Ascorbic acid for the treatment of Charcot‐Marie‐Tooth disease

Burkhard Gess; Jonathan Baets; Peter De Jonghe; Mary M Reilly; Davide Pareyson; Peter Young

doi:10.1002/14651858.CD011952

Askorbatna kiselina za liječenje Charcot‐Marie‐Tooth bolesti

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Referencias

References to studies included in this review

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estudios excluidos
otras referencias
otras versiones publicadas

Burns J, Ouvrier RA, Yiu EM, Joseph PD, Kornberg AJ, Fahey MC, et al. Ascorbic acid for Charcot–Marie–Tooth disease type 1A in children: a randomised, double‐blind, placebo‐controlled, safety and efficacy trial. Lancet Neurology 2009;8(6):537‐44. [PUBMED: 19427269]

Lewis RA, McDermott MP, Herrmann DN, Hoke A, Clawson LL, Siskind C, et al. for the Muscle Study Group. High‐dosage ascorbic acid treatment in Charcot‐Marie‐Tooth disease type 1A: results of a randomized, double‐masked, controlled trial. JAMA Neurology 2013;70(8):981‐7. [PUBMED: 23797954]

Mazanec R. CMT Cochrane Review [personal communication]. Email to: B Gess 12 August 2013.

Micallef J, Attarian S, Dubourg O, Gonnaud PM, Hogrel JY, Stojkovic T, et al. Effect of ascorbic acid in patients with Charcot‐Marie‐Tooth disease type 1A: a multicentre, randomised, double‐blind, placebo‐controlled trial. Lancet Neurology 2009;8(12):1103‐10. [PUBMED: 19818690]

Pareyson D, Reilly MM, Schenone A, Fabrizi GM, Cavallaro T, Santoro L, et al. Ascorbic acid in Charcot‐Marie‐Tooth disease type 1A (CMT‐TRIAAL and CMT‐TRAUK): a double‐blind randomised trial. Lancet Neurology 2001;10(4):320‐8. [PUBMED: 23525455]

Verhamme C, de Haan RJ, Vermeulen M, Baas F, de Visser M, van Schaik IN. Oral high dose ascorbic acid treatment for one year in young CMT1A patients: a randomised, double‐blind, placebo‐controlled phase II trial. BMC Medicine 2009;7:70. [http://www.biomedcentral.com/1741‐7015/7/70; PUBMED: 19909499]

References to studies excluded from this review

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estudios incluidos
otras referencias
otras versiones publicadas

Toth C. Poor tolerability of high dose ascorbic acid in a population of genetically confirmed adult Charcot‐Marie‐Tooth 1A patients. Acta Neurologica Scandinavica 2009;120(2):134‐8.

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References to other published versions of this review

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estudios excluidos
otras referencias

Young P, Stögbauer F, Butterfass‐Bahloul T, de Jonghe P. Treatment for Charcot‐Marie‐Tooth disease. Cochrane Database of Systematic Reviews 2006, Issue 2. [DOI: 10.1002/14651858.CD006052]

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos

Burns 2009

Methods	Randomised, placebo‐controlled, double‐blind clinical trial
Participants	80 children with genetically proven CMT1A; aged 2 to 16 years; both sexes
Interventions	Oral ascorbic acid dose (approximately 30 mg/kg body weight/day) (N = 41): age 2 to 3 years: 375 mg/day age 4 to 8 years: 625 mg/day age 9 to 13 years: 1125 mg/day age 14 to 16 years: 1625 mg/day versus matching placebo (N = 39) for 12 months
Outcomes	Primary: change in median nerve conduction velocity (m/s) after 12 months Secondary: change in foot and hand strength, motor function, walking ability and quality of life after 12 months
Funding sources	"The University of Sydney Research and Development Scheme (#K2701 U3332), National Health and Medical Research Council of Australia (NHMRC #336705), James N Kirby Foundation, New South Wales Podiatrists Registration Board, Australian Podiatry Education and Research Foundation, and Charcot–Marie–Tooth Association of Australia"
Conflicts of interest	No conflicts of interest reported
Notes	Date study was performed: June 2007 to December 2008
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were randomly assigned in a 1:1 ratio by a computer‐generated algorithm"
Allocation concealment (selection bias)	Unclear risk	"Randomisation data were retained by central pharmacy"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"The principal investigator (JB) and the other investigators, study coordinators, assessors, children, and their parents were unaware of the treatment assignment"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"The principal investigator (JB) and the other investigators, study coordinators, assessors [...] were unaware of the treatment assignment"
Incomplete outcome data (attrition bias) All outcomes	Low risk	"Analysis of treatment effect between groups was by intention to treat"
Selective reporting (reporting bias)	Low risk	Study protocol available on www.ANZCTR.org.au; outcome reporting according to protocol
Other bias	Low risk	None identified

