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NAD+ and Exercise in FA (ExRx in FA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04192136
Recruitment Status : Recruiting
First Posted : December 10, 2019
Last Update Posted : March 16, 2020
Sponsor:
Collaborator:
National Institutes of Health (NIH)
Information provided by (Responsible Party):
Children's Hospital of Philadelphia

Tracking Information
First Submitted Date  ICMJE December 6, 2019
First Posted Date  ICMJE December 10, 2019
Last Update Posted Date March 16, 2020
Actual Study Start Date  ICMJE March 2, 2020
Estimated Primary Completion Date December 31, 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 6, 2019)
Within-Participant Change in V02 Max (Maximal Oxygen Uptake on Cardiopulmonary Exercise Testing) [ Time Frame: Baseline to 12 Weeks ]
V02 Max will be assessed by completion of an incremental symptom-limited cardio-pulmonary Exercise Stress Test (EST) on a recumbent leg cycle ergometer.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 6, 2019)
Within-Participant Change in Whole Body Insulin Sensitivity (Si) [ Time Frame: Baseline to 12 Weeks ]
Whole Body Insulin Sensitivity (Si) will be assessed by completion of a stable isotope tracer-enhanced Oral Glucose Tolerance Test (OGTT). Samples will be collected at 9 time points for analysis.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE NAD+ and Exercise in FA
Official Title  ICMJE NAD+ Precursor Supplementation With Exercise Training to Increase Aerobic Capacity in Friedreich's Ataxia
Brief Summary

Randomized, placebo-controlled trial with a 2x2 factorial design testing the effects of an NAD+ precursor (NR) and exercise on VO2max and Si in Friedreich's Ataxia (FA).

The primary objective of this research is to measure the effect of combination administration (NR + exercise) on aerobic capacity (VO2max) in FA. A key secondary objective is to measure the effect of combination administration (NR + exercise) on glucose homeostasis (Si) in FA.

Detailed Description

Friedreich's Ataxia (FA) is a progressive neurodegenerative disease affecting 1 in 50,000 individuals in the U.S. Currently, there is no approved treatment.

There is a critical knowledge gap regarding the best ways to intervene to increase aerobic capacity (VO2max on exercise testing) in FA. Exercise is the most potent known stimulus for increasing muscle mass and mitochondrial oxidative phosphorylation (OXPHOS) capacity, increasing VO2max, and increasing insulin sensitivity (Si), however, it has not been studied in FA. One adaptation seen in exercised muscles is an increase in muscle nicotinamide adenine dinucleotide (NAD+), a cofactor required for glycolytic and mitochondrial adenosine triphosphate (ATP) production. In skeletal- and cardiac muscle-specific frataxin (FXN) knock-out animals, NAD+ precursors rescued cardiac function to near-normal, additionally highlighting its translational potential in FA. Nicotinamide riboside (NR) is a NAD+ precursor currently available as a dietary supplement (Tru Niagen ®, ChromaDex, Irvine CA) that is expected to be safe and well-tolerated in adults and children. The central hypothesis is that exercise + NR will increase skeletal muscle mitochondrial OXPHOS and increase muscle mass to increase VO2max in FA. The investigators expect that exercise + NR will also increase Si in this cohort.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE 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.
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
Condition  ICMJE Friedreich Ataxia 1
Intervention  ICMJE
  • 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.

  • 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: 3 aerobic sessions per week on the in-home bike trainer, and 2 resistance exercise sessions per week using resistance bands.

    On aerobic training days, subjects will be given instruction on a recumbent Catrike trainer, titrated such that they spend 20 minutes at their target heart rate as determined by baseline Exercise Stress Test (EST) (60-80% of their heart rate at peak VO2) and as measured by their wearable device.

    On resistance training days, subjects will be given instructions to complete circuits of resistance exercises. Resistance training intensity (as determined by graded resistance bands) will be maintained at 60% of pre-training maximal voluntary contraction for each muscle group.

Study Arms  ICMJE
  • 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 12 wks.

    For individuals with weight > 48 kg and ≤ 72 kg: 600 mg po qd x 12 wks.

