A clinical trial of creatine in ALS

J. M. Shefner, M. E. Cudkowicz, D. Schoenfeld, T. Conrad, J. Taft, M. Chilton, Leo Urbinelli, M. Qureshi, H. Zhang, A. Pestronk, J. Caress, P. Donofrio, E. Sorenson, W. Bradley, C. Lomen-Hoerth, E. Pioro, K. Rezania, M. Ross, R. Pascuzzi, T. Heiman-Patterson & 6 others R. Tandan, H. Mitsumoto, J. Rothstein, T. Smith-Palmer, D. MacDonald, D. Burke

Research output: Contribution to journalArticle

211 Citations (Scopus)

Abstract

Background: Mitochondrial dysfunction occurs early in the course of ALS, and the mitochondria may be an important site for therapeutic intervention. Creatine stabilizes the mitochondrial transition pore, and is important in mitochondrial ATP production. In a transgenic mouse model of ALS, administration of creatine prolongs survival and preserves motor function and motor neurons. Methods: The authors conducted a randomized double-blind, placebo controlled trial on 104 patients with ALS from 14 sites to evaluate the efficacy of creatine supplementation in ALS. The primary outcome measure was maximum voluntary isometric contraction of eight upper extremity muscles, with secondary outcomes including grip strength, ALS Functional Rating Scale-Revised, and motor unit number estimates. Patients were treated for 6 months, and evaluated monthly. Results: Creatine was tolerated well, but no benefit of creatine could be demonstrated in any outcome measure. CI analysis showed that the study, although powered to detect a 50% or greater change in rate of decline of muscle strength, actually made an effect size of greater than 23% unlikely. It was also demonstrated that motor unit number estimation was performed with acceptable reproducibility and tolerability, and may be a useful outcome measure in future clinical trials. Conclusion: Any beneficial effect of creatine at 5 g per day in ALS must be small. Other agents should be considered in future studies of therapeutic agents to address mitochondrial dysfunction in ALS. In addition, motor unit number estimation may be a useful outcome measure for future clinical trials in ALS.

Original languageEnglish (US)
Pages (from-to)1656-1661
Number of pages6
JournalNeurology
Volume63
Issue number9
DOIs
StatePublished - Nov 9 2004
Externally publishedYes

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Creatine
Clinical Trials
Outcome Assessment (Health Care)
Isometric Contraction
Muscle Strength
Motor Neurons
Hand Strength
Upper Extremity
Transgenic Mice
Mitochondria
Adenosine Triphosphate
Placebos
Muscles
Survival
Therapeutics

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Shefner, J. M., Cudkowicz, M. E., Schoenfeld, D., Conrad, T., Taft, J., Chilton, M., ... Burke, D. (2004). A clinical trial of creatine in ALS. Neurology, 63(9), 1656-1661. https://doi.org/10.1212/01.WNL.0000142992.81995.F0

A clinical trial of creatine in ALS. / Shefner, J. M.; Cudkowicz, M. E.; Schoenfeld, D.; Conrad, T.; Taft, J.; Chilton, M.; Urbinelli, Leo; Qureshi, M.; Zhang, H.; Pestronk, A.; Caress, J.; Donofrio, P.; Sorenson, E.; Bradley, W.; Lomen-Hoerth, C.; Pioro, E.; Rezania, K.; Ross, M.; Pascuzzi, R.; Heiman-Patterson, T.; Tandan, R.; Mitsumoto, H.; Rothstein, J.; Smith-Palmer, T.; MacDonald, D.; Burke, D.

In: Neurology, Vol. 63, No. 9, 09.11.2004, p. 1656-1661.

