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

Phase 2

Recruiting

• Conditions: Lymphoblastic Leukemia; Myelodysplastic Syndromes; Cancer Survivors; Myeloid Leukemia; Aplastic Anemia

• Registration Number: NCT05194397
• Lead Sponsor: Children's Hospital of Philadelphia

Brief Summary

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.

Study Timeline

• Study First Submitted: 2021-12-09
• Study First Submitted QC: 2022-01-14
• Study First Posted: 2022-01-18
• Study Start: 2023-02-23
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-28
• Last Update Posted: 2025-04-29
• Primary Completion: 2026-06-30
• Study Completion: 2026-06-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

1. Males and females, ages 10-30 years at enrollment
2. Able to understand and speak English
3. Diagnosis of leukemia (myeloid, lymphoid), aplastic anemia, or myelodysplastic syndrome requiring allogeneic HCT
4. 6-48 months from allogeneic HCT
5. 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.
6. Subject's informed consent or parental/guardian permission (informed consent) and if appropriate, child assent
7. Minimum weight of 24 kg

Exclusion Criteria

1. Known sensitivity to NR
2. Concurrent use of any medications, including statins, likely to increase risk of NR toxicity
3. Active malignancy, investigational agent(s) within 4 wks, or supraphysiological glucocorticoids at the baseline visit
4. Currently meeting public health exercise guidelines
5. Use of NAD+ precursors (supra-physiologic) within 4 weeks
6. Hemoglobin < 10 g/dL
7. Platelets < 50K
8. Diabetes Mellitus requiring insulin or insulin secretagogue
9. 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.
10. Kidney disease (eGFR < 60 ml/min/1.73 m2)
11. Liver disease Alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) (ALT/AST > 3 x ULN)
12. Limitations in physical function preventing exercise testing/training
13. Unstable angina or history of acute myocardial infarction (<5 days of planned study procedures)
14. Recurrent syncope
15. Symptomatic severe aortic stenosis
16. Uncontrolled arrhythmia causing symptoms
17. Pulmonary embolus <3 months of study procedures
18. Thrombosis of lower extremities
19. Symptomatic moderate or severe persistent asthma based on Forced Expiratory Volume (FEV) from pre-HCT pulmonary function testing
20. Room air desaturation at rest ≤85%
21. Females: Pregnant or planning pregnancy
22. 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)
23. Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.
24. 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.
25. Current weight precludes safe completion of study procedures

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Primary Outcome Measures

Name	Time	Method
Within participant changes in muscle strength (Isometric knee extension, Z-score)	Baseline to 16 Weeks	Muscle Strength will be assessed by completion of isometric contractions using a Biodex dynamometer.

Secondary Outcome Measures

Name	Time	Method
Within participant change in muscle strength (Ankle Plantarflexion)	Baseline to 16 Weeks	Muscle Strength will be assessed by completion of isometric contractions using a Biodex dynamometer.
Within participant change in grip strength (Hand Grip Dynamometry)	Baseline to 16 Weeks	Grip Strength will be assessed using a hand grip dynamometry device.
Within participant changes in muscle mass (lower leg lean muscle mass by DXA)	Baseline to 16 Weeks	Muscle mass will be assessed by completion of whole body DXA scanning.
Within participant changes in post-exercise oxidative phosphorylation capacity (OXPHOS).	Baseline to 16 Weeks	OXPHOS capacity will be assessed by completion of non-invasive MRI scanning using creatine chemical exchange saturation transfer (CrCEST).
Within participant change in aerobic capacity (VO2 max, Maximal Oxygen Uptake on Cardiopulmonary Exercise Testing).	Baseline to 16 Weeks	VO2 Max will be assessed by completion of an incremental cardio-pulmonary Exercise Stress Test (EST) on an upright leg cycle ergometer

Trial Locations

Locations (3)

City of Hope Medical Center; 🇺🇸 Duarte, California, United States

Children's Hospital of Philadelphia; 🇺🇸 Philadelphia, Pennsylvania, United States

St. Jude Children's Research Hospital; 🇺🇸 Memphis, Tennessee, United States