Lewis 2013

Methods	Randomised, placebo‐controlled, double‐blind clinical trial
Participants	110 participants between 14 and 69 years old with CMT1A proven genetically, both sexes
Interventions	4 g ascorbic acid per day (N = 87), versus matching placebo (N = 23) for 24 months
Outcomes	Primary: CMTNS after 24 months Secondary: Neuropathy Impairment Score, nerve conduction studies, SF‐36, serum ascorbic acid levels, PMP22 mRNA in skin biopsy (RT‐PCR) after 24 months
Funding sources	"Muscular Dystrophy Association and the Charcot‐Marie‐Tooth Association. Wayne State University, the University of Rochester, and Johns Hopkins University were members of the Inherited Neuropathy Consortium of the Rare Disease Clinical Research Network supported by the National Institute of Neurological Disorders and Stroke and Office of Rare Diseases."
Conflicts of interest	"Dr. Lewis has consulted for Baxter, CSL Behring, AxelaCare, Novartis, and Bristol‐Myers Squibb. Dr. Shy has received grant support from the National Institute of Neurological Disorders and Stroke, Muscular Dystrophy Association, and Charcot‐Marie‐Tooth Association."
Notes	Study start date: April 2007; completion date: December 2012 (as stated on ClinicalTrials.gov)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The randomization plan was computer generated"
Allocation concealment (selection bias)	Unclear risk	"Subjects were randomly assigned with 4:1 allocation to AA (80%) or placebo (20%)"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Only a programmer in the Muscle Study Group Biostatistics Center and the investigational pharmacy had access to the treatment assignments during the trial."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Only a programmer in the Muscle Study Group Biostatistics Center and the investigational pharmacy had access to the treatment assignments during the trial."
Incomplete outcome data (attrition bias) All outcomes	Low risk	"This approach appropriately accounts for missing data when estimating the model parameters under the “missing at random” assumption."
Selective reporting (reporting bias)	Unclear risk	Study protocol available on www.ClinicalTrials.gov; all pre‐specified outcomes reported; some additional, not pre‐specified outcomes reported
Other bias	Low risk	None identified

Mazanec 2013 [pers comm]

Methods	Randomised, placebo‐controlled, double‐blind clinical trial
Participants	People with CMT1A genetically carrying the duplication on chromosome 17q11.2; between 18 and 70 years; both sexes
Interventions	Ascorbic acid 1500 mg/day (N = 26) versus matching placebo (N = 25) for 24 months
Outcomes	Primary: change in CMTNS after 24 months Secondary: change in MVIC, 10‐m walking, nine‐hole peg test, ONLS, VAS for pain and fatigue, SF36 after 24 months
Funding sources	"The clinical trial was funded by grant of The Czech Internal Grant Agency of Ministry of Health of Czech Republic (No NR/9517)"
Conflicts of interest	No conflict of interest for any investigator
Notes	Study not published yet, data obtained by communication with principal investigator Date study was performed: 1 January 2007 to 31 December 2009
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomization was performed by the pharmaceutical company FAVEA s.r.o, which prepared the study medication for this trial
Allocation concealment (selection bias)	Unclear risk	The investigator at each centre obtained the study medication and allocation concealment code from the pharmaceutical company
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The case report form included only initials and study number, not the names or further data about participants
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The two investigators in each centre (one examining and one treating neurologist) were not in contact about the participants; only the case report form documents were transmitted from examining to treating neurologist
Incomplete outcome data (attrition bias) All outcomes	High risk	The study evaluation did not include the data of participants who dropped out
Selective reporting (reporting bias)	Unclear risk	Study protocol not available
Other bias	Low risk	None identified

