Clinical trial NCT05194397: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Lymphoblastic Leukemia
Cancer Survivors
Aplastic Anemia
Myelodysplastic Syndromes
Myeloid Leukemia
Keywords: Sarcopenia
NAD+
Exercise Intervention
OXPHOS Capacity
VO2 Max
Adolescent young adults
Cancer Survivors
Hematopoietic Stem Cell Transplantation (HCT)
Lead sponsor: Children's Hospital of Philadelphia
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: City of Hope Medical Center
name: St. Jude Children's Research Hospital
name: National Cancer Institute (NCI)
name: University of Pennsylvania
First posted: 2022-01-18
Enrollment: 80
Sex: ALL
Minimum age (years): 10
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: Randomized, placebo-controlled trial with a 2x2 factorial design testing the effects of an NAD+ precursor (NR) and exercise.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Within participant changes in muscle strength (Isometric knee extension, Z-score)
timeFrame: Baseline to 16 Weeks
Secondary outcomes:
measure: Within participant change in muscle strength (Ankle Plantarflexion)
timeFrame: Baseline to 16 Weeks
measure: Within participant change in grip strength (Hand Grip Dynamometry)
timeFrame: Baseline to 16 Weeks
measure: Within participant changes in muscle mass (lower leg lean muscle mass by DXA)
timeFrame: Baseline to 16 Weeks
measure: Within participant changes in post-exercise oxidative phosphorylation capacity (OXPHOS).
timeFrame: Baseline to 16 Weeks
measure: Within participant change in aerobic capacity (VO2 max, Maximal Oxygen Uptake on Cardiopulmonary Exercise Testing).
timeFrame: Baseline to 16 Weeks
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope Medical Center
state: California
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
Study officials:
affiliation: Children's Hospital of Philadelphia
name: Sogol Mostoufi-Moab, MD, MSCE
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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/s12885-022-09845-1.