Creatine Supplementation for Homocystinuria

Overseen By Kendall Plant, BSc

Age: 18 - 65

Sex: Male

Trial Phase: Academic

Sponsor: University of British Columbia

Disqualifiers: Metabolic, Neurological, Genetic, Immune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: 2

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if creatine supplements can reduce homocysteine levels, which are harmful in individuals with homocystinuria, a rare metabolic disorder. Initially, the study will test healthy adult men to observe how creatine affects methionine breakdown, a protein building block. Participants will follow a low-protein diet and then add creatine supplements to assess the impact on homocysteine levels. Men who are healthy, of normal weight, and not following unusual diets qualify for this trial. As an unphased trial, this study allows participants to contribute to groundbreaking research that could lead to new treatments for metabolic disorders.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you must be in good health and free of any concurrent illnesses to participate.

Is there any evidence suggesting that creatine supplementation is likely to be safe for humans?

Research has shown that creatine is generally safe for people. Studies have found that creatine monohydrate, a common type of creatine, is well-tolerated and usually doesn't cause problems when used short-term. The FDA considers creatine monohydrate "Generally Recognized As Safe" (GRAS) for its intended uses, meaning it is safe under normal conditions.

Most people do not experience serious side effects. However, consulting a doctor before trying new supplements is always advisable, especially for those with health issues or taking other medications. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Most treatments for homocystinuria focus on managing the condition with vitamin B6, vitamin B12, folic acid, and sometimes betaine to help lower homocysteine levels. However, creatine supplementation is unique because it introduces a new approach by potentially supporting energy metabolism and neurotransmitter function, which could benefit patients beyond just lowering homocysteine. Researchers are excited about this treatment because creatine is a well-known supplement with a strong safety profile, and it may offer a novel way to address the symptoms of homocystinuria by enhancing cellular energy, providing a complementary benefit to existing treatments.

What evidence suggests that creatine supplementation might be an effective treatment for homocystinuria?

Research has shown that creatine might lower homocysteine levels in the blood. One study found that creatine reduced homocysteine, which is beneficial because high levels can harm the heart, brain, and bones. While some studies have observed this effect in animals, research in humans continues. This trial will compare creatine supplementation with no supplementation to evaluate its effects on homocysteine levels in participants with homocystinuria. Current thinking suggests that creatine might help by providing the body with an alternative way to process certain amino acids, like methionine and homocysteine. This could make creatine a promising option for people with homocystinuria, a condition where the body struggles to process these amino acids. ^{2 6 7 8 9}

Who Is on the Research Team?

Rajavel Elango, PhD

Principal Investigator

University of British Columbia

Are You a Good Fit for This Trial?

This trial is for healthy adult men who can follow a low-protein diet and are interested in participating in a study that investigates the effects of creatine supplementation on homocysteine levels. Participants will need to commit to two 8-hour study days, adhere to dietary requirements, and provide various samples.

Inclusion Criteria

Not claustrophobic (a clear hood will be placed over your head for approximately 20 min to measure energy expenditure)

Not enrolled in any other research studies

I am a cisgender male.

Exclusion Criteria

Smokers

I have taken creatine supplements recently or am currently taking them.

Following a non-traditional dietary pattern (e.g. Keto diet, Atkins diet, paleo diet, intermittent fasting, strict vegan, calorie-restricted diet etc.)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline

Participants follow a controlled diet of 1g protein/kg body weight/day for 7 days before the baseline study day

1 week

1 visit (8-hour study day)

Treatment

Participants follow a controlled diet of 1g protein/kg body weight/day and take 20g creatine supplement for 7 days before the treatment study day

1 week

1 visit (8-hour study day)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Creatine

Trial Overview

The study tests if creatine supplements can lower homocysteine production by monitoring changes in digestion of methionine (using an isotope) and measuring blood levels of homocysteine, methionine, and related metabolites after taking creatine.

How Is the Trial Designed?

Group I: Treatment - Creatine Supplementation 20mg Experimental Treatment 2 Interventions

Each participant will complete a supplemented study day. For 7 days prior to the study day each participant will eat a controlled diet of 1g protein/kg body weight/day, and the provided 20mg creatine supplement.

Group II: Baseline - no creatine supplementation Experimental Treatment 1 Intervention

Each participant will complete a baseline study day. For 7 days prior to the study day each participant will eat a controlled diet of 1g protein/kg body weight/day.

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

Approved in United States as Creatine Monohydrate for:

• Dietary supplement for muscle growth and performance
• Potential treatment for post-concussive symptoms

Approved in European Union as Creatine Monohydrate for:

• Dietary supplement for muscle growth and performance
• Potential treatment for post-concussive symptoms

Who Is Running the Clinical Trial?

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

Published Research Related to This Trial

In a study involving 36 resistance-trained individuals, traditional creatine monohydrate (CrM) supplementation was found to be more effective than buffered creatine (KA) in increasing muscle creatine content and improving strength, with no significant differences in side effects reported between the two forms.

The results showed that neither the recommended lower dose of KA nor the higher equivalent loading dose provided any additional benefits over CrM, challenging claims that buffered creatine is superior in efficacy or safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A buffered form of creatine does not promote greater changes in muscle creatine content, body composition, or training adaptations than creatine monohydrate. Jagim, AR., Oliver, JM., Sanchez, A., et al.[2021]

There are potential risks associated with uncontrolled supplementation of pure creatine monohydrate (Cr.H2O) in athletes, as the body has a natural feedback mechanism that regulates creatine production.

The article suggests that instead of pure Cr.H2O, a complex nutritional supplement using natural alpha-ketoglutarate could be a safer and more effective alternative for delivering creatine and other beneficial compounds.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Scientific facts behind creatine monohydrate as sport nutrition supplement. Silber, ML.[2017]

The novel creatine blend CN-CRN significantly increased serum creatine levels more than both pure creatine nitrate and regular creatine monohydrate in a study of 10 healthy young men, indicating superior bioavailability.

After 5 days of supplementation, CN-CRN also led to a greater increase in muscle creatine levels compared to the other formulations, while showing no clinically relevant side effects, suggesting it is a safe and effective alternative to traditional creatine supplements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Searching for a better formulation to enhance muscle bioenergetics: A randomized controlled trial of creatine nitrate plus creatinine vs. creatine nitrate vs. creatine monohydrate in healthy men. Ostojic, SM., Stajer, V., Vranes, M., et al.[2023]

A one-month creatine supplementation (5 g/day) significantly reduced plasma homocysteine levels in a subject with the MTHFR 677TT genotype, suggesting a potential therapeutic effect of creatine on methylation processes.

Creatine supplementation may enhance the body's ability to produce sarcosine, which could improve the activity of the MTHFR enzyme, potentially benefiting individuals with reduced enzyme activity due to genetic polymorphisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of the MTHFR 677C/T polymorphism on homocysteinemia in response to creatine supplementation: a case study. Petr, M., Steffl, M., Kohlíková, E.[2020]

Creatine nitrate (CrN) supplementation at 3 g was well-tolerated and showed no safety concerns, with minimal side effects reported across all treatment groups in a study involving 48 participants over 28 days.

In terms of exercise performance, the CrN-High group significantly increased bench press lifting volume compared to the placebo group, demonstrating that CrN can provide similar performance benefits to traditional creatine monohydrate (CrM).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute and chronic safety and efficacy of dose dependent creatine nitrate supplementation and exercise performance. Galvan, E., Walker, DK., Simbo, SY., et al.[2018]

In a pilot study with 81 patients and a follow-up study with 21 patients, creatine monohydrate supplementation significantly increased strength measures, including handgrip and knee extensor strength.

The treatment involved administering 10 g daily for 5 days, followed by 5 g daily for another 5 days, demonstrating that short-term creatine use can effectively enhance high-intensity strength in individuals with neuromuscular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Creatine monohydrate increases strength in patients with neuromuscular disease. Tarnopolsky, M., Martin, J.[2019]

Creatine supplementation significantly increases creatine levels in vegetarians, often surpassing those found in omnivores, and enhances muscle mass, strength, and endurance, making it beneficial for vegetarian athletes.

While creatine improved various physical and cognitive performance metrics in vegetarians, the evidence on whether it enhances exercise performance more than in omnivores remains mixed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefits of Creatine Supplementation for Vegetarians Compared to Omnivorous Athletes: A Systematic Review. Kaviani, M., Shaw, K., Chilibeck, PD.[2020]

Creatine nitrate (CN) supplementation at doses of 1 g and 2 g daily for 28 days was found to be safe for young adults, with no significant adverse effects on most blood safety markers.

While some participants experienced slight increases in blood urea nitrogen (BUN) levels, these changes were minor and not clinically concerning, suggesting that CN could be a viable alternative to traditional creatine monohydrate supplements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

28 days of creatine nitrate supplementation is apparently safe in healthy individuals. Joy, JM., Lowery, RP., Falcone, PH., et al.[2018]

Creatine monohydrate is generally considered safe for healthy adults at a daily intake of 3 grams, with some minor side effects like gastrointestinal issues and muscle cramps reported.

While most creatine forms are unlikely to pose safety concerns, there are specific safety concerns associated with creatine orotate, creatine phosphate, and magnesium creatine chelate, indicating that not all creatine supplements are equally safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Creatine and creatine forms intended for sports nutrition. Andres, S., Ziegenhagen, R., Trefflich, I., et al.[2018]

Creatine monohydrate (CrM) remains the only form of creatine with substantial evidence supporting its bioavailability, efficacy, and safety, as confirmed by a review of various marketed creatine forms.

Despite ongoing claims about other 'novel forms' of creatine, many lack sufficient evidence for effectiveness and safety, and CrM is still the recommended source by professional organizations and regulatory authorities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review. Kreider, RB., Jäger, R., Purpura, M.[2022]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12445187/

Effects of six weeks of high-dose creatine monohydrate ...

Results. Analysis of blood data revealed significant group ×time interaction effects in creatinine (p = 0.041) and HbA1c (p = 0.011) while homocysteine levels ...

2.

withpower.com

withpower.com/trial/phase-homocystinuria-7-2024-b325c

Creatine Supplementation for Homocystinuria

In a study involving 36 resistance-trained individuals, traditional creatine monohydrate (CrM) supplementation was found to be more effective than buffered ...

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06495567?cond=Homocystinuria&aggFilters=status:not%20rec%20enr%20act&viewType=Table&rank=1

Study Details | NCT06495567 | Proof of Concept Creatine ...

We would ultimately like to see if creatine supplements are a potential alternate treatment of Homocystinuria in this proof of concept study, before studying ...

4.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/30506745/

Effects of dietary supplementation with creatine on ...

Creatine supplementation (CrS) reduces plasma homocysteine levels and enhances vascular reactivity in the microcirculation.

5.

sciencedirect.com

sciencedirect.com/science/article/pii/S2352385915300220

Creatine supplementation decreased homocysteine ...

Our data demonstrated Cr supplementation is effective in decrease Hcy blood concentration in rats; the same effect however, is not demonstrated humans studies.

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8912867/

Bioavailability, Efficacy, Safety, and Regulatory Status of ...

As will be seen, CrM continues to be the only source of creatine that has substantial evidence to support bioavailability, efficacy, and safety.

7.

fda.gov

fda.gov/media/143525/download

GRAS Notice No GRN 931; Creatine Monohydrate

• Relevant safety data on creatine monohydrate;. • Reviewers' evaluation and conclusion that creatine monohydrate is GRAS for its intended uses.

8.

jissn.biomedcentral.com

jissn.biomedcentral.com/articles/10.1186/s12970-017-0173-z

safety and efficacy of creatine supplementation in exercise ...

The breadth and repetition of these findings provide compelling evidence that creatine monohydrate is well-tolerated and is safe to consume in ...

9.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7353222/

Risk of Adverse Outcomes in Females Taking Oral ...

In females, CrM does not appear to cause weight gain, nor adversely impact other major organ systems. Our findings support those of previous safety reviews ...