Vitamin B3 Derivative for Mitochondrial Myopathy

Overseen By Alexandra Miller

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Ralitza Gavrilova

Disqualifiers: Pregnancy, Breastfeeding, Renal failure, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a vitamin B3 derivative called Nicotinamide Riboside to determine its effectiveness for individuals with mitochondrial myopathy, a condition where muscles lack sufficient energy. Participants will receive either the vitamin supplement or a placebo daily for 12 months to monitor changes in symptoms. It suits those with confirmed mitochondrial myopathy who can avoid other vitamin B3 supplements. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must avoid vitamin supplements or products with vitamin B3 forms for 14 days before and during the study.

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

Research has shown that Nicotinamide Riboside (NR), a type of Vitamin B3, is generally safe for people. Studies have found that NR can increase levels of NAD+ in the body, which benefits energy production and cell repair.

In previous studies, participants took NR without experiencing serious side effects. One study tested doses as high as 3000 mg per day with safety checks in place. NR is also considered safe for use in food products in the U.S., further supporting its safety.

Overall, the evidence suggests that NR is well-tolerated by most people. However, safety measures should always be in place, especially when trying a new treatment. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for mitochondrial myopathy?

Unlike the standard treatments for mitochondrial myopathy, which often focus on symptom management and supportive care, Nicotinamide Riboside (NR) is unique because it targets cellular energy production directly. NR is a derivative of Vitamin B3 that acts as a precursor to NAD+ (nicotinamide adenine dinucleotide), a crucial molecule in energy metabolism. Researchers are excited about NR because boosting NAD+ levels may enhance mitochondrial function, potentially offering a novel approach to improving energy levels and muscle strength in patients with mitochondrial myopathy.

What evidence suggests that Nicotinamide Riboside might be an effective treatment for mitochondrial myopathy?

Research has shown that Nicotinamide Riboside (NR), a form of Vitamin B3, may help treat mitochondrial myopathy. Studies have found that NR can enhance mitochondrial function, crucial for cellular energy production. It increases levels of NAD+, a molecule that supports better mitochondrial performance, potentially leading to healthier muscles. Early results also suggest that NR might reduce symptoms related to mitochondrial issues. Additionally, NR may help decrease inflammation, which could benefit various health conditions. In this trial, participants in the Nicotinamide Riboside treatment group will receive NR daily for 12 months to evaluate its effectiveness in treating mitochondrial myopathy. ^{3 5 6 7 8}

Who Is on the Research Team?

Ralitza H. Gavrilova, MD

Principal Investigator

Mayo Clinic

Are You a Good Fit for This Trial?

This trial is for adults with confirmed mitochondrial myopathy who agree to use effective contraception and avoid other vitamin B3 supplements. It's not for pregnant or breastfeeding individuals, those in another drug study, or with conditions that could affect results.

Inclusion Criteria

Agreed to avoid vitamin supplementation or nutritional products with vitamin B3 forms 14 days prior to the enrollment and during the study in order to not exceed 200 mg/day of vitamin B3 derivatives intake

I am a woman who can have children and agree to use birth control during the study.

Written, informed consent to participate in the study

Exclusion Criteria

Concurrent participation in another investigational drug study or within washout period of treatment

Presence of other medical symptoms or condition, which may interfere with interpretation of outcome measures as determined by the study PI

Unwilling to comply with the follow-up schedule

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 daily for 12 months

12 months

Regular visits at baseline, 6 months, and 12 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nicotinamide Riboside
• Placebo

Trial Overview The study tests the effects of Nicotinamide Riboside (NR), a Vitamin B3 derivative, on adult-onset symptoms of mitochondrial myopathy compared to a placebo (a substance with no therapeutic effect).

How Is the Trial Designed?

Group I: Nicotinamide Riboside treatment group Experimental Treatment 1 Intervention

Subjects will receive vitamin B3 derivative Nicotinamide Riboside (NR) daily for 12 months

Group II: Placebo Group Placebo Group 1 Intervention

Subjects will receive a placebo daily for 12 months

Nicotinamide Riboside is already approved in United States, European Union for the following indications:

Approved in United States as Niagen for:

• Dietary supplement for general health and wellness

Approved in European Union as Niagen for:

• Dietary supplement for general health and wellness

Who Is Running the Clinical Trial?

