Table 1 World Health Organization Trial Registration Data Set {2b}

Primary registry and trial identifying number

ClinicalTrials.gov

NCT05194397

Date of registration in primary registry

January 18, 2022

Secondary identifying numbers

20–017,320

1R01CA254955-01A1 (U.S. NIH Grant/Contract)

Source(s) of monetary or material support

National Cancer Institute (NCI)

Primary sponsor {5b}

National Cancer Institute

Sponsor’s Reference: 1R01CA254955-01A1

Contact name: Frank Perna, Ph.D

Address: 37 Convent Dr, Bethesda, MD 20,814

Telephone: 240–276-6782

Email: pernafm@mail.nih.gov

Secondary sponsor(s)

 Contact for public queries

Sogol Mostoufi-Moab, MD, MSCE

267–426-6725

moab@chop.edu

 Contact for scientific queries

Sogol Mostoufi-Moab, MD, MSCE

267–426-6725

moab@chop.edu

 Public title

Exercise Training and NR Supplementation Trial to Improve Fitness in AYA HCT Survivors

 Scientific title

Intensive Tailored Exercise Training With NAD + Precursor Supplementation to Improve Muscle Mass and Fitness in Childhood Cancer Survivors

 Countries of recruitment

United States of America

 Health condition(s) or problem(s) studied

Acute Lymphoblastic Leukemia in Remission, Cancer Survivors

 Intervention(s)

Dietary Supplement:

Nicotinamide Riboside—GMP-grade 300 mg capsules of the dietary supplement nicotinamide riboside (ChromaDex, Irvine CA)

Placebo—same excipients without the active supplement and is generally recognized as safe

Other: Exercise Intervention—at-home training sessions and will include aerobic and strengthening components designed to progress persons gradually to 150–300 min of the equivalent of moderate aerobic activity, and twice weekly strengthening over 16 weeks

 Key inclusion and exclusion criteria

Ages eligible for study: 15 – 30 years at enrollment, inclusive

Sexes eligible for study: both

Accepts healthy volunteers: no

Inclusion Criteria: Males and females, ages 15–30 years at enrollment; able to understand and speak English; diagnosis of acute leukemia (myeloid, lymphoid) requiring allogeneic HCT; 6–24 months from allogeneic HCT; if female, negative urine/serum pregnancy test and must use an acceptable method of contraception, including abstinence, a barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive, for the duration of the study; Parental/guardian permission (informed consent) and if appropriate, child assent

Exclusion Criteria: Known sensitivity to NR; Concurrent use of any medications, including statins, likely to increase risk of NR toxicity; Active malignancy, investigational agent(s) within 4 wks, or systemic glucocorticoids within 12 wks; Currently meeting public health exercise guidelines; Use of NAD + precursors (supra-physiologic) within 4 weeks; Hemoglobin < 10 g/dL; Platelets < 50 K; Diabetes Mellitus requiring insulin or insulin secretagogue; HbA1C ≥ 8%; Kidney disease (eGFR < 60 ml/min/1.73 m2); Liver disease Alanine aminotransferase/Aspartate aminotransferase(ALT/AST) > 3 × ULN; Limitations in physical function preventing exercise testing/training; Contraindications to MRI; Unstable angina or history of acute myocardial infarction (< 5 days of planned study procedures); Recurrent syncope; Symptomatic severe aortic stenosis; Uncontrolled arrhythmia causing symptoms; Pulmonary embolus < 3 months of study procedures; Thrombosis of lower extremities; Symptomatic moderate or severe persistent asthma based on forced expiratory volume (FEV) from pre-HCT pulmonary function testing; Room air desaturation at rest ≤ 85%; Females: Pregnant or planning pregnancy; Non-cardiopulmonary disorders that may affect exercise performance or be aggravated by exercise (e.g. infection, renal failure, thyrotoxicosis, > moderate graft versus host disease (GVHD) resulting in physical or functional impairment); Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures

 Study type

allocation: Randomized

Intervention Model: Factorial Assignment

Intervention Model Description: Randomized, placebo-controlled trial with a 2 × 2 factorial design testing the effects of an NAD + precursor (NR) and exercise

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description: The participants and the investigator team will be blinded as to the group assignment: NR vs Placebo. All collected data (e.g., questionnaires) will be coded, so initial analysis will be conducted without knowledge of the participant's group status

While the assignment of participants to the exercise groups will not be blinded to the participant or majority of the study team, a designated blinded technician will perform the follow-up Cardio Pulmonary Exercise Testing. Follow-Up Cardio Pulmonary Exercise Testing will be performed by a dedicated blinded study team member, an exercise technician, who will not know if the participant was assigned to an arm including the exercise intervention

Phase II

 Date of first enrolment

June 2022

 Target sample size

80

 Recruitment status

Recruiting

 Primary outcome(s)

Within participant changes in muscle strength (Isometric knee extension, Z-score) [ Time Frame: Baseline to 16 Weeks]

 Key secondary outcomes

Within participant change in muscle strength (Ankle Plantarflexion) using Biodex dynamometer [ Time Frame: Baseline to 16 Weeks]

Within participant change in grip strength (Hand Grip Dynamometry) [ Time Frame: Baseline to 16 Weeks]

Within participant changes in muscle mass (lower leg lean muscle mass by DXA) [ Time Frame: Baseline to 16 Weeks]

Within participant changes in post-exercise oxidative phosphorylation capacity (OXPHOS) using non-invasive MRI scanning using creatine chemical exchange saturation transfer (CrCEST) [ Time Frame: Baseline to 16 Weeks]

Within participant change in aerobic capacity (VO2 max, Maximal Oxygen Uptake on Cardiopulmonary Exercise Testing). [ Time Frame: Baseline to 16 Weeks]