Creatine ALS Trial

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Creatine ALS Trial

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Overview

Creatine, a naturally occurring compound found in muscle and brain tissue, was evaluated in a large Phase 3 clinical trial for the treatment of amyotrophic lateral sclerosis (ALS). The rationale was based on the hypothesis that supplementing energy metabolism might protect motor neurons from the energetic dysfunction observed in ALS[@creatine2006].

Creatine is a naturally occurring amino acid derivative that plays a critical role in cellular energy homeostasis. Through its conversion to phosphocreatine, it serves as a rapidly mobilizable reserve of high-energy phosphate groups for the regeneration of ATP. This function is particularly important in tissues with high energy demands, such as skeletal muscle and brain.

Trial Details

NCT Number: NCT00145574 (also associated with sodium phenylbutyrate trial)
Phase: Phase 3
Status: Completed (Results published)
Sponsor: National Institutes of Health (NIH), ALS Association
Drug: Creatine monohydrate
Dosage: 10 grams daily (5g twice daily)
Patient Population: Adults with clinically definite or probable ALS (El Escorial criteria)
Duration: 12 months
Enrollment: 1100 patients (largest ALS trial at the time)

Background and Rationale

Energy Dysfunction in ALS

Multiple lines of evidence support the role of energy dysfunction in ALS:

...

Overview

Creatine, a naturally occurring compound found in muscle and brain tissue, was evaluated in a large Phase 3 clinical trial for the treatment of amyotrophic lateral sclerosis (ALS). The rationale was based on the hypothesis that supplementing energy metabolism might protect motor neurons from the energetic dysfunction observed in ALS[@creatine2006].

Creatine is a naturally occurring amino acid derivative that plays a critical role in cellular energy homeostasis. Through its conversion to phosphocreatine, it serves as a rapidly mobilizable reserve of high-energy phosphate groups for the regeneration of ATP. This function is particularly important in tissues with high energy demands, such as skeletal muscle and brain.

Trial Details

NCT Number: NCT00145574 (also associated with sodium phenylbutyrate trial)
Phase: Phase 3
Status: Completed (Results published)
Sponsor: National Institutes of Health (NIH), ALS Association
Drug: Creatine monohydrate
Dosage: 10 grams daily (5g twice daily)
Patient Population: Adults with clinically definite or probable ALS (El Escorial criteria)
Duration: 12 months
Enrollment: 1100 patients (largest ALS trial at the time)

Background and Rationale

Energy Dysfunction in ALS

Multiple lines of evidence support the role of energy dysfunction in ALS:

Mitochondrial Abnormalities: Reduced Complex I and IV activity in ALS spinal cord
Metabolic Changes: Altered glucose metabolism in ALS patients
Muscle Energy Deficit: Reduced phosphocreatine in ALS muscle
Bioenergetic Crisis: Progressive decline in cellular energy reserves

Creatine as Energy Supplement

Creatine supplementation has been shown to:

Increase muscle phosphocreatine stores
Improve exercise capacity in healthy subjects
Protect against excitotoxicity in vitro
Have neuroprotective effects in animal models

Preclinical Evidence

In the SOD1 G93A mouse model of ALS:

Creatine supplementation improved survival
Enhanced motor performance
Reduced motor neuron loss
Decreased markers of oxidative stress

These preclinical findings provided the rationale for clinical testing in human ALS.

Mechanism of Action

Creatine supports cellular energy through multiple mechanisms:

Energy Metabolism

Phosphocreatine Formation: Creatine combines with ATP to form phosphocreatine via creatine kinase[@creatine]
ATP Regeneration: Facilitates rapid regeneration of ATP from ADP
Cellular Energy Reserve: Acts as an energy buffer during high-demand periods
PCr Shuttle: Transfers energy from mitochondria to cytosol

Neuroprotective Effects

Mitochondrial Function: Supports mitochondrial energy production
Calcium Homeostasis: Helps maintain intracellular calcium homeostasis
Excitotoxicity Reduction: May reduce excitotoxic stress through multiple mechanisms
Osmotic Regulation: May help with cellular volume regulation

Additional Mechanisms

Antioxidant Effects: Some direct and indirect antioxidant properties
Neuronal Survival: Promotes survival under stress conditions
Muscle Function: May improve muscle energy in ALS patients

Trial Design

The Phase 3 trial employed a rigorous, large-scale design:

Design Elements

Randomized, Double-Blind, Placebo-Controlled Design

Treatment Arms: Creatine 10g/day (5g twice daily) vs. placebo

Treatment Duration: 12 months

Background Therapy: Riluzole allowed and continued

Primary Endpoint

ALSFRS-R Slope: Rate of decline in ALSFRS-R score over 12 months
Statistical Power: 90% power to detect 25% slowing of decline

Secondary Endpoints

Survival: Time to death or tracheostomy
Pulmonary Function: Rate of FVC decline
Muscle Strength: Megascore assessment
Quality of Life: ALSAQ-40 questionnaire

Inclusion Criteria

Age 18-85 years
Definite or probable ALS by El Escorial criteria
Disease duration ≤36 months
FVC ≥50% predicted
Not using creatine supplements within 3 months

Results

Key findings from the Phase 3 trial[@creatine2006]:

Primary Endpoint

No Significant Benefit: No significant difference in ALSFRS-R decline rate between treatment and placebo groups
Slope of Decline: Both groups declined at similar rates
Effect Size: Treatment effect <10% (not statistically significant)

Secondary Endpoints

Survival: No significant difference in survival time
Pulmonary Function: No significant difference in FVC decline
Muscle Strength: No significant difference in strength decline
Quality of Life: No significant differences in QoL measures

Safety Profile

Safe and Well-Tolerated: No significant safety concerns
Gastrointestinal: Mild GI symptoms in some patients
Renal Function: No significant changes in renal markers
Weight Gain: Modest weight gain in some participants

Subgroup Analyses

Disease Duration: No differential effect by disease duration
Baseline Function: No differential effect by baseline severity
Site of Onset: No difference between limb and bulbar onset

Clinical Significance

The creatine trial provides important insights for ALS clinical trials:

Energy Metabolism as Target

Validated Pathway: Confirms energy metabolism is a relevant target
Mechanism Validation: Preclinical findings translated to clinical setting
Timing Issue: May need to intervene earlier in disease process

Negative Trial Lessons

Complex Disease: ALS may require combination therapy approaches
Biomarker Need: Highlights need for target engagement biomarkers
Preclinical Limitations: Mouse models may not fully predict human response

Future Directions

Combination Approaches: Rationale for combining energy support with other mechanisms
Biomarker-Guided Trials: Selecting patients with energetic dysfunction
Prevention Trials: Testing in pre-symptomatic genetic carriers

Comparison with Other Energy-Targeting Approaches

| Agent | Mechanism | Trial Outcome |
|-------|-----------|---------------|
| Creatine | Phosphocreatine | Negative (Phase 3) |
| CoQ10 | Mitochondrial function | Negative |
| Idebenone | Mitochondrial antioxidant | Negative |
| Sodium phenylbutyrate | HDAC, stress response | Safety positive |

The consistent failure of metabolic monotherapies suggests that energy dysfunction may be downstream of primary disease mechanisms in ALS.

Pharmacokinetics and Dosing

Absorption and Distribution

Oral Bioavailability: Near complete absorption
Time to Peak: 1-2 hours post-dose
Tissue Distribution: Skeletal muscle, brain, heart
Blood-Brain Barrier: Crosses BBB, reaches CNS

Dosing Considerations

Loading Phase: Not required for efficacy (different from athletic use)
Maintenance: 10g/day appears optimal based on Phase 2 studies
Long-term: No loss of effect over 12 months

External Links

[ClinicalTrials.gov NCT00145574](https://clinicaltrials.gov/study/NCT00145574)
[PubMed PMID:16475019](https://pubmed.ncbi.nlm.nih.gov/16475019/)
[Lancet Creatine ALS Paper](https://pubmed.ncbi.nlm.nih.gov/16475019/)

References

[Shefner et al., Creatine in ALS (2006)](https://pubmed.ncbi.nlm.nih.gov/16475019/)

[Shefner et al., Creatine trial design in ALS (2004)](https://doi.org/10.1016/j.jns.2004.09.014)

[Tarnopolsky et al., Creatine monohydrate in neuromuscular disease (2004)](https://doi.org/10.1177/08830738040190050701)

[Nettblad et al., Creatine in mouse ALS model (2005)](https://doi.org/10.1016/j.nbd.2004.12.015)

Pathway Diagram

The following diagram shows key molecular relationships for Creatine ALS Trial based on knowledge graph edges:

Mermaid diagram (expand to render)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

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[PARP1 Inhibition Therapy](/hypothesis/h-69919c49) — 0.67 · Target: PARP1
[Cryptic Exon Silencing Restoration](/hypothesis/h-4fabd9ce) — 0.66 · Target: TARDBP
[Arginine Methylation Enhancement Therapy](/hypothesis/h-19003961) — 0.65 · Target: PRMT1
[Cross-Seeding Prevention Strategy](/hypothesis/h-eea667a9) — 0.65 · Target: TARDBP
[RNA Granule Nucleation Site Modulation](/hypothesis/h-fffd1a74) — 0.64 · Target: G3BP1
[Axonal RNA Transport Reconstitution](/hypothesis/h-8196b893) — 0.63 · Target: HNRNPA2B1

Related Analyses:

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Pathway Diagram

The following diagram shows the key molecular relationships involving Creatine ALS Trial discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

clinical-trials-creatine-als

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📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

35

Outgoing

231

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

Creatine ALS Trial

Overview

Trial Details

Background and Rationale

Energy Dysfunction in ALS

Overview

Trial Details

Background and Rationale

Energy Dysfunction in ALS

Creatine as Energy Supplement

Preclinical Evidence

Mechanism of Action

Energy Metabolism

Neuroprotective Effects

Additional Mechanisms

Trial Design

Design Elements

Primary Endpoint

Secondary Endpoints

Inclusion Criteria

Results

Primary Endpoint

Secondary Endpoints

Safety Profile

Subgroup Analyses

Clinical Significance

Energy Metabolism as Target

Negative Trial Lessons

Future Directions

Comparison with Other Energy-Targeting Approaches

Pharmacokinetics and Dosing

Absorption and Distribution

Dosing Considerations

See Also

External Links

References

Pathway Diagram

Pathway Diagram

💬 Discussion

📗 Cite This Artifact

Creatine ALS Trial

Overview

Trial Details

Background and Rationale

Energy Dysfunction in ALS

Overview

Trial Details

Background and Rationale

Energy Dysfunction in ALS

Creatine as Energy Supplement

Preclinical Evidence

Mechanism of Action

Energy Metabolism

Neuroprotective Effects

Additional Mechanisms

Trial Design

Design Elements

Primary Endpoint

Secondary Endpoints

Inclusion Criteria

Results

Primary Endpoint

Secondary Endpoints

Safety Profile

Subgroup Analyses

Clinical Significance

Energy Metabolism as Target

Negative Trial Lessons

Future Directions

Comparison with Other Energy-Targeting Approaches

Pharmacokinetics and Dosing

Absorption and Distribution

Dosing Considerations

See Also

External Links

References

Pathway Diagram

Related Hypotheses

Pathway Diagram

💬 Discussion