Micallef 2009

Methods	Randomised, placebo‐controlled, double‐blind clinical trial
Participants	179 participants with CMT1A aged 34 to 58 years, genetically confirmed, both sexes
Interventions	1 g/day ascorbic acid (N = 56), 3 g/day ascorbic acid (N = 61), versus matching placebo (N = 62) for 12 months
Outcomes	Primary: change in CMTNS after 12 months Secondary: change in CMTES, quantitative motor testing, SF‐36, ODSS, time to walk 10‐m, VAS, Clinical Global Impression Severity scale, ascorbic acid blood concentration, nerve conduction studies after 12 months
Funding sources	"French Ministry of Health (National PHRC 2004) and Association Française Contre les Myopathies." (p. 1)
Conflicts of interest	"Ascorbic acid for the treatment of CMT1A is under patent and its application has been registered by INSERM, AFM, and Marseille II University. MF is one of the inventors of the patent, which has been licensed to Murigenetics. MF and OB participate in the activities of Murigenetics as scientific advisers and are each 15% shareholders in the company. The other authors have no conflict of interest." (p. 8)
Notes	Date study was performed: recruitment from September 2005 to September 2007
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The randomisation sequence was generated using randomization.com"
Allocation concealment (selection bias)	Unclear risk	"Active treatment and placebo were prepared by CLIPA Clinical Packaging."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Both patients and investigators were unaware of the treatment allocation."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Both patients and investigators were unaware of the treatment allocation."
Incomplete outcome data (attrition bias) All outcomes	Low risk	"Analyses were done on the intention to treat population."
Selective reporting (reporting bias)	Unclear risk	Study protocol not available
Other bias	Low risk	None identified

Pareyson 2011

Methods	Randomised, placebo‐controlled, double‐blind clinical trial
Participants	People with CMT1A genetically carrying the duplication on chromosome 17q11.2; between 18 and 70 years old; both sexes
Interventions	1500 mg/day ascorbic acid (N = 138) versus matching placebo (N = 133) for 24 months
Outcomes	Primary: change in CMTNS after 24 months Secondary: change in MVIC, 10‐m walking, nine‐hole peg test, ONLS, VAS for pain and fatigue, SF‐36, skin biopsy (expression of PMP22) after 24 months
Funding sources	"Telethon‐UILDM (grant numbers GUP04002 and GUP05007) and AIFA (Italian Medicines Agency; grant number FARM53APAH) in Italy, and Muscular Dystrophy Campaign in the UK (grant number RA3/736/1). MMR also receives funding from CMTUK and the UK Medical Research Council. In the UK, this work was undertaken at University College London Hospitals and University College London, which received a proportion of funding from the UK Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme."
Conflicts of interest	"RACH was a consultant for Octapharma, Baxter, Laboratoires Français de Fractionnement et des Biotechnologies (LFB), and Novartis. AS was a board member for Novartis, and has received speaker honoraria from Sanofi‐Aventis. All other authors declare that they have no conflicts of interest."
Notes	Date study was performed: inclusion from March 2006 to September 2007
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The randomisation sequence was computer generated (by a pseudo‐random number generator)"
Allocation concealment (selection bias)	Low risk	"Treatment was allocated centrally by telephone, and was stratified by centre and disease severity (CMTNS ≤ 10 vs > 10, or CMTES ≤ 8 vs > 8 if electrophysiological assessment was not done in the previous 3 months), with a block size of four (unknown to investigators) within each centre. The sequence was available in opaque sealed envelopes at every centre for emergency unmasking."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Patients, treating physicians, [...] were masked to treatment allocation."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"[...] physicians assessing outcomes with clinical scales at baseline and during follow‐up were masked to treatment allocation."
Incomplete outcome data (attrition bias) All outcomes	Low risk	"The main analysis of the primary outcome included all randomised patients who took at least one dose of study treatment. [...] For patients who were unavailable, missing data were imputed according to Rubin's multiple imputation approach."; six participants dropped out after allocation due to withdrawal of consent.
Selective reporting (reporting bias)	Low risk	Study protocol available on www.ClinicalTrialsRegister.eu and separate publication; outcome reporting according to protocol
Other bias	Low risk	None identified

