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

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia in Remission Cancer Survivors	Dietary Supplement: Nicotinamide Riboside Dietary Supplement: Placebo Other: Exercise Intervention	Phase 2

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 Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Intervention Model Description:

Randomized, placebo-controlled trial with a 2x2 factorial design testing the effects of an NAD+ precursor (NR) and exercise.Randomized, placebo-controlled trial with a 2x2 factorial design testing the effects of an NAD+ precursor (NR) and exercise.

Masking:

Quadruple (Participant, Care Provider, 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.

Primary Purpose:

Other

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

Anticipated Study Start Date :

Jun 30, 2022

Anticipated Primary Completion Date :

Jun 30, 2026

Anticipated Study Completion Date :

Jun 30, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nicotinamide Riboside (NR) 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 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 Comparator: Placebo 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 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)
Experimental: Exercise Intervention and NR 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 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. 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.
Experimental: Exercise Intervention and Placebo 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 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.

Outcome Measures

Primary Outcome Measures

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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years to 30 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Males and females, ages 15-30 years at enrollment
Able to understand and speak English
Diagnosis of acute leukemia (myeloid, lymphoid) requiring allogeneic HCT
6-24 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

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 systemic glucocorticoids within 12 wks
Currently meeting public health exercise guidelines
Use of NAD+ precursors (supra-physiologic) within 4 weeks
Hemoglobin < 10 g/dL
Platelets < 50K
Diabetes Mellitus requiring insulin or insulin secretagogue
HbA1C ≥ 8%
Kidney disease (eGFR < 60 ml/min/1.73 m2)
Liver disease Alanine aminotransferase/Aspartate aminotransferase(ALT/AST) > 3 x ULN
Limitations in physical function preventing exercise testing/training
Contraindications to MRI. Including:

ANY intra-luminal implant, filter, stent or valve replacement
ANY type of life assist device, pump, or prosthetic
ANY vascular clip or clamp
ANY surgically placed clips or clamps or bands on visceral organs
ANY intracranial implants of any type other than dental fillings
ANY non-removable piercings, jewelry, or medicinal patch
ANY personal history of intraocular injury or fragment in or around the orbit that cannot be cleared through radiologic examination.
ANY personal history of bullet, shrapnel, or stabbing wounds that cannot be cleared through radiologic evaluation.
Inability to lie flat in the MRI scanner for 60-90 minutes

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.