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

Primary Purpose

Acute Lymphoblastic Leukemia in Remission, Cancer Survivors, Aplastic Anemia

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Nicotinamide Riboside
Placebo
Exercise Intervention
Sponsored by
Children's Hospital of Philadelphia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Acute Lymphoblastic Leukemia in Remission focused on measuring Sarcopenia, NAD+, Exercise Intervention, OXPHOS Capacity, VO2 Max, Adolescent young adults, Cancer Survivors, Hematopoietic Stem Cell Transplantation (HCT)

Eligibility Criteria

10 Years - 30 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Males and females, ages 10-30 years at enrollment
  2. Able to understand and speak English
  3. Diagnosis of acute leukemia (myeloid, lymphoid) requiring allogeneic HCT
  4. 6-24 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 systemic glucocorticoids within 12 wks
  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%
  10. Kidney disease (eGFR < 60 ml/min/1.73 m2)
  11. Liver disease Alanine aminotransferase/Aspartate aminotransferase(ALT/AST) > 3 x ULN
  12. Limitations in physical function preventing exercise testing/training

  13. 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
  14. Unstable angina or history of acute myocardial infarction (<5 days of planned study procedures)
  15. Recurrent syncope
  16. Symptomatic severe aortic stenosis
  17. Uncontrolled arrhythmia causing symptoms
  18. Pulmonary embolus <3 months of study procedures
  19. Thrombosis of lower extremities
  20. Symptomatic moderate or severe persistent asthma based on forced expiratory volume (FEV) from pre-HCT pulmonary function testing
  21. Room air desaturation at rest ≤85%
  22. Females: Pregnant or planning pregnancy
  23. 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)
  24. Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.

Sites / Locations

  • City of Hope Medical CenterRecruiting
  • Children's Hospital of PhiladelphiaRecruiting
  • St. Jude Children's Research Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Experimental

Arm Label

Nicotinamide Riboside (NR)

Placebo

Exercise Intervention and NR

Exercise Intervention and Placebo

Arm Description

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.

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.

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.

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Within participant change in muscle strength (Ankle Plantarflexion)
Muscle Strength will be assessed by completion of isometric contractions using a Biodex dynamometer.
Within participant change in grip strength (Hand Grip Dynamometry)
Grip Strength will be assessed using a hand grip dynamometry device.
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.
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).
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

Full Information

First Posted
December 9, 2021
Last Updated
September 29, 2023
Sponsor
Children's Hospital of Philadelphia
Collaborators
National Institutes of Health (NIH), City of Hope Medical Center, St. Jude Children's Research Hospital, National Cancer Institute (NCI), University of Pennsylvania
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1. Study Identification

Unique Protocol Identification Number
NCT05194397
Brief Title
Exercise Training and NR Supplementation Trial to Improve Fitness in AYA HCT Survivors
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 21, 2023 (Actual)
Primary Completion Date
June 30, 2026 (Anticipated)
Study Completion Date
June 30, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Hospital of Philadelphia
Collaborators
National Institutes of Health (NIH), City of Hope Medical Center, St. Jude Children's Research Hospital, National Cancer Institute (NCI), University of Pennsylvania

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Lymphoblastic Leukemia in Remission, Cancer Survivors, Aplastic Anemia, Myelodysplastic Syndromes
Keywords
Sarcopenia, NAD+, Exercise Intervention, OXPHOS Capacity, VO2 Max, Adolescent young adults, Cancer Survivors, Hematopoietic Stem Cell Transplantation (HCT)

