High-dosage ascorbic acid treatment in charcot-marie-tooth disease type 1A results of a randomized, double-masked, controlled trial

Richard A. Lewis, Michael P. McDermott, David N. Herrmann, Ahmet Hoke, Lora Clawson, Carly Siskind, Shawna M E Feely, Lindsey J. Miller, Richard J. Barohn, Patricia Smith, Elizabeth Luebbe, Xingyao Wu, Michael E. Shy

Research output: Contribution to journalArticle

Abstract

IMPORTANCE No current medications improve neuropathy in subjects with Charcot-Marie-Tooth disease type 1A (CMT1A). Ascorbic acid (AA) treatment improved the neuropathy of a transgenic mouse model of CMT1A and is a potential therapy. A lower dosage (1.5 g/d) did not cause improvement in humans. It is unknown whether a higher dosage would prove more effective. OBJECTIVE To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A. DESIGN A futility design to determine whether AA was unable to reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50% over a 2-year period relative to a natural history control group. SETTING Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and University of Rochester). PARTICIPANTS One hundred seventy-four subjects with CMT1A were assessed for eligibility; 48 did not meet eligibility criteria and 16 declined to participate. The remaining 110 subjects, aged 13 to 70 years, were randomly assigned in a double-masked fashion with 4:1 allocation to oral AA (87 subjects) or matching placebo (23 subjects). Sixty-nine subjects from the treatment group and 16 from the placebo group completed the study. Two subjects from the treatment group and 1 from the placebo group withdrew because of adverse effects. INTERVENTIONS Oral AA (4 g/d) or matching placebo. MAIN OUTCOMES AND MEASURES Change from baseline to year 2 in the CMTNS, a validated composite impairment score for CMT. RESULTS The mean 2-year change in the CMTNS was -0.21 for the AA group and -0.92 for the placebo group, both better than natural history (+1.33). This was well below 50% reduction of CMTNS worsening from natural history, so futility could not be declared (P > .99). CONCLUSIONS AND RELEVANCE Both treated patients and those receiving placebo performed better than natural history. It seems unlikely that our results support undertaking a larger trial of 4-g/d AA treatment in subjects with CMT1A.

Original languageEnglish (US)
Pages (from-to)981-987
Number of pages7
JournalJAMA Neurology
Volume70
Issue number8
DOIs
StatePublished - 2013

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Charcot-Marie-Tooth Disease
Ascorbic Acid
Placebos
Natural History
Medical Futility
Therapeutics
Peripheral Nerves
Transgenic Mice
Referral and Consultation
Control Groups

ASJC Scopus subject areas

  • Clinical Neurology

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High-dosage ascorbic acid treatment in charcot-marie-tooth disease type 1A results of a randomized, double-masked, controlled trial. / Lewis, Richard A.; McDermott, Michael P.; Herrmann, David N.; Hoke, Ahmet; Clawson, Lora; Siskind, Carly; Feely, Shawna M E; Miller, Lindsey J.; Barohn, Richard J.; Smith, Patricia; Luebbe, Elizabeth; Wu, Xingyao; Shy, Michael E.

In: JAMA Neurology, Vol. 70, No. 8, 2013, p. 981-987.

Research output: Contribution to journalArticle

Lewis, RA, McDermott, MP, Herrmann, DN, Hoke, A, Clawson, L, Siskind, C, Feely, SME, Miller, LJ, Barohn, RJ, Smith, P, Luebbe, E, Wu, X & Shy, ME 2013, 'High-dosage ascorbic acid treatment in charcot-marie-tooth disease type 1A results of a randomized, double-masked, controlled trial', JAMA Neurology, vol. 70, no. 8, pp. 981-987. https://doi.org/10.1001/jamaneurol.2013.3178
Lewis, Richard A. ; McDermott, Michael P. ; Herrmann, David N. ; Hoke, Ahmet ; Clawson, Lora ; Siskind, Carly ; Feely, Shawna M E ; Miller, Lindsey J. ; Barohn, Richard J. ; Smith, Patricia ; Luebbe, Elizabeth ; Wu, Xingyao ; Shy, Michael E. / High-dosage ascorbic acid treatment in charcot-marie-tooth disease type 1A results of a randomized, double-masked, controlled trial. In: JAMA Neurology. 2013 ; Vol. 70, No. 8. pp. 981-987.
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abstract = "IMPORTANCE No current medications improve neuropathy in subjects with Charcot-Marie-Tooth disease type 1A (CMT1A). Ascorbic acid (AA) treatment improved the neuropathy of a transgenic mouse model of CMT1A and is a potential therapy. A lower dosage (1.5 g/d) did not cause improvement in humans. It is unknown whether a higher dosage would prove more effective. OBJECTIVE To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A. DESIGN A futility design to determine whether AA was unable to reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50{\%} over a 2-year period relative to a natural history control group. SETTING Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and University of Rochester). PARTICIPANTS One hundred seventy-four subjects with CMT1A were assessed for eligibility; 48 did not meet eligibility criteria and 16 declined to participate. The remaining 110 subjects, aged 13 to 70 years, were randomly assigned in a double-masked fashion with 4:1 allocation to oral AA (87 subjects) or matching placebo (23 subjects). Sixty-nine subjects from the treatment group and 16 from the placebo group completed the study. Two subjects from the treatment group and 1 from the placebo group withdrew because of adverse effects. INTERVENTIONS Oral AA (4 g/d) or matching placebo. MAIN OUTCOMES AND MEASURES Change from baseline to year 2 in the CMTNS, a validated composite impairment score for CMT. RESULTS The mean 2-year change in the CMTNS was -0.21 for the AA group and -0.92 for the placebo group, both better than natural history (+1.33). This was well below 50{\%} reduction of CMTNS worsening from natural history, so futility could not be declared (P > .99). CONCLUSIONS AND RELEVANCE Both treated patients and those receiving placebo performed better than natural history. It seems unlikely that our results support undertaking a larger trial of 4-g/d AA treatment in subjects with CMT1A.",
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AU - Herrmann, David N.

