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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Breast Cancer; Metastatic Breast Cancer; Cardiotoxicity; Cancer Therapy-Related Cardiac Dysfunction
• Intervention / Treatment: Dietary supplement: Placebo; Dietary supplement: Nicotinamide Riboside

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Torbjørn Omland, MD, PhD; Phone Number: +47 40107050; Email: torbjorn.omland@medisin.uio.no
• Study Contact Backup: Name: Victoria Vinje, MD; Phone Number: +47 92033665; Email: victoria.vinje@ahus.no

Study Locations

• Norway
  • Akershus
    • Lørenskog, Akershus, Norway, 1478
      • Recruiting
      • Akershus University Hospital
      • Contact: Torbjørn Omland, MD, PhD; Phone Number: +47 40107050; Email: torbjorn.omland@medisin.uio.no
      • Contact: Victoria Vinje, MD; Phone Number: +47 92033665; Email: victoria.vinje@ahus.no
      • Principal Investigator: Torbjørn Omland, MD, PhD
      • Sub-Investigator: Jürgen Geisler, MD, PhD
      • Sub-Investigator: Evandro F Fang, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment Arm; 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; Nicotinamide Riboside 500mg b.i.d as long as the patient is receiving anthracycline therapy; Other Names: Niagen (serial number 85932490, registration number 4606519)
Placebo Comparator: Placebo Control Arm; 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; Matching placebo b.i.d as long as the patient is receiving anthracycline therapy

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tertiary objective: Less aortic stiffness measured by CMR	Change in the aortic pulse wave velocity measured by CMR	Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy
Tertiary objective: Less myocardial injury and dysfunction measured by cardiac biomarkers other than troponin	Chance in circulating cardiac myosin binding protein C (cMyC)	Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy
Tertiary objective: Less skeletal muscle injury	Change in circulating creatine kinase (CK)	Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy
Tertiary objective: Less skeletal muscle injury	Change in circulating myoglobin	Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy
Tertiary objective: Less worsening in health-related quality of life	Quality of life measured by Chalder Fatigue Scale. Items are rated on a 4-point Likert scale (0 = better than usual, 1 = no more than usual, 2 = worse than usual, 3 = much worse than usual), with higher scores indicating greater fatigue.	Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy
Tertiary objective: Less worsening in health-related quality of life	Quality of life measured by European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L). Each dimension in the EQ-5D-5L has five response levels: no problems (Level 1); slight; moderate; severe; and extreme problems (Level 5). There are 3,125 possible health states defined by combining one level from each dimension, ranging from 11111 (full health) to 55555 (worst health).	Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy
Pharmacological endpoint: Change in circulating Nicotinamide adenine dinucleotide (NAD+) concentration from baseline to end of blinded therapy.	Changes in the amount of circulating NAD+ will be measured using commercial kits and Liquid chromatography-mass spectrometry analyses (LC-MS analyses)	Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy
Tertiary objective: Less myocardial injury expressed as oedema or fibrosis by CMR	Change in transverse relaxation time (T2) measured by CMR	Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy
Tertiary objective: Less myocardial injury expressed as oedema or fibrosis by CMR	Change in longitudinal relaxation time (T1) measured by CMR	Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy
Tertiary objective: Less myocardial injury expressed as oedema or fibrosis by CMR	Change in T1 rho measured by CMR	Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy
Tertiary objective: Less reduction in left ventricular diastolic function measured by echocardiography	Change in left ventricular diastolic function as measured by echocardiography	Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy
Tertiary objective: Less myocardial injury and dysfunction measured by cardiac biomarkers other than troponin	Chance in circulating N-terminal pro b-type natriuretic peptide (NT-proBNP)	Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy
Tertiary objective: Less worsening in health-related quality of life	Quality of life measured by European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / Quality of life (QoL) represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.	Baseline, 3 months, 6 months for patients receiving extended chemotherapy, and extended follow up 12 months after initiation of chemotherapy

Collaborators and Investigators

• Sponsor: University Hospital, Akershus
• Collaborators: Norwegian Cancer Society; Helse Sor-Ost; ChromaDex, Inc.; Norwegian Breast Cancer Association
• Investigators: Principal Investigator: Torbjørn Omland, MD, PhD, University Hospital, Akershus

Study record dates

Study Major Dates

• Study Start (Actual): March 16, 2023
• Primary Completion (Anticipated): August 1, 2025
• Study Completion (Anticipated): September 30, 2035

Study Registration Dates

• First Submitted: January 25, 2023
• First Submitted That Met QC Criteria: February 14, 2023
• First Posted (Actual): February 16, 2023

Study Record Updates

• Last Update Posted (Actual): March 17, 2023
• Last Update Submitted That Met QC Criteria: March 16, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Breast Cancer; Cardiotoxicity; Anthracyclines; Niagen; Nicotinamide adenine dinucleotide; Cardio-oncology; Cardiac Dysfunction; Reactive oxygen species; Nicotinamide riboside; Cancer Therapy-Related Cardiac Dysfunction
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Wounds and Injuries; Breast Diseases; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Breast Neoplasms; Cardiotoxicity; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Antimetabolites; Micronutrients; Hypolipidemic Agents; Lipid Regulating Agents; Vitamins; Vitamin B Complex; Nicotinic Acids; Niacinamide; Niacin
• Other Study ID Numbers: 2021/156064(REK)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes