NAD+ Precursor (NR) + Exercise for Ataxia

(ExRx in FA Trial)

Overseen By Anna DeDio, MPH

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Children's Hospital of Philadelphia

Must not be taking: Statins, Supraphysiologic steroids

Disqualifiers: Diabetes, Anemia, Kidney disease, others

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

80 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Do I need to stop my current medications for the trial?

Yes, you may need to stop certain medications. The trial excludes participants using medications, including statins, that could increase the risk of NR toxicity. If you're on such medications, you might need to stop them to participate.

Will I have to stop taking my current medications?

The trial requires that you do not take any medications, including statins, that might increase the risk of NR toxicity. If you are on such medications, you may need to stop them to participate.

What data supports the idea that NAD+ Precursor (NR) + Exercise for Ataxia is an effective treatment?

The available research does not provide specific data on the effectiveness of NAD+ Precursor (NR) combined with exercise for treating Ataxia. Instead, the studies focus on exercise interventions for cancer patients, showing that exercise can improve quality of life and reduce fatigue in those undergoing cancer treatments. While these findings highlight the benefits of exercise in other conditions, they do not directly support the effectiveness of NAD+ Precursor (NR) combined with exercise for Ataxia. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment involving exercise and NAD+ precursor (NR) for ataxia?

Research shows that exercise can improve quality of life and reduce fatigue in cancer patients, suggesting it may help with physical function in other conditions like ataxia. While specific data on NAD+ precursor (NR) for ataxia is not available, exercise has been beneficial in other health contexts. ^{1 2 3 4 5}

What safety data exists for the treatment of NAD+ precursor (NR) and exercise for ataxia?

Nicotinamide riboside (NR) has been tested in humans and is considered safe. A clinical trial involving healthy overweight adults showed that NR significantly increased NAD+ levels without causing significant adverse events compared to placebo. No flushing or negative effects on cholesterol or metabolism were reported. NR is generally recognized as safe (GRAS) for use in foods and supplements. These findings support the development of a tolerable upper intake limit for NR based on human data. ^{6 7 8 9 10}

Is Nicotinamide Riboside (NR) safe for human use?

Nicotinamide Riboside (NR) has been tested in humans and is considered safe, with no significant differences in adverse events compared to a placebo in clinical trials. It is generally recognized as safe for use in foods and dietary supplements, and no serious side effects have been reported in studies. ^{6 7 8 9 10}

Is the treatment with exercise and the drug nicotinamide riboside (NR) promising for ataxia?

Yes, combining exercise with the drug nicotinamide riboside (NR) is promising because NR can boost energy levels and improve muscle and heart function, which may help with conditions like ataxia. ^{6 7 8 9 11}

How does the treatment of Nicotinamide Riboside (NR) and exercise differ from other treatments for ataxia?

This treatment combines Nicotinamide Riboside (NR), a vitamin B3 derivative that boosts energy metabolism, with exercise to potentially improve physical performance and cellular function, which is unique compared to other treatments that may not address energy metabolism directly. ^{6 7 8 9 11}

Eligibility Criteria

This trial is for individuals aged 10-40 with a confirmed diagnosis of Friedreich's Ataxia, weighing over 24 kg, and not currently meeting recommended exercise guidelines. Participants must be able to perform physical activities and use contraception if applicable. Exclusions include sensitivity to NR, certain medication use, pregnancy, severe heart or kidney conditions, uncontrolled arrhythmias, inability to perform required exercises or MRI procedures.

Inclusion Criteria

Kids and teens should do activities that strengthen their muscles at least 3 days a week as part of their physical activity routine.

I am a girl aged 11 or older, not pregnant, and will use birth control during the study.

I am between 10 and 40 years old.

Exclusion Criteria

You have a medical condition that makes it unsafe for you to have an MRI scan.

You are allergic to NR.

Your liver function tests show significant abnormalities.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Nicotinamide Riboside (NR) or placebo, combined with an exercise intervention, for 12 weeks

12 weeks

Weekly at-home sessions

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Exercise Intervention
• Nicotinamide Riboside
• Placebo

Trial Overview The study tests the effects of Nicotinamide Riboside (NR), an NAD+ precursor supplement combined with an exercise regimen on aerobic capacity (VO2max) and glucose homeostasis in patients with Friedreich's Ataxia. It uses a randomized placebo-controlled design where participants are assigned by chance to receive either NR or a placebo while following an exercise program.

Participant Groups

Group I: Nicotinamide Riboside (NR) Experimental Treatment 1 Intervention

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.

Group II: Exercise Intervention and Placebo Experimental Treatment 2 Interventions

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.

Group III: Exercise Intervention and NR Experimental Treatment 2 Interventions

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.

Group IV: Placebo Placebo Group 1 Intervention

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.

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

Exercise interventions during and after cancer treatment, particularly resistance training, show promising physiological and psychological benefits, as highlighted in a review of 26 studies, mostly involving breast cancer patients.

Despite the positive outcomes, many studies lack robust designs, such as randomized controlled trials, and often have small sample sizes, indicating a need for more comprehensive research across various cancer types to better understand the dose-response effects of exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of exercise intervention studies in cancer patients. Galvão, DA., Newton, RU.[2022]

The NEXTAC program is a newly developed multimodal intervention that combines nutrition and exercise therapy specifically designed for older patients with advanced cancer at high risk of cachexia.

This program aims to address the lack of evidence and standardization in exercise therapy for cancer cachexia, highlighting the importance of a comprehensive approach that includes both nutritional support and physical activity from the start of chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Exercise Therapy for Cancer Cachexia]. Tatematsu, N.[2022]

In a study involving 14 cancer patients undergoing treatment, a 4-week NMES (neuromuscular electrical stimulation) exercise intervention significantly improved functional muscle strength and exercise capacity, with participants able to perform more sit-to-stand repetitions and walk further in 6 minutes.