Ralitza Gavrilova

Lead Sponsor

Trials

2

Recruited

40+

Eduardo N. Chini

Lead Sponsor

Trials

1

Recruited

30+

Published Research Related to This Trial

A study on patients with adult-onset mitochondrial myopathy revealed systemic NAD+ deficiency, which was effectively addressed by administering niacin (a form of vitamin B3) at doses of 750-1,000 mg/day for 10 months, resulting in up to an 8-fold increase in blood NAD+ levels.

The treatment not only normalized muscle NAD+ levels but also improved muscle strength, mitochondrial biogenesis, and reduced liver fat by up to 50%, suggesting that niacin is a promising NAD+ booster for managing symptoms of mitochondrial myopathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Niacin Cures Systemic NAD+ Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy. Pirinen, E., Auranen, M., Khan, NA., et al.[2021]

Disruption of NAD+ levels is a significant factor in the development of mitochondrial myopathy, a serious muscle disease in humans.

Administering niacin, a precursor to NAD+, may help restore NAD+ levels and offers a potential treatment strategy for mitochondrial myopathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Of Mice and Men: NAD+ Boosting with Niacin Provides Hope for Mitochondrial Myopathy Patients. Chini, EN.[2023]

In a phase 2 study involving boys aged 4 to 8 with Duchenne muscular dystrophy, edasalonexent was found to be well-tolerated, with mild gastrointestinal side effects and no serious adverse events reported.

The treatment with edasalonexent at 100 mg/kg/day showed promising results in slowing disease progression and preserving muscle function, alongside reductions in NF-κB-regulated gene levels and improvements in muscle health biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Disease-modifying effects of edasalonexent, an NF-κB inhibitor, in young boys with Duchenne muscular dystrophy: Results of the MoveDMD phase 2 and open label extension trial. Finkel, RS., Finanger, E., Vandenborne, K., et al.[2021]

In a Phase 2 study involving 51 ambulant Duchenne muscular dystrophy (DMD) patients, drisapersen at a dose of 6 mg/kg/week showed a potential benefit in improving the 6-minute walking distance (6MWD) compared to placebo, with a mean difference of 27.1 meters at week 24.

Drisapersen was generally well-tolerated, with the most common side effects being injection site reactions and subclinical proteinuria, indicating a manageable safety profile for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo-controlled Phase 2 Trial of Drisapersen for Duchenne Muscular Dystrophy. McDonald, CM., Wong, B., Flanigan, KM., et al.[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]

Nicotinamide riboside (NR) was found to significantly reduce inflammation in mouse liver cells (hepatocytes) by decreasing pro-inflammatory markers and increasing anti-inflammatory molecules, indicating its potential as an anti-inflammatory agent.

NR also enhanced mitochondrial biogenesis in these cells, as evidenced by increased levels of mitochondrial markers, suggesting it may support cellular energy production and health in conditions of stress like fatty liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside regulates inflammation and mitochondrial markers in AML12 hepatocytes. Lee, HJ., Yang, SJ.[2020]

KPT-8602 (eltanexor) has shown promise as an oral treatment for Duchenne muscular dystrophy (DMD) in pre-clinical models, improving muscle integrity and overall outcomes in both zebrafish and mouse models.

The treatment not only enhanced locomotor behavior and muscle histology in D2-mdx mice but also shifted the immune response towards a more anti-inflammatory profile, suggesting it could be a safer alternative to corticosteroids for managing DMD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Next-Generation SINE Compound KPT-8602 Ameliorates Dystrophic Pathology in Zebrafish and Mouse Models of DMD. English, KG., Reid, AL., Samani, A., et al.[2023]

A 24-week study involving 29 patients with various types of muscular dystrophy showed that the flavonoids- and omega-3-based supplement (FLAVOMEGA) was well tolerated with no adverse events reported, indicating its safety as a treatment option.

