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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether combining Nicotinamide Riboside (NR) with exercise can improve aerobic fitness and blood sugar control in individuals with Friedreich's Ataxia (FA), a rare genetic disorder affecting movement. Participants will receive either the supplement and exercise, just the supplement, just exercise, or a placebo. The trial seeks individuals diagnosed with FA who do not currently meet recommended exercise guidelines. Participants must be able to engage in physical activities like cycling and must not be using medications that could interfere with the trial treatments. As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could enhance the quality of life for those with 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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that nicotinamide riboside (NR) is generally safe for people. Studies have found that NR is well-tolerated at doses similar to those in this trial, with only mild side effects such as stomach upset or slight tiredness. It has received GRAS status, meaning it is "generally regarded as safe."

Regarding the exercise part of the trial, past research on home-based aerobic and resistance training for people with cerebellar ataxias (a condition affecting coordination) found no serious side effects. Participants followed the exercise routines well, and safety was not a concern.

These findings suggest that both NR and the exercise program have been tested in people and are safe. However, as with any treatment, monitoring for any new side effects is important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for ataxia because they explore a novel combination of exercise and a supplement called Nicotinamide Riboside (NR). Unlike traditional treatments that primarily focus on symptom management through medications or physical therapy, NR aims to boost cellular energy by increasing levels of NAD+, a crucial molecule for cell function. The combination of NR with a structured exercise program might enhance both cellular health and physical performance, offering a dual approach that could be more effective than existing options. Additionally, using a dietary supplement like NR is a non-invasive alternative that could potentially have fewer side effects compared to conventional drug therapies.

What evidence suggests that this trial's treatments could be effective for Friedreich's Ataxia?

Research has shown that nicotinamide riboside (NR), a type of vitamin B3, might help with muscle problems and reduce inflammation, common in conditions like Friedreich's Ataxia. Animal studies with similar conditions demonstrated better nerve health with NR treatment. Exercise has also greatly reduced symptoms of ataxia and improved balance and strength. One study found that doing aerobic exercises at home helped people with degenerative ataxia feel better and get fitter. This trial will test the effects of NR alone and in combination with exercise to determine if combining NR with exercise enhances these benefits, potentially helping those with Friedreich's Ataxia by improving fitness and blood sugar control. ^{1 2 3 6 7}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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 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) 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]

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]

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]

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]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11757114/

Effects of physiotherapy on degenerative cerebellar ataxia

The results of this systematic review and meta-analysis demonstrated that physiotherapy significantly reduces ataxia symptoms with no adverse ...

2.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8932090/

Home Aerobic Training for Cerebellar Degenerative ...

The primary outcome was improvement in ataxia as measured by the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes ...

3.

jamanetwork.com

jamanetwork.com/journals/jamaneurology/article-abstract/2838884

Home Training for Cerebellar Ataxias

Conclusions and Relevance In this randomized clinical trial, home high-intensity aerobic training improved ataxia symptoms, fatigue, and aerobic ...

4.

onlinelibrary.wiley.com

onlinelibrary.wiley.com/doi/10.1002/pri.70068

A Randomized Clinical Trial Comparing the Effectiveness ...

The aerobic intervention was found only marginally superior to the circuit training, while both were helpful for improving balance in ataxia.

5.

link.springer.com

link.springer.com/article/10.1007/s12311-019-01063-z

Exercise and Physical Therapy Interventions for Children ...

The effectiveness of exercise and physical therapy for children with ataxia is poorly understood. The aim of this systematic review was to ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC6761087/

Exercise and Physical Therapy Interventions for Children with ...

The effectiveness of exercise and physical therapy for children with ataxia is poorly understood. The aim of this systematic review was to ...

7.

intechopen.com

intechopen.com/chapters/87179

Adapted Physical Activity and Ataxia

This chapter discusses the effects of various training programs on people with ataxia. Exercises that target balance, coordination, and muscular strength ...