No adverse events were reported during the intervention, suggesting that NMES exercise is a safe and effective option for enhancing physical function in cancer patients with moderate to poor functional status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional, physiological and subjective responses to concurrent neuromuscular electrical stimulation (NMES) exercise in adult cancer survivors: a controlled prospective study. O'Connor, D., Lennon, O., Fernandez, MM., et al.[2021]

Exercise significantly improves muscle strength, exercise tolerance, and helps manage body fat and sexual function in prostate cancer patients undergoing androgen deprivation therapy (ADT), based on a meta-analysis of 15 studies with 1135 participants.

No significant differences were found between aerobic and resistance exercise in alleviating ADT-related obesity, fatigue, or exercise tolerance, and exercise duration was linked to reduced fatigue levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exercise overcome adverse effects among prostate cancer patients receiving androgen deprivation therapy: An update meta-analysis. Yunfeng, G., Weiyang, H., Xueyang, H., et al.[2021]

A study involving 163 prostate cancer patients on androgen deprivation therapy showed that different exercise modes, including impact loading plus resistance training (ILRT) and aerobic plus resistance training (ART), significantly reduced fatigue and improved vitality over 12 months.

All exercise programs were effective, with the most significant benefits observed in patients who started with the highest levels of fatigue and lowest vitality, indicating that exercise is beneficial for managing fatigue during ADT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Different Exercise Modalities on Fatigue in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: A Year-long Randomised Controlled Trial. Taaffe, DR., Newton, RU., Spry, N., et al.[2022]

Nicotinamide riboside (NR), a precursor to NAD+, may help improve energy metabolism and cellular function, which could enhance the effectiveness of exercise in older adults who often experience lower NAD+ levels due to aging.

While NR supplementation is considered safe and has shown promise in preclinical studies, its specific effects on physical performance in older humans remain unclear, highlighting the need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside-A missing piece in the puzzle of exercise therapy for older adults? Custodero, C., Saini, SK., Shin, MJ., et al.[2021]

Nicotinamide riboside (NR) supplementation alone did not enhance aerobic performance in sedentary or trained mice, but it did increase NAD+ levels in skeletal muscle after 5 weeks.

When combined with aerobic training, NR supplementation significantly improved aerobic performance and increased the content of key mitochondrial proteins, suggesting it may enhance mitochondrial metabolism and capacity for exercise.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NAD+ precursor increases aerobic performance in mice. Crisol, BM., Veiga, CB., Braga, RR., et al.[2021]

Nicotinamide riboside (NR) supplementation significantly increased NAD+ levels in muscle tissue and improved physical performance in middle-aged mice, enhancing endurance and preventing grip strength decline after 4 weeks of treatment.

NR also positively affected muscle stem cells, boosting their energy production and improving their ability to differentiate into larger, functional muscle fibers, suggesting potential benefits for maintaining muscle health during aging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short-term nicotinamide riboside treatment improves muscle quality and function in mice and increases cellular energetics and differentiating capacity of myogenic progenitors. Seldeen, KL., Shahini, A., Thiyagarajan, R., et al.[2022]

Nicotinamide riboside (NR) is a promising NAD+ precursor that has shown potential health benefits in treating various conditions, including cardiovascular, neurodegenerative, and metabolic disorders, based on numerous animal and human studies.

Research indicates that NR may also have therapeutic applications against infections, such as SARS-CoV-2, but challenges related to its bioavailability and safety need to be addressed for effective translation into clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide Riboside-The Current State of Research and Therapeutic Uses. Mehmel, M., Jovanović, N., Spitz, U.[2021]

In an 8-week clinical trial with overweight but healthy participants, nicotinamide riboside (NR) significantly increased whole blood NAD+ levels in a dose-dependent manner, with increases of 22%, 51%, and 142% for doses of 100, 300, and 1000 mg, respectively.

The study found NR to be safe, with no significant adverse effects reported compared to placebo, and it did not negatively impact cholesterol levels or 1-carbon metabolism, supporting its potential as a dietary supplement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Conze, D., Brenner, C., Kruger, CL.[2023]

In a study involving 18 Wistar rats, chronic administration of nicotinamide riboside, an NAD(+) precursor, did not improve exercise performance and showed a tendency towards worse performance compared to the control group.

The results suggest that instead of enhancing physical performance, nicotinamide riboside may have a negative impact, potentially due to its complex effects on metabolism and cellular redox states.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The NAD(+) precursor nicotinamide riboside decreases exercise performance in rats. Kourtzidis, IA., Stoupas, AT., Gioris, IS., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Review of exercise intervention studies in cancer patients. [2022]

2. Japan pubmed.ncbi.nlm.nih.gov

[Exercise Therapy for Cancer Cachexia]. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Functional, physiological and subjective responses to concurrent neuromuscular electrical stimulation (NMES) exercise in adult cancer survivors: a controlled prospective study. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Exercise overcome adverse effects among prostate cancer patients receiving androgen deprivation therapy: An update meta-analysis. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Effects of Different Exercise Modalities on Fatigue in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy: A Year-long Randomised Controlled Trial. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside-A missing piece in the puzzle of exercise therapy for older adults? [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

NAD+ precursor increases aerobic performance in mice. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Short-term nicotinamide riboside treatment improves muscle quality and function in mice and increases cellular energetics and differentiating capacity of myogenic progenitors. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Nicotinamide Riboside-The Current State of Research and Therapeutic Uses. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

The NAD(+) precursor nicotinamide riboside decreases exercise performance in rats. [2021]