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

Myelodysplastic Syndromes Clinical Trial

— IAMFIT  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05194397
• Other study ID #: 20-017320
• Secondary ID: 1R01CA254955-01A
• Status: Recruiting
• Phase: Phase 2
• Start date: March 21, 2023
• Est. completion date: June 30, 2026

Study information

• Verified date: November 2023
• Source: Children's Hospital of Philadelphia
• Contact: Minkeun Song
• Phone: 267-602-4603
• Email: songm2[@]chop.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: June 30, 2026
• Est. primary completion date: June 30, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Years to 30 Years

Eligibility

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. 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 guidelines1

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.

Related Conditions & MeSH terms

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

Intervention

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.
• 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 be a load/weight that results in fatigue after 3 sets of 10-12 repetitions on 8-10 exercises 2 days/week.

Locations

Country	Name	City	State
United States	City of Hope Medical Center	Duarte	California
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania

Sponsors (6)

Lead Sponsor	Collaborator
Children's Hospital of Philadelphia	City of Hope Medical Center, National Cancer Institute (NCI), National Institutes of Health (NIH), St. Jude Children's Research Hospital, University of Pennsylvania

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Within participant change in grip strength (Hand Grip Dynamometry)	Grip Strength will be assessed using a hand grip dynamometry device.	Baseline to 16 Weeks
Secondary	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
Secondary	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
Secondary	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