Verhamme 2009a

Methods	Randomised, placebo‐controlled, double‐blind clinical trial
Participants	People with CMT1A, genetically carrying the duplication on chromosome 17q11.2, between 12 and 25 years, both sexes
Interventions	Ascorbic acid 2 g/day (N = 5) versus matching placebo (N = 6) for 12 months
Outcomes	Primary: change in motor nerve conduction velocity of the median nerve after 12 months Secondary: change in: minimal F response latency of the median nerve, compound muscle action potential amplitude and area, motor unit number estimation of the abductor pollicis brevis muscle, handgrip strength, strength of arm flexors, foot dorsiflexors, knee extensors and hip flexors, overall disability sum score, CMTNS, Academic Medical Center Linear Disability Scale score, serum ascorbic acid concentrations after 12 months
Funding sources	"internally funded at the Department of Neurology and Clinical Neurophysiology, Academic Medical Centre, University of Amsterdam."
Conflicts of interest	No competing interests declared
Notes	Date study was performed: inclusion December 2005 and June 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The pharmacist, who did not have any further role in the study, generated a computerized randomization sequence."
Allocation concealment (selection bias)	Unclear risk	"Eligible patients were randomly allocated to oral ascorbic acid or placebo."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Participants and investigators were unaware of the treatment assignment."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Participants and investigators were unaware of the treatment assignment."
Incomplete outcome data (attrition bias) All outcomes	Low risk	"Randomised patients with at least one follow‐up measure of the primary outcome were analyzed according to the intention‐to‐treat principle. In case of incomplete data, we used the last observation carried forward approach."
Selective reporting (reporting bias)	Low risk	Study protocol available on www.ClinicalTrials.gov; outcome reporting according to protocol
Other bias	Low risk	None identified

N: number of participants

CMT1A: Charcot‐Marie‐Tooth disease type 1A

CMTES: Charcot‐Marie‐Tooth disease examination score

CMTNS: Charcot‐Marie‐Tooth disease neuropathy score

MVIC: maximal voluntary isometric contraction

ODSS: Overall Disability Sum Score

ONLS: Overall Neuropathy Limitations Scale

SF‐36: Short‐Form 36 Health Survey Questionnaire

PMP22: peripheral myelin protein 22 kDa

mRNA: messenger ribonucleic acid

RT‐PCR: reverse transcription polymerase chain reaction

VAS: visual analogue scale

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study	Reason for exclusion
Toth 2009	Controlled by untreated cohort group, not randomised

