Friedreich Ataxia 1
Conditions
Brief summary
Randomized, placebo-controlled trial with a 2x2 factorial design testing the effects of an NAD+ precursor (NR) and exercise on Peak VO2 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 (Peak VO2) 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 (Peak VO2 on exercise testing) in FA. Exercise is the most potent known stimulus for increasing muscle mass and mitochondrial oxidative phosphorylation (OXPHOS) capacity, increasing Peak VO2, 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 Peak VO2 in FA. The investigators expect that exercise + NR will also increase Si in this cohort.
Interventions
DIETARY_SUPPLEMENTNicotinamide 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_SUPPLEMENTPlacebo
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).
OTHERExercise 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.
Sponsors
Children's Hospital of Philadelphia
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, 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.
Intervention model description
Randomized, placebo-controlled trial with a 2x2 factorial design testing the effects of an NAD+ precursor (NR) and exercise.
Eligibility
Sex/Gender
ALL
Age
10 Years to 40 Years
Healthy volunteers
No
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. Not currently meeting exercise guidelines as outlined by The Physical Activity Guidelines for Americans. * Children and Adolescents should do 60 minutes (1 hour) or more of moderate-to-vigorous physical activity daily. * As a part of their physical activity, children and adolescents should include muscle-strengthening physical activity on at least 3 days a week. * Adults should do at least 150 minutes (2 hours and 30 minutes) to 300 minutes (5 hours) a week of moderate-intensity, or 75 minutes (1 hour and 15 minutes) to 150 minutes (2 hours and 30 minutes) a week of vigorous-intensity aerobic physical activity. * Adults should also do muscle-strengthening activities of moderate or greater intensity that involve all major muscle groups on 2 or more days a week. 5. Cardiac echocardiogram or cardiac MRI, performed within 1 year of enrollment, showing an LVEF \> 45% 6. ECG, performed within 1 year of enrollment, without clinically significant arrhythmia. 7. Weight \> 24 kg 8. 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. Use of supraphysiologic steroids. 5. Laboratory abnormalities that indicate clinically significant anemia or bleeding risk. (Hemoglobin \< 10 g/dL or Platelets \< 100K) 6. 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) 7. 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) 8. Uncontrolled and persistent arrhythmias that are felt to be clinically significant. 9. Known history of moderate or severe left ventricular systolic dysfunction (Left Ventricular Ejection Fraction (LVEF) \< 45%) 10. Standard contraindications to exercise testing. 11. Inability to sit and pedal unassisted in a cycle ergometry chair, at a cadence of at least 55 rotations per minute (rpm) during unloaded warm up, in a cycle ergometry chair and complete a maximal Cardio Pulmonary Exercise Test (CPET) 12. Inability to sit and pedal unassisted in a recumbent tricycle. 13. 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. * 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Within-Participant Change in Peak V02 (Maximal Oxygen Uptake on Cardiopulmonary Exercise Testing) | Baseline to 12 Weeks | Peak V02 will be assessed by completion of an incremental symptom-limited cardio-pulmonary Exercise Stress Test (EST) on a recumbent leg cycle ergometer. The index is based on the change in peak V02 given in liters per minute (L/min), and a higher value indicates greater oxygen uptake. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Within-Participant Change in Whole Body Insulin Sensitivity (Si) | 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 10 time points for analysis. The unit of measure is based on the change insulin values given in microunits per milliliter (μU/mL) and those of glucose, in milligrams per deciliter, and a higher value indicates greater insulin sensitivity. The whole body insulin sensitivity index (WBISI), also known as the Matsuda index or composite ISI, is dimensionless (unitless). |
Countries
United States
Participant flow
Pre-assignment details
Once consent was obtained, participants were reviewed for eligibility and inclusion in the trial. Individuals meeting criteria were randomized. In total, 75 participants signed informed consent. There was 1 withdrawal of consent prior to in-person screening (ankle injury). 74 completed in-person screening. 8 were considered ineligible after screening due to: not reaching cadence during CPET (7) and not able to complete blood draw (1)
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 19.6 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 55 Participants |
| Region of Enrollment United States | 16 participants |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 17 | 0 / 16 | 0 / 16 |
| other Total, other adverse events | 17 / 17 | 17 / 17 | 16 / 16 | 14 / 16 |
| serious Total, serious adverse events | 0 / 17 | 0 / 17 | 0 / 16 | 0 / 16 |
Outcome results
None listed