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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Lymphoblastic Leukemia, Cancer Survivors, Aplastic Anemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Dietary Supplement: Nicotinamide Riboside
* Dietary Supplement: Placebo
* Other: Exercise Intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females, ages 10-30 years at enrollment Able to understand and speak English Diagnosis of leukemia (myeloid, lymphoid), aplastic anemia, 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. 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 guidelines1 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.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Randomized, placebo-controlled trial with a 2x2 factorial design testing the effects of an NAD+ precursor (NR) and exercise.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nicotinamide Riboside (NR)<br>Investigators will use Good Manufacturing Process (GMP)-grade 300 mg capsules of the dietary supplement nicotinamide riboside (ChromaDex, Irvine CA). Investigators dose based on body weight, and monitor for adverse effects (AEs). For individuals with weight > 72 kg: 900 mg po qd x 16 wks. For individuals with weight > 48 kg and ≤ 72 kg: 600 mg po qd x 16 wks. For individuals with weight 24 ≤ 48 kg: 300 mg po qd x 16 wks. | Dietary Supplement: Nicotinamide Riboside<br>* 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.<br>|
| Placebo Comparator: Placebo<br>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). Doses of placebo will match the body weight schema for dosing of NR. Investigators dose based on body weight, and monitor for adverse effects (AEs). For individuals with weight > 72 kg: 900 mg po qd x 16 wks. For individuals with weight > 48 kg and ≤ 72 kg: 600 mg po qd x 16 wks. For individuals with weight 24 ≤ 48 kg: 300 mg po qd x 16 wks. | Dietary Supplement: Placebo<br>* 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)<br>|
| Experimental: Exercise Intervention and NR<br>The exercise program consists of at-home training sessions including: aerobic and strengthening components designed to progress persons gradually to 150-300 minutes of the equivalent of moderate aerobic activity, and twice weekly strength training exercises. Participants in this arm will receive both the Exercise Intervention and the NR. | Dietary Supplement: Nicotinamide Riboside<br>* 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.<br>Other: Exercise Intervention<br>* 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.<br>|
| Experimental: Exercise Intervention and Placebo<br>The exercise program consists of at-home training sessions including: aerobic and strengthening components designed to progress persons gradually to 150-300 minutes of the equivalent of moderate aerobic activity, and twice weekly strength training exercises. Participants in this arm will receive both the Exercise Intervention and the Placebo | Dietary Supplement: Placebo<br>* 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)<br>Other: Exercise Intervention<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sarcopenia, NAD+, Exercise Intervention, OXPHOS Capacity, VO2 Max, Adolescent young adults, Cancer Survivors, Hematopoietic Stem Cell Transplantation (HCT)