Data and analyses

Open in table viewer

Comparison 1. Ascorbic acid versus placebo 12 months (adults)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Impairment ‐ CMTNS (scale 0 to 36 points) Show forest plot	5	533	Mean Difference (IV, Fixed, 95% CI)	‐0.37 [‐0.83, 0.09]
Open in figure viewer Analysis 1.1 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 1 Impairment ‐ CMTNS (scale 0 to 36 points).
2 Impairment ‐ CMTES (scale 0 to 28 points) Show forest plot	3	460	Mean Difference (IV, Fixed, 95% CI)	‐0.15 [‐0.57, 0.27]
Open in figure viewer Analysis 1.2 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 2 Impairment ‐ CMTES (scale 0 to 28 points).
3 Impairment ‐ NIS (scale ‐26 to 26 points) Show forest plot	1	110	Mean Difference (IV, Fixed, 95% CI)	1.91 [‐2.24, 6.06]
Open in figure viewer Analysis 1.3 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 3 Impairment ‐ NIS (scale ‐26 to 26 points).
4 Disability ‐ ODSS (scale 0 to 12 points) Show forest plot	2	134	Mean Difference (IV, Fixed, 95% CI)	‐0.09 [‐0.36, 0.18]
Open in figure viewer Analysis 1.4 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 4 Disability ‐ ODSS (scale 0 to 12 points).
5 Disability ‐ ONLS (scale 0 to 12 points) Show forest plot	2	289	Mean Difference (IV, Fixed, 95% CI)	0.07 [‐0.02, 0.17]
Open in figure viewer Analysis 1.5 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 5 Disability ‐ ONLS (scale 0 to 12 points).
6 Disability ‐ ALDS (scale 0 to 100 points) Show forest plot	1	11	Mean Difference (IV, Fixed, 95% CI)	‐1.3 [‐4.28, 1.68]
Open in figure viewer Analysis 1.6 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 6 Disability ‐ ALDS (scale 0 to 100 points).
7 CMAP, ulnar nerve (abductor digiti minimi) Show forest plot	2	161	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.34, 0.59]
Open in figure viewer Analysis 1.7 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 7 CMAP, ulnar nerve (abductor digiti minimi).
8 CMAP, median nerve (abductor pollicis brevis) Show forest plot	1	11	Mean Difference (IV, Fixed, 95% CI)	‐0.18 [‐1.19, 0.83]
Open in figure viewer Analysis 1.8 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 8 CMAP, median nerve (abductor pollicis brevis).
9 CMAP summatory from ulnar, median and peroneal nerves Show forest plot	1	217	Mean Difference (IV, Fixed, 95% CI)	0.23 [‐0.48, 0.94]
Open in figure viewer Analysis 1.9 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 9 CMAP summatory from ulnar, median and peroneal nerves.
10 Sensation ‐ INCAT Sensory Sum score (scale 0 to 20 points) Show forest plot	1	10	Mean Difference (IV, Fixed, 95% CI)	‐2.0 [‐5.53, 1.53]
Open in figure viewer Analysis 1.10 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 10 Sensation ‐ INCAT Sensory Sum score (scale 0 to 20 points).
11 SNAP amplitude Show forest plot	1	123	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.42, 0.42]
Open in figure viewer Analysis 1.11 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 11 SNAP amplitude.
12 Hand grip Show forest plot	3	412	Mean Difference (IV, Fixed, 95% CI)	1.39 [‐4.17, 6.95]
Open in figure viewer Analysis 1.12 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 12 Hand grip.
13 Three‐point pinch Show forest plot	3	300	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐1.53, 2.73]
Open in figure viewer Analysis 1.13 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 13 Three‐point pinch.
14 Foot dorsiflexion Show forest plot	4	423	Mean Difference (IV, Fixed, 95% CI)	1.10 [‐3.47, 5.67]
Open in figure viewer Analysis 1.14 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 14 Foot dorsiflexion.
15 Quality of life ‐ SF36 ‐ physical functioning Show forest plot	4	522	Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐1.32, 1.22]
Open in figure viewer Analysis 1.15 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 15 Quality of life ‐ SF36 ‐ physical functioning.
16 Quality of life ‐ SF36 ‐ bodily pain Show forest plot	3	401	Mean Difference (IV, Fixed, 95% CI)	‐0.53 [‐2.69, 1.62]
Open in figure viewer Analysis 1.16 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 16 Quality of life ‐ SF36 ‐ bodily pain.
17 Quality of life ‐ SF36 ‐ energy Show forest plot	2	291	Mean Difference (IV, Fixed, 95% CI)	0.45 [‐2.84, 3.74]
Open in figure viewer Analysis 1.17 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 17 Quality of life ‐ SF36 ‐ energy.
18 Quality of life ‐ SF36 ‐ psychological Show forest plot	1	123	Mean Difference (IV, Fixed, 95% CI)	0.90 [‐2.65, 4.45]
Open in figure viewer Analysis 1.18 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 18 Quality of life ‐ SF36 ‐ psychological.
19 Quality of life ‐ SF36 ‐ MCS Show forest plot	1	110	Mean Difference (IV, Fixed, 95% CI)	0.46 [‐3.80, 4.72]
Open in figure viewer Analysis 1.19 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 19 Quality of life ‐ SF36 ‐ MCS.
20 Quality of life ‐ SF36 ‐ PCS Show forest plot	1	110	Mean Difference (IV, Fixed, 95% CI)	0.39 [‐2.98, 3.76]
Open in figure viewer Analysis 1.20 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 20 Quality of life ‐ SF36 ‐ PCS.
21 9‐hole peg test Show forest plot	3	286	Mean Difference (IV, Fixed, 95% CI)	‐0.39 [‐0.76, ‐0.02]
Open in figure viewer Analysis 1.21 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 21 9‐hole peg test.
22 Timed 10 m walk Show forest plot	3	401	Mean Difference (IV, Fixed, 95% CI)	‐0.02 [‐0.32, 0.29]
Open in figure viewer Analysis 1.22 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 22 Timed 10 m walk.
23 50 m walk Show forest plot	1	11	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐2.49, 1.89]
Open in figure viewer Analysis 1.23 Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 23 50 m walk.