Significant improvements were observed in muscle function, specifically in the 6-minute walk distance and knee extension strength, particularly in patients with Limb Girdle Muscular Dystrophy and Facioscapulohumeral Muscular Dystrophy, suggesting FLAVOMEGA's potential efficacy as an adjuvant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary Evidences of Safety and Efficacy of Flavonoids- and Omega 3-Based Compound for Muscular Dystrophies Treatment: A Randomized Double-Blind Placebo Controlled Pilot Clinical Trial. Sitzia, C., Meregalli, M., Belicchi, M., et al.[2020]

Skeletal muscle cells primarily use the enzymes NAMPT, NRK1, and NRK2 to synthesize NAD+ from dietary supplements like nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), which are crucial for maintaining muscle health as we age.

Inhibition of NAMPT reduces NAD+ levels in muscle, but this can be restored by NMN and NR, indicating that both supplements are effective in enhancing NAD+ availability through pathways that depend on NRK1 and NRK2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells. Fletcher, RS., Ratajczak, J., Doig, CL., et al.[2022]

A 55-year-old patient with primary myoadenylate deaminase deficiency experienced complete relief from exercise-induced muscle pain and stiffness by taking D-ribose, starting with a dose of 4 grams before exercise.

The patient was able to tolerate total daily doses of 50-60 grams of D-ribose without any side effects, indicating its safety and efficacy for managing symptoms during physical activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myoadenylate deaminase deficiency: successful symptomatic therapy by high dose oral administration of ribose. Zöllner, N., Reiter, S., Gross, M., et al.[2019]

Nicotinamide riboside (NR), a precursor to NAD(+), was found to effectively delay the progression of mitochondrial myopathy in mice by promoting mitochondrial biogenesis and preventing structural abnormalities in mitochondria.

The treatment with NR also stimulated the mitochondrial unfolded protein response, highlighting its potential as a protective strategy against mitochondrial diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. Khan, NA., Auranen, M., Paetau, I., et al.[2021]

In a 12-week randomized, placebo-controlled trial with 40 middle-aged, obese, insulin-resistant men, nicotinamide riboside (NR) supplementation did not significantly affect mitochondrial function, content, or morphology in skeletal muscle.

Despite a 14% decrease in the protein abundance of NAMPT, an enzyme involved in NAD+ biosynthesis, NR supplementation did not change NAD+ levels or the respiratory capacity of muscle mitochondria, suggesting limited efficacy in improving mitochondrial health in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinamide riboside does not alter mitochondrial respiration, content or morphology in skeletal muscle from obese and insulin-resistant men. Dollerup, OL., Chubanava, S., Agerholm, M., et al.[2021]

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]

Citations

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Effective treatment of mitochondrial myopathy by nicotinamide ... These results indicate that NR and strategies boosting NAD + levels are a promising treatment strategy for mitochondrial myopathy.

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Nicotinamide riboside improves muscle mitochondrial ... Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study

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Nicotinamide Riboside and Mitochondrial Biogenesis The aim of this study is to investigate if the same B vitamin, Nicotinamide Riboside, can increase energy production and reduce symptoms in humans with ...

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What is really known about the effects of nicotinamide ... Nicotinamide riboside may play a role in the reduction of inflammatory states and has shown some potential in the treatment of diverse severe diseases.

5. sciencedirect.com sciencedirect.com/science/article/pii/S2211124718307423

The NAD+ Precursor Nicotinamide Riboside Rescues ... We report that increasing NAD+ via the NAD+ precursor nicotinamide riboside (NR) significantly ameliorates mitochondrial function in patient neurons.

6. fda.gov fda.gov/files/food/published/GRAS-Notice-000635--Nicotinamide-riboside-chloride.pdf

GRAS Notice 635: Nicotinamide riboside chloride CORROBORATIVE SAFETY DATA ON NICOTINAMIDE ........... ... Effective treatment of mitochondrial myopathy by nicotinamide riboside, a Vitamin B3 .

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Safety and Metabolism of Long-term Administration of ... NIAGEN is Generally Recognized as Safe (GRAS) in the United States for use in food products and the subject of two new dietary ingredient ...

8. nature.com nature.com/articles/s41467-023-43514-6

NR-SAFE: a randomized, double-blind safety trial of high ... Our results support extending the dose range of NR in phase II clinical trials to 3000 mg per day, with appropriate safety monitoring.