (CMR), compared to placebo. | Change in left ventricular ejection fraction (LVEF), as determined by CMR from randomization to end of blinded therapy. | Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess whether the administration of nicotinamide riboside is associated with less reduction in left ventricular systolic function measured by echocardiography | From randomization to the end of blinded therapy: Change in LVEF, as determined by echocardiography | Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy | 
| Assess whether the administration of nicotinamide riboside is associated with less reduction in left ventricular systolic function measured by echocardiography | From randomization to the end of blinded therapy: Change in left ventricular global longitudinal strain (GLS), as determined by echocardiography | Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy | 
| Assess whether the administration of nicotinamide riboside is associated with less reduction in left ventricular systolic function measured by CMR | From randomization to the end of blinded therapy: Change in left ventricular global circumferential strain (GCS) and GLS, as determined by CMR | Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy | 
| Assess whether the administration of nicotinamide riboside is associated with less reduction in left ventricular systolic function measured by CMR | From randomization to the end of blinded therapy: Change in left ventricular end-systolic volume measured by CMR | Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy | 
| To assess whether the administration of nicotinamide riboside is associated with less myocardial injury measured by high-sensitive cardiac troponin T (hs-cTnT) | From randomization to the end of blinded therapy: Change in circulating hs-cTnT | Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy | 
| To assess whether the administration of nicotinamide riboside is associated with less myocardial injury measured by high-sensitive cardiac troponin I (hs-cTnI) | From randomization to the end of blinded therapy: Change in circulating hs-cTnI | Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy | 
| To assess whether the administration of nicotinamide riboside is associated with less worsening in functional capacity | From randomization to the end of blinded therapy: Change in distance in meters during 6-minute walk test | Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy | 
| To assess whether the administration of nicotinamide riboside is associated with less worsening in functional capacity | From randomization to the end of blinded therapy: Change in force generated by handgrip strength test | Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, Anthracyclines, Niagen, Nicotinamide riboside, Nicotinamide adenine dinucleotide, Reactive oxygen species, Cardiac Dysfunction, Cardio-oncology, Cardiotoxicity, Cancer Therapy-Related Cardiac Dysfunction