Open in table viewer

Comparison 2. Ascorbic acid versus placebo 24 months (adults)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Impairment ‐ CMTNS (scale 0 to 36 points) Show forest plot	3	388	Mean Difference (IV, Fixed, 95% CI)	‐0.21 [‐0.81, 0.39]
Open in figure viewer Analysis 2.1 Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 1 Impairment ‐ CMTNS (scale 0 to 36 points).
2 Impairment ‐ CMTES (scale 0 to 28 points) Show forest plot	2	337	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.67, 0.42]
Open in figure viewer Analysis 2.2 Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 2 Impairment ‐ CMTES (scale 0 to 28 points).
3 Disability ‐ ONLS (scale 0 to 12 points) Show forest plot	2	276	Mean Difference (IV, Fixed, 95% CI)	0.14 [‐0.05, 0.34]
Open in figure viewer Analysis 2.3 Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 3 Disability ‐ ONLS (scale 0 to 12 points).
4 CMAP, ulnar nerve (abductor digiti minimi) Show forest plot	2	161	Mean Difference (IV, Fixed, 95% CI)	0.06 [‐0.10, 0.23]
Open in figure viewer Analysis 2.4 Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 4 CMAP, ulnar nerve (abductor digiti minimi).
5 Hand grip Show forest plot	2	186	Mean Difference (IV, Fixed, 95% CI)	1.25 [‐3.86, 6.37]
Open in figure viewer Analysis 2.5 Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 5 Hand grip.
6 Three‐point pinch Show forest plot	2	276	Mean Difference (IV, Fixed, 95% CI)	0.73 [‐3.62, 5.08]
Open in figure viewer Analysis 2.6 Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 6 Three‐point pinch.
7 Foot dorsiflexion Show forest plot	2	278	Mean Difference (IV, Fixed, 95% CI)	0.77 [‐7.21, 8.76]
Open in figure viewer Analysis 2.7 Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 7 Foot dorsiflexion.
8 Quality of life ‐ SF36 ‐ physical functioning Show forest plot	3	382	Mean Difference (IV, Fixed, 95% CI)	‐0.07 [‐2.41, 2.26]
Open in figure viewer Analysis 2.8 Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 8 Quality of life ‐ SF36 ‐ physical functioning.
9 Quality of life ‐ SF36 ‐ bodily pain Show forest plot	3	385	Mean Difference (IV, Fixed, 95% CI)	‐1.57 [‐4.93, 1.80]
Open in figure viewer Analysis 2.9 Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 9 Quality of life ‐ SF36 ‐ bodily pain.
10 Quality of life ‐ SF36 ‐ energy Show forest plot	2	267	Mean Difference (IV, Fixed, 95% CI)	0.71 [‐3.35, 4.77]
Open in figure viewer Analysis 2.10 Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 10 Quality of life ‐ SF36 ‐ energy.
11 9‐hole peg test Show forest plot	2	275	Mean Difference (IV, Fixed, 95% CI)	‐1.16 [‐1.96, ‐0.37]
Open in figure viewer Analysis 2.11 Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 11 9‐hole peg test.
12 Timed 10 m walk Show forest plot	2	278	Mean Difference (IV, Fixed, 95% CI)	0.09 [‐0.64, 0.82]
Open in figure viewer Analysis 2.12 Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 12 Timed 10 m walk.
13 PMP22 mRNA (skin biopsy) Show forest plot	2	114	Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐0.13, 0.03]
Open in figure viewer Analysis 2.13 Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 13 PMP22 mRNA (skin biopsy).

