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Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III.
Ann Neurol. 2009 Aug; 66(2):235-44.AN

Abstract

OBJECTIVE

Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial.

METHODS

We designed and implemented a multicenter trial with an adaptive, two-stage, bias-adjusted, randomized, placebo-controlled, double-blind, Phase II design (n = 185). The primary outcome in both stages was a decline in the ALS Functional Rating Scale-revised (ALSFRSr) score over 9 months. Stage 1 (dose selection, 35 participants per group) compared CoQ10 doses of 1,800 and 2,700 mg/day. Stage 2 (futility test, 75 patients per group) compared the dose selected in Stage 1 against placebo.

RESULTS

Stage 1 selected the 2,700 mg dose. In Stage 2, the pre-specified primary null hypothesis that this dose is superior to placebo was not rejected. It was rejected, however, in an accompanying prespecified sensitivity test, and further supplementary analyses. Prespecified secondary analyses showed no significant differences between CoQ10 at 2,700 mg/day and placebo. There were no safety concerns.

INTERPRETATION

CoQ10 at 2,700 mg daily for 9 months shows insufficient promise to warrant Phase III testing. Given this outcome, the adaptive Phase II design incorporating a dose selection and a futility test avoided the need for a much larger conventional Phase III trial.

Authors+Show Affiliations

Department of Neurology, Clinical Coordinating Center, Columbia University, New York, NY 10032, USA. pk88@columbia.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

19743457

Citation

Kaufmann, Petra, et al. "Phase II Trial of CoQ10 for ALS Finds Insufficient Evidence to Justify Phase III." Annals of Neurology, vol. 66, no. 2, 2009, pp. 235-44.
Kaufmann P, Thompson JL, Levy G, et al. Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III. Ann Neurol. 2009;66(2):235-44.
Kaufmann, P., Thompson, J. L., Levy, G., Buchsbaum, R., Shefner, J., Krivickas, L. S., Katz, J., Rollins, Y., Barohn, R. J., Jackson, C. E., Tiryaki, E., Lomen-Hoerth, C., Armon, C., Tandan, R., Rudnicki, S. A., Rezania, K., Sufit, R., Pestronk, A., Novella, S. P., ... Levin, B. (2009). Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III. Annals of Neurology, 66(2), 235-44. https://doi.org/10.1002/ana.21743
Kaufmann P, et al. Phase II Trial of CoQ10 for ALS Finds Insufficient Evidence to Justify Phase III. Ann Neurol. 2009;66(2):235-44. PubMed PMID: 19743457.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III. AU - Kaufmann,Petra, AU - Thompson,John L P, AU - Levy,Gilberto, AU - Buchsbaum,Richard, AU - Shefner,Jeremy, AU - Krivickas,Lisa S, AU - Katz,Jonathan, AU - Rollins,Yvonne, AU - Barohn,Richard J, AU - Jackson,Carlayne E, AU - Tiryaki,Ezgi, AU - Lomen-Hoerth,Catherine, AU - Armon,Carmel, AU - Tandan,Rup, AU - Rudnicki,Stacy A, AU - Rezania,Kourosh, AU - Sufit,Robert, AU - Pestronk,Alan, AU - Novella,Steven P, AU - Heiman-Patterson,Terry, AU - Kasarskis,Edward J, AU - Pioro,Erik P, AU - Montes,Jacqueline, AU - Arbing,Rachel, AU - Vecchio,Darleen, AU - Barsdorf,Alexandra, AU - Mitsumoto,Hiroshi, AU - Levin,Bruce, AU - ,, PY - 2009/9/11/entrez PY - 2009/9/11/pubmed PY - 2009/10/2/medline SP - 235 EP - 44 JF - Annals of neurology JO - Ann Neurol VL - 66 IS - 2 N2 - OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating, and currently incurable, neuromuscular disease in which oxidative stress and mitochondrial impairment are contributing to neuronal loss. Coenzyme Q10 (CoQ10), an antioxidant and mitochondrial cofactor, has shown promise in ALS transgenic mice, and in clinical trials for neurodegenerative diseases other than ALS. Our aims were to choose between two high doses of CoQ10 for ALS, and to determine if it merits testing in a Phase III clinical trial. METHODS: We designed and implemented a multicenter trial with an adaptive, two-stage, bias-adjusted, randomized, placebo-controlled, double-blind, Phase II design (n = 185). The primary outcome in both stages was a decline in the ALS Functional Rating Scale-revised (ALSFRSr) score over 9 months. Stage 1 (dose selection, 35 participants per group) compared CoQ10 doses of 1,800 and 2,700 mg/day. Stage 2 (futility test, 75 patients per group) compared the dose selected in Stage 1 against placebo. RESULTS: Stage 1 selected the 2,700 mg dose. In Stage 2, the pre-specified primary null hypothesis that this dose is superior to placebo was not rejected. It was rejected, however, in an accompanying prespecified sensitivity test, and further supplementary analyses. Prespecified secondary analyses showed no significant differences between CoQ10 at 2,700 mg/day and placebo. There were no safety concerns. INTERPRETATION: CoQ10 at 2,700 mg daily for 9 months shows insufficient promise to warrant Phase III testing. Given this outcome, the adaptive Phase II design incorporating a dose selection and a futility test avoided the need for a much larger conventional Phase III trial. SN - 1531-8249 UR - https://www.unboundmedicine.com/medline/citation/19743457/Phase_II_trial_of_CoQ10_for_ALS_finds_insufficient_evidence_to_justify_phase_III_ L2 - https://doi.org/10.1002/ana.21743 DB - PRIME DP - Unbound Medicine ER -