AU - Hoke, Ahmet

AU - Clawson, Lora

AU - Siskind, Carly

AU - Feely, Shawna M E

AU - Miller, Lindsey J.

AU - Barohn, Richard J.

AU - Smith, Patricia

AU - Luebbe, Elizabeth

AU - Wu, Xingyao

AU - Shy, Michael E.

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N2 - IMPORTANCE No current medications improve neuropathy in subjects with Charcot-Marie-Tooth disease type 1A (CMT1A). Ascorbic acid (AA) treatment improved the neuropathy of a transgenic mouse model of CMT1A and is a potential therapy. A lower dosage (1.5 g/d) did not cause improvement in humans. It is unknown whether a higher dosage would prove more effective. OBJECTIVE To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A. DESIGN A futility design to determine whether AA was unable to reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50% over a 2-year period relative to a natural history control group. SETTING Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and University of Rochester). PARTICIPANTS One hundred seventy-four subjects with CMT1A were assessed for eligibility; 48 did not meet eligibility criteria and 16 declined to participate. The remaining 110 subjects, aged 13 to 70 years, were randomly assigned in a double-masked fashion with 4:1 allocation to oral AA (87 subjects) or matching placebo (23 subjects). Sixty-nine subjects from the treatment group and 16 from the placebo group completed the study. Two subjects from the treatment group and 1 from the placebo group withdrew because of adverse effects. INTERVENTIONS Oral AA (4 g/d) or matching placebo. MAIN OUTCOMES AND MEASURES Change from baseline to year 2 in the CMTNS, a validated composite impairment score for CMT. RESULTS The mean 2-year change in the CMTNS was -0.21 for the AA group and -0.92 for the placebo group, both better than natural history (+1.33). This was well below 50% reduction of CMTNS worsening from natural history, so futility could not be declared (P > .99). CONCLUSIONS AND RELEVANCE Both treated patients and those receiving placebo performed better than natural history. It seems unlikely that our results support undertaking a larger trial of 4-g/d AA treatment in subjects with CMT1A.

AB - IMPORTANCE No current medications improve neuropathy in subjects with Charcot-Marie-Tooth disease type 1A (CMT1A). Ascorbic acid (AA) treatment improved the neuropathy of a transgenic mouse model of CMT1A and is a potential therapy. A lower dosage (1.5 g/d) did not cause improvement in humans. It is unknown whether a higher dosage would prove more effective. OBJECTIVE To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A. DESIGN A futility design to determine whether AA was unable to reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50% over a 2-year period relative to a natural history control group. SETTING Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and University of Rochester). PARTICIPANTS One hundred seventy-four subjects with CMT1A were assessed for eligibility; 48 did not meet eligibility criteria and 16 declined to participate. The remaining 110 subjects, aged 13 to 70 years, were randomly assigned in a double-masked fashion with 4:1 allocation to oral AA (87 subjects) or matching placebo (23 subjects). Sixty-nine subjects from the treatment group and 16 from the placebo group completed the study. Two subjects from the treatment group and 1 from the placebo group withdrew because of adverse effects. INTERVENTIONS Oral AA (4 g/d) or matching placebo. MAIN OUTCOMES AND MEASURES Change from baseline to year 2 in the CMTNS, a validated composite impairment score for CMT. RESULTS The mean 2-year change in the CMTNS was -0.21 for the AA group and -0.92 for the placebo group, both better than natural history (+1.33). This was well below 50% reduction of CMTNS worsening from natural history, so futility could not be declared (P > .99). CONCLUSIONS AND RELEVANCE Both treated patients and those receiving placebo performed better than natural history. It seems unlikely that our results support undertaking a larger trial of 4-g/d AA treatment in subjects with CMT1A.

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