Open in table viewer

Comparison 3. Ascorbic acid vs placebo (children)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 CMAP amplitude (M. abductor pollicis brevis) Show forest plot	1	80	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.75, 1.35]
Open in figure viewer Analysis 3.1 Comparison 3 Ascorbic acid vs placebo (children), Outcome 1 CMAP amplitude (M. abductor pollicis brevis).
2 Hand grip Show forest plot	1	80	Mean Difference (IV, Fixed, 95% CI)	9.80 [‐18.10, 37.70]
Open in figure viewer Analysis 3.2 Comparison 3 Ascorbic acid vs placebo (children), Outcome 2 Hand grip.
3 Finger pinch Show forest plot	1	80	Mean Difference (IV, Fixed, 95% CI)	1.60 [‐1.84, 5.04]
Open in figure viewer Analysis 3.3 Comparison 3 Ascorbic acid vs placebo (children), Outcome 3 Finger pinch.
4 Foot dorsiflexion Show forest plot	1	80	Mean Difference (IV, Fixed, 95% CI)	‐1.0 [‐11.90, 9.90]
Open in figure viewer Analysis 3.4 Comparison 3 Ascorbic acid vs placebo (children), Outcome 4 Foot dorsiflexion.
5 Foot plantar flexion Show forest plot	1	80	Mean Difference (IV, Fixed, 95% CI)	‐10.20 [‐36.29, 15.89]
Open in figure viewer Analysis 3.5 Comparison 3 Ascorbic acid vs placebo (children), Outcome 5 Foot plantar flexion.
6 Median nerve motor conduction velocity Show forest plot	1	80	Mean Difference (IV, Fixed, 95% CI)	2.0 [‐0.89, 4.89]
Open in figure viewer Analysis 3.6 Comparison 3 Ascorbic acid vs placebo (children), Outcome 6 Median nerve motor conduction velocity.
7 9‐hole peg test Show forest plot	1	78	Mean Difference (IV, Fixed, 95% CI)	‐0.80 [‐2.85, 1.25]
Open in figure viewer Analysis 3.7 Comparison 3 Ascorbic acid vs placebo (children), Outcome 7 9‐hole peg test.
8 6 min walk Show forest plot	1	65	Mean Difference (IV, Fixed, 95% CI)	‐3.0 [‐32.34, 26.34]
Open in figure viewer Analysis 3.8 Comparison 3 Ascorbic acid vs placebo (children), Outcome 8 6 min walk.
9 Balance Show forest plot	1	74	Mean Difference (IV, Fixed, 95% CI)	‐1.30 [‐4.62, 2.02]
Open in figure viewer Analysis 3.9 Comparison 3 Ascorbic acid vs placebo (children), Outcome 9 Balance.
10 Agility Show forest plot	1	72	Mean Difference (IV, Fixed, 95% CI)	‐1.70 [‐5.43, 2.03]
Open in figure viewer Analysis 3.10 Comparison 3 Ascorbic acid vs placebo (children), Outcome 10 Agility.
11 Long jump Show forest plot	1	72	Mean Difference (IV, Fixed, 95% CI)	2.20 [‐11.10, 15.50]
Open in figure viewer Analysis 3.11 Comparison 3 Ascorbic acid vs placebo (children), Outcome 11 Long jump.
12 Speed Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐9.33, 8.93]
Open in figure viewer Analysis 3.12 Comparison 3 Ascorbic acid vs placebo (children), Outcome 12 Speed.
13 Cadence Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	0.80 [‐6.54, 8.14]
Open in figure viewer Analysis 3.13 Comparison 3 Ascorbic acid vs placebo (children), Outcome 13 Cadence.
14 Step time Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.05, 0.05]
Open in figure viewer Analysis 3.14 Comparison 3 Ascorbic acid vs placebo (children), Outcome 14 Step time.
15 Step length Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.90 [‐4.97, 3.17]
Open in figure viewer Analysis 3.15 Comparison 3 Ascorbic acid vs placebo (children), Outcome 15 Step length.
16 Stride length Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	‐1.80 [‐9.58, 5.98]
Open in figure viewer Analysis 3.16 Comparison 3 Ascorbic acid vs placebo (children), Outcome 16 Stride length.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Green (+) = low risk of bias; yellow (?) = unclear risk of bias; red (‐) = high risk of bias.

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Figure 3

Forest plot of comparison: 1 Ascorbic acid versus placebo 12 months, outcome: 1.1 CMTNS.

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Figure 4

Forest plot of comparison: 1 Ascorbic acid versus placebo 12 months (adults), outcome: 1.21 9‐hole peg test [s].

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Figure 5

Forest plot of comparison: 2 Ascorbic acid versus placebo 24 months (adults), outcome: 2.1 Impairment ‐ CMTNS.

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Figure 6

Forest plot of comparison: 2 Ascorbic acid versus placebo 24 months (adults), outcome: 2.11 Impairment ‐ 9‐hole peg test [s].

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Analysis 1.1

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 1 Impairment ‐ CMTNS (scale 0 to 36 points).

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Analysis 1.2

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 2 Impairment ‐ CMTES (scale 0 to 28 points).

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Analysis 1.3

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 3 Impairment ‐ NIS (scale ‐26 to 26 points).

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Analysis 1.4

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 4 Disability ‐ ODSS (scale 0 to 12 points).

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Analysis 1.5

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 5 Disability ‐ ONLS (scale 0 to 12 points).

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Analysis 1.6

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 6 Disability ‐ ALDS (scale 0 to 100 points).

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Analysis 1.7

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 7 CMAP, ulnar nerve (abductor digiti minimi).

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Analysis 1.8

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 8 CMAP, median nerve (abductor pollicis brevis).

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Analysis 1.9

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 9 CMAP summatory from ulnar, median and peroneal nerves.

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Analysis 1.10

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 10 Sensation ‐ INCAT Sensory Sum score (scale 0 to 20 points).

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Analysis 1.11

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 11 SNAP amplitude.

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Analysis 1.12

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 12 Hand grip.