7. Study Design

Primary Purpose
Other
Study Phase
Phase 2
Interventional Study Model
Factorial Assignment
Model Description
Randomized, placebo-controlled trial with a 2x2 factorial design testing the effects of an NAD+ precursor (NR) and exercise.
Masking
ParticipantCare ProviderInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
80 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Nicotinamide Riboside (NR)
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Arm Title
Exercise Intervention and NR
Arm Type
Experimental
Arm Description
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.
Arm Title
Exercise Intervention and Placebo
Arm Type
Experimental
Arm Description
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
Intervention Type
Dietary Supplement
Intervention Name(s)
Nicotinamide Riboside
Intervention Description
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.
Intervention Type
Dietary Supplement
Intervention Name(s)
Placebo
Intervention Description
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)
Intervention Type
Other
Intervention Name(s)
Exercise Intervention
Intervention Description
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.
Primary Outcome Measure Information:
Title
Within participant changes in muscle strength (Isometric knee extension, Z-score)
Description
Muscle Strength will be assessed by completion of isometric contractions using a Biodex dynamometer.
Time Frame
Baseline to 16 Weeks
Secondary Outcome Measure Information:
Title
Within participant change in muscle strength (Ankle Plantarflexion)
Description
Muscle Strength will be assessed by completion of isometric contractions using a Biodex dynamometer.
Time Frame
Baseline to 16 Weeks
Title
Within participant change in grip strength (Hand Grip Dynamometry)
Description
Grip Strength will be assessed using a hand grip dynamometry device.
Time Frame
Baseline to 16 Weeks
Title
Within participant changes in muscle mass (lower leg lean muscle mass by DXA)
Description
Muscle mass will be assessed by completion of whole body DXA scanning.
Time Frame
Baseline to 16 Weeks
Title
Within participant changes in post-exercise oxidative phosphorylation capacity (OXPHOS).
Description
OXPHOS capacity will be assessed by completion of non-invasive MRI scanning using creatine chemical exchange saturation transfer (CrCEST).
Time Frame
Baseline to 16 Weeks
Title
Within participant change in aerobic capacity (VO2 max, Maximal Oxygen Uptake on Cardiopulmonary Exercise Testing).
Description
VO2 Max will be assessed by completion of an incremental cardio-pulmonary Exercise Stress Test (EST) on an upright leg cycle ergometer
Time Frame
Baseline to 16 Weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
10 Years
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Males and females, ages 10-30 years at enrollment Able to understand and speak English Diagnosis of acute 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Minkeun Song
Phone
267-602-4603
Email
songm2@chop.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Kristin Wade
Phone
2673985761
Email
wadekl@chop.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sogol Mostoufi-Moab, MD, MSCE
Organizational Affiliation
Children's Hospital of Philadelphia
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lanie Lindenfeld, MA, CCRP
Phone
626-218-1150
Email
llindenfeld@coh.org
First Name & Middle Initial & Last Name & Degree
Saro H Armenian, DO, MPH
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Minkeun Song
Phone
267-602-4603
Email
songm2@chop.edu
First Name & Middle Initial & Last Name & Degree
Susan Lee
Phone
267-602-4603
Email
leess@chop.edu
First Name & Middle Initial & Last Name & Degree
Sogol Mostoufi-Moab, MD, MSCE
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sarah Terrell, MS
Phone
901-595-4466
Email
sarah.terrell@stjude.org
First Name & Middle Initial & Last Name & Degree
Kirsten K. Ness, PhD

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
No identifiable data will be used for future study without first obtaining IRB approval. The investigator will obtain a fully executed data use agreement between the provider (the PI) of the data and any recipient researchers [(including others at CHOP) before sharing a limited dataset (or the data will only be provided to users under a fully executed data use (or data sharing) agreement approved by the Children's Hospital of Philadelphia (CHOP) Institutional Review Board (IRB)]. The execution of the agreement will require approval by the Children's Hospital of Philadelphia (CHOP) Institutional Review Board (IRB) or a demonstration of IRB exemption per institutional policy.
IPD Sharing Time Frame
The investigator will make data available after the completion of the trial and posting of results on ClinicalTrials.gov and in conjunction with NIH policies.
IPD Sharing Access Criteria
Access will be limited to only using the data for research purposes that do not identify an individual participant and ensuring the data is securely maintained.
Citations:
PubMed Identifier
35854224
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.
Results Reference
derived

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

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