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.
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.
- 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
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 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
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.
Creatine supports cellular energy through multiple mechanisms:
- 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
- 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
- Antioxidant Effects: Some direct and indirect antioxidant properties
- Neuronal Survival: Promotes survival under stress conditions
- Muscle Function: May improve muscle energy in ALS patients
The Phase 3 trial employed a rigorous, large-scale design:
- 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
- ALSFRS-R Slope: Rate of decline in ALSFRS-R score over 12 months
- Statistical Power: 90% power to detect 25% slowing of decline
- Survival: Time to death or tracheostomy
- Pulmonary Function: Rate of FVC decline
- Muscle Strength: Megascore assessment
- Quality of Life: ALSAQ-40 questionnaire
- 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
Key findings from the Phase 3 trial:
- 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)
- 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
- 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
- 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
The creatine trial provides important insights for ALS clinical trials:
- 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
- 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
- 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
| 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
- 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