Aplastic Anemia, Cancer Survivors, Lymphoblastic Leukemia, Myelodysplastic Syndromes, Myeloid Leukemia
Conditions
Keywords
Sarcopenia, NAD+, Exercise Intervention, OXPHOS Capacity, VO2 Max, Adolescent young adults, Cancer Survivors, Hematopoietic Stem Cell Transplantation (HCT)
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.
Interventions
DIETARY_SUPPLEMENTNicotinamide 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_SUPPLEMENTPlacebo
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)
OTHERExercise 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 be a load/weight that results in fatigue after 3 sets of 10-12 repetitions on 8-10 exercises 2 days/week.
Sponsors
National Institutes of Health (NIH)
City of Hope Medical Center
St. Jude Children's Research Hospital
National Cancer Institute (NCI)
University of Pennsylvania
Children's Hospital of Philadelphia
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, 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.
Intervention model description
Randomized, placebo-controlled trial with a 2x2 factorial design testing the effects of an NAD+ precursor (NR) and exercise.
Eligibility
Sex/Gender
ALL
Age
10 Years to 30 Years
Healthy volunteers
No
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, bone marrow failure syndrome, 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Contacts
Primary ContactKatherine Cambareri, MPH
Backup ContactKristin Wade
Outcome results
None listed