Research output: Contribution to journalArticle

Shefner, JM, Cudkowicz, ME, Schoenfeld, D, Conrad, T, Taft, J, Chilton, M, Urbinelli, L, Qureshi, M, Zhang, H, Pestronk, A, Caress, J, Donofrio, P, Sorenson, E, Bradley, W, Lomen-Hoerth, C, Pioro, E, Rezania, K, Ross, M, Pascuzzi, R, Heiman-Patterson, T, Tandan, R, Mitsumoto, H, Rothstein, J, Smith-Palmer, T, MacDonald, D & Burke, D 2004, 'A clinical trial of creatine in ALS', Neurology, vol. 63, no. 9, pp. 1656-1661. https://doi.org/10.1212/01.WNL.0000142992.81995.F0
Shefner JM, Cudkowicz ME, Schoenfeld D, Conrad T, Taft J, Chilton M et al. A clinical trial of creatine in ALS. Neurology. 2004 Nov 9;63(9):1656-1661. https://doi.org/10.1212/01.WNL.0000142992.81995.F0
Shefner, J. M. ; Cudkowicz, M. E. ; Schoenfeld, D. ; Conrad, T. ; Taft, J. ; Chilton, M. ; Urbinelli, Leo ; Qureshi, M. ; Zhang, H. ; Pestronk, A. ; Caress, J. ; Donofrio, P. ; Sorenson, E. ; Bradley, W. ; Lomen-Hoerth, C. ; Pioro, E. ; Rezania, K. ; Ross, M. ; Pascuzzi, R. ; Heiman-Patterson, T. ; Tandan, R. ; Mitsumoto, H. ; Rothstein, J. ; Smith-Palmer, T. ; MacDonald, D. ; Burke, D. / A clinical trial of creatine in ALS. In: Neurology. 2004 ; Vol. 63, No. 9. pp. 1656-1661.
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abstract = "Background: Mitochondrial dysfunction occurs early in the course of ALS, and the mitochondria may be an important site for therapeutic intervention. Creatine stabilizes the mitochondrial transition pore, and is important in mitochondrial ATP production. In a transgenic mouse model of ALS, administration of creatine prolongs survival and preserves motor function and motor neurons. Methods: The authors conducted a randomized double-blind, placebo controlled trial on 104 patients with ALS from 14 sites to evaluate the efficacy of creatine supplementation in ALS. The primary outcome measure was maximum voluntary isometric contraction of eight upper extremity muscles, with secondary outcomes including grip strength, ALS Functional Rating Scale-Revised, and motor unit number estimates. Patients were treated for 6 months, and evaluated monthly. Results: Creatine was tolerated well, but no benefit of creatine could be demonstrated in any outcome measure. CI analysis showed that the study, although powered to detect a 50{\%} or greater change in rate of decline of muscle strength, actually made an effect size of greater than 23{\%} unlikely. It was also demonstrated that motor unit number estimation was performed with acceptable reproducibility and tolerability, and may be a useful outcome measure in future clinical trials. Conclusion: Any beneficial effect of creatine at 5 g per day in ALS must be small. Other agents should be considered in future studies of therapeutic agents to address mitochondrial dysfunction in ALS. In addition, motor unit number estimation may be a useful outcome measure for future clinical trials in ALS.",
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AU - Shefner, J. M.

AU - Cudkowicz, M. E.

AU - Schoenfeld, D.

AU - Conrad, T.

AU - Taft, J.

AU - Chilton, M.

AU - Urbinelli, Leo

AU - Qureshi, M.

AU - Zhang, H.

AU - Pestronk, A.

AU - Caress, J.

AU - Donofrio, P.

AU - Sorenson, E.

AU - Bradley, W.

AU - Lomen-Hoerth, C.

AU - Pioro, E.

AU - Rezania, K.

AU - Ross, M.

AU - Pascuzzi, R.

AU - Heiman-Patterson, T.

AU - Tandan, R.

AU - Mitsumoto, H.

AU - Rothstein, J.

AU - Smith-Palmer, T.

AU - MacDonald, D.

AU - Burke, D.

PY - 2004/11/9

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N2 - Background: Mitochondrial dysfunction occurs early in the course of ALS, and the mitochondria may be an important site for therapeutic intervention. Creatine stabilizes the mitochondrial transition pore, and is important in mitochondrial ATP production. In a transgenic mouse model of ALS, administration of creatine prolongs survival and preserves motor function and motor neurons. Methods: The authors conducted a randomized double-blind, placebo controlled trial on 104 patients with ALS from 14 sites to evaluate the efficacy of creatine supplementation in ALS. The primary outcome measure was maximum voluntary isometric contraction of eight upper extremity muscles, with secondary outcomes including grip strength, ALS Functional Rating Scale-Revised, and motor unit number estimates. Patients were treated for 6 months, and evaluated monthly. Results: Creatine was tolerated well, but no benefit of creatine could be demonstrated in any outcome measure. CI analysis showed that the study, although powered to detect a 50% or greater change in rate of decline of muscle strength, actually made an effect size of greater than 23% unlikely. It was also demonstrated that motor unit number estimation was performed with acceptable reproducibility and tolerability, and may be a useful outcome measure in future clinical trials. Conclusion: Any beneficial effect of creatine at 5 g per day in ALS must be small. Other agents should be considered in future studies of therapeutic agents to address mitochondrial dysfunction in ALS. In addition, motor unit number estimation may be a useful outcome measure for future clinical trials in ALS.

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