    For individuals with weight 24 ≤ 48 kg: 300 mg po qd x 12 wks.

    Intervention: Dietary Supplement: Nicotinamide Riboside
  • 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 12 wks.

    For individuals with weight > 48 kg and ≤ 72 kg: 600 mg po qd x 12 wks.

    For individuals with weight 24 ≤ 48 kg: 300 mg po qd x 12 wks.

    Intervention: Dietary Supplement: Placebo
  • Experimental: Exercise Intervention and NR

    The exercise program consists of at-home training sessions: 3 aerobic sessions per week on the in-home bike trainer, and 2 resistance exercise sessions per week using resistance bands. All sessions will begin with stretching and brief aerobic warm-up exercise on the in-home bike trainer. On resistance training days, subjects will be given instructions to complete circuits of resistance exercises.

    Participants in this arm will receive both the Exercise Intervention and the NR.

    Interventions:
    • Dietary Supplement: Nicotinamide Riboside
    • Other: Exercise Intervention
  • Experimental: Exercise Intervention and Placebo

    The exercise program consists of at-home training sessions: 3 aerobic sessions per week on the in-home bike trainer, and 2 resistance exercise sessions per week using resistance bands. All sessions will begin with stretching and brief aerobic warm-up exercise on the in-home bike trainer. On resistance training days, subjects will be given instructions to complete circuits of resistance exercises.

    Participants in this arm will receive both the Exercise Intervention and the Placebo.

    Interventions:
    • Dietary Supplement: Placebo
    • Other: Exercise Intervention
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 6, 2019)
72
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2025
Estimated Primary Completion Date December 31, 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Molecular diagnosis of Friedrich's Ataxia (FA).
  2. Males and Females, Age 10 to 40 years (inclusive).
  3. Girls, 11 years of age and older, 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.
  4. Cardiac echocardiogram or cardiac MRI, performed within 1 year of enrollment, showing an LVEF > 45%
  5. ECG, performed within 1 year of enrollment, without clinically significant arrhythmia.
  6. Parental/guardian permission (informed consent) and if appropriate, child assent.

Exclusion Criteria:

  1. Known sensitivity to NR.
  2. Concurrent use of any medications, including statins, likely to increase risk of NR toxicity.
  3. HgbA1c > 8.5% and/or Diabetes Mellitus (DM) requiring insulin or insulin secretagogue.
  4. Laboratory abnormalities that indicate clinically significant kidney disease using serum creatinine and Modification of Diet in Renal Disease (MDRD) equation. (Estimated Glomerular Filtration Rate (eGFR) < 60 ml/min/1.73 m2)
  5. Laboratory abnormalities that indicate clinically significant liver disease. (Aspartate Aminotransferase (AST)/Serum Glutamic Oxaloacetic Transaminase (SGOT) 3.0 x Upper Limit of Normal and/or Alanine Aminotransferase (ALT)/Serum Glutamic Pyruvic Transaminase (SGPT) 3.0 x Upper Limit of Normal)
  6. Known history of arrhythmia
  7. Known history of moderate or severe left ventricular systolic dysfunction (Left Ventricular Ejection Fraction (LVEF) < 45%)
  8. Standard contraindications to exercise testing
  9. Inability to sit and pedal unassisted in a cycle ergometry chair
  10. Inability to sit and pedal unassisted in a recumbent tricycle
  11. Any contraindication 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.
  12. Use of any investigational agent within 4 weeks of enrollment.
  13. Females: pregnant, lactating, or planning to become pregnant during their participation.
  14. Any medical condition, in the opinion of the investigator that will interfere with the safe completion of the study.
  15. Parents/guardians or participants who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 10 Years to 40 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kristin L Wade, MLitt (267) 426-8724 wadekl@email.chop.edu
Contact: Anna DeDio, MPH (267) 425-1998 dedioa@email.chop.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04192136
Other Study ID Numbers  ICMJE 19-016634
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Children's Hospital of Philadelphia
Study Sponsor  ICMJE Children's Hospital of Philadelphia
Collaborators  ICMJE National Institutes of Health (NIH)
Investigators  ICMJE Not Provided
PRS Account Children's Hospital of Philadelphia
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP