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

Official title

Intensive Tailored Exercise Training With NAD+ Precursor Supplementation to Improve Muscle Mass and Fitness in Adolescent and Young Adult Hematopoietic Cell Transplant Survivors

Overview

This will be a randomized, placebo-controlled trial with a 2x2 factorial design testing the effects of an NAD+ precursor (NR) and exercise on skeletal muscle quality and VO2max in AYA HCT survivors. The primary outcome is the change in muscle strength (isometric knee extension) from baseline to 16 weeks. Key secondary outcomes are the change in muscle strength (ankle plantarflexion) from baseline to 16 weeks, the change in grip strength from baseline to 16 weeks, the change in lower extremity muscle mass from baseline to 16 weeks, the change in muscle OXPHOS capacity from baseline to 16 weeks, and the change in aerobic capacity (VO2 max) from baseline to 16 weeks.

Detailed description

Adolescents and young adults (AYAs) who undergo hematopoietic cell transplantation (HCT) are at an especially high risk of developing sarcopenia (loss of skeletal muscle mass), which occurs earlier than would be expected from advancing age alone. This is important as not only it doubles their risk for non-relapse mortality, but it also leads to premature cardiovascular disease. The investigators propose a mechanistic randomized controlled trial of home-based remotely supervised exercise (aerobic and resistance) training and supplementation with nicotinamide riboside, a precursor of NAD+, a metabolite that is critical for muscle metabolism, in AYA survivors of HCT. The findings will lay the critical groundwork for future trials to prevent or mitigate the myriad downstream adverse effects of low muscle mass in AYA HCT survivors.

Interventions

• Dietary supplement Nicotinamide Riboside
  Investigators will use (Good Manufacturing Process) GMP-grade 300 mg capsules of the dietary supplement nicotinamide riboside (ChromaDex, Irvine CA). NR is distributed by ChromaDex, Inc., Irvine, CA. NR is available as 300 mg capsules. The dietary supplement will be re-labeled by the Hospital of the University of Pennsylvania (HUP) Investigational Drug Service according to FDA regulations, including subject and physician name and NR or Placebo 300 mg capsules.
• Dietary supplement Placebo
  The matched placebo will contain the same excipients without the active supplement and is generally recognized as safe. The placebo will be covered in an identical capsule (NR will be covered in the same capsule)
• Other Exercise Intervention
  The exercise program consists of at-home training sessions and will include aerobic and strengthening components designed to progress persons gradually to 150-300 minutes of the equivalent of moderate aerobic activity, and twice weekly strengthening over 16 weeks. For aerobic training, the eventual intensity and duration goal (adapted for each person as necessary) will be for persons to train at 70-80% of peak 2MSPT heart rate 20-45 minutes 3-5 days/week. For resistance exercises the goal will b

Primary outcome measures

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

Secondary outcome measures (5)

• Within participant change in muscle strength (Ankle Plantarflexion) [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). [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]

Eligibility criteria

Inclusion criteria

• Males and females, ages 10-30 years at enrollment
• Able to understand and speak English
• Diagnosis of leukemia (myeloid, lymphoid), aplastic anemia, bone marrow failure syndrome, or myelodysplastic syndrome requiring allogeneic HCT
• 6-48 months from allogeneic HCT
• Females must have a 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.
• Subject's informed consent or parental/guardian permission (informed consent) and if appropriate, child assent
• Minimum weight of 24 kg

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 supraphysiological glucocorticoids at the baseline visit
• Currently meeting public health exercise guidelines
• Use of NAD+ precursors (supra-physiologic) within 4 weeks
• Hemoglobin < 10 g/dL
• Platelets < 50K
• Diabetes Mellitus requiring insulin or insulin secretagogue
• HbA1C ≥ 8% or fasting glucose > 125 mg/dL; However if the participant is diabetic, both fasting glucose level and HbA1C must meet the criteria to be deemed eligible.
• Kidney disease (eGFR < 60 ml/min/1.73 m2)
• Liver disease Alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) (ALT/AST > 3 x ULN)
• Limitations in physical function preventing exercise testing/training
• 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.
• For MRI procedure: Contraindications to MRI. Individuals will be screened to ensure they can safely complete the MRI. \*participants who cannot complete the MRI will not be excluded from participation in the remainder of the study procedures if they meet those inclusion and exclusion criteria.
• Current weight precludes safe completion of study procedures

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Factorial

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 3 centers

• City of Hope Medical Center — Duarte
• Children's Hospital of Philadelphia — Philadelphia
• St. Jude Children's Research Hospital — Memphis

Publications

• Song M, Armenian SH, Bhandari R, Lee K, Ness K, Putt M, Lindenfeld L, Manoukian S, Wade K, Dedio A, Guzman T, Hampton I, Lin K, Baur J, McCormack S, Mostoufi-Moab S. Exercise training and NR supplementation to improve muscle mass and fitness in adolescent and young adult hematopoietic cell transplant survivors: a randomized controlled trial 1. BMC Cancer. 2022 Jul 19;22(1):795. doi: 10.1186/s12885 PMID 35854224

Identifiers

NCT: NCT05194397 · 20-017320 · 1R01CA254955-01A1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