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Analysis 1.13

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 13 Three‐point pinch.

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Analysis 1.14

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 14 Foot dorsiflexion.

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Analysis 1.15

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 15 Quality of life ‐ SF36 ‐ physical functioning.

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Analysis 1.16

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 16 Quality of life ‐ SF36 ‐ bodily pain.

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Analysis 1.17

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 17 Quality of life ‐ SF36 ‐ energy.

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Analysis 1.18

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 18 Quality of life ‐ SF36 ‐ psychological.

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Analysis 1.19

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 19 Quality of life ‐ SF36 ‐ MCS.

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Analysis 1.20

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 20 Quality of life ‐ SF36 ‐ PCS.

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Analysis 1.21

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 21 9‐hole peg test.

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Analysis 1.22

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 22 Timed 10 m walk.

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Analysis 1.23

Comparison 1 Ascorbic acid versus placebo 12 months (adults), Outcome 23 50 m walk.

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Analysis 2.1

Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 1 Impairment ‐ CMTNS (scale 0 to 36 points).

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Analysis 2.2

Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 2 Impairment ‐ CMTES (scale 0 to 28 points).

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Analysis 2.3

Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 3 Disability ‐ ONLS (scale 0 to 12 points).

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Analysis 2.4

Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 4 CMAP, ulnar nerve (abductor digiti minimi).

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Analysis 2.5

Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 5 Hand grip.

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Analysis 2.6

Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 6 Three‐point pinch.

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Analysis 2.7

Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 7 Foot dorsiflexion.

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Analysis 2.8

Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 8 Quality of life ‐ SF36 ‐ physical functioning.

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Analysis 2.9

Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 9 Quality of life ‐ SF36 ‐ bodily pain.

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Analysis 2.10

Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 10 Quality of life ‐ SF36 ‐ energy.

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Analysis 2.11

Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 11 9‐hole peg test.

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Analysis 2.12

Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 12 Timed 10 m walk.

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Analysis 2.13

Comparison 2 Ascorbic acid versus placebo 24 months (adults), Outcome 13 PMP22 mRNA (skin biopsy).

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Analysis 3.1

Comparison 3 Ascorbic acid vs placebo (children), Outcome 1 CMAP amplitude (M. abductor pollicis brevis).

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Analysis 3.2

Comparison 3 Ascorbic acid vs placebo (children), Outcome 2 Hand grip.

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Analysis 3.3

Comparison 3 Ascorbic acid vs placebo (children), Outcome 3 Finger pinch.

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Analysis 3.4

Comparison 3 Ascorbic acid vs placebo (children), Outcome 4 Foot dorsiflexion.

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Analysis 3.5

Comparison 3 Ascorbic acid vs placebo (children), Outcome 5 Foot plantar flexion.

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Analysis 3.6

Comparison 3 Ascorbic acid vs placebo (children), Outcome 6 Median nerve motor conduction velocity.

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Analysis 3.7

Comparison 3 Ascorbic acid vs placebo (children), Outcome 7 9‐hole peg test.

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Analysis 3.8

Comparison 3 Ascorbic acid vs placebo (children), Outcome 8 6 min walk.

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Analysis 3.9

Comparison 3 Ascorbic acid vs placebo (children), Outcome 9 Balance.

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Analysis 3.10

Comparison 3 Ascorbic acid vs placebo (children), Outcome 10 Agility.

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Analysis 3.11

Comparison 3 Ascorbic acid vs placebo (children), Outcome 11 Long jump.

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Analysis 3.12

Comparison 3 Ascorbic acid vs placebo (children), Outcome 12 Speed.

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Analysis 3.13

Comparison 3 Ascorbic acid vs placebo (children), Outcome 13 Cadence.

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Analysis 3.14

Comparison 3 Ascorbic acid vs placebo (children), Outcome 14 Step time.

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Analysis 3.15

Comparison 3 Ascorbic acid vs placebo (children), Outcome 15 Step length.

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Analysis 3.16

Comparison 3 Ascorbic acid vs placebo (children), Outcome 16 Stride length.

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Ascorbic acid treatment compared with placebo for CMT1A in adults
Participants or population: adults with CMT1A Intervention: oral ascorbic acid (1 g to 4 g/day) Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Ascorbic acid
Impairment ‐ change in CMTNS at 24 months (0 to 36 points)	The mean change in CMTNS ranged across control groups from ‐0.92 to 1 point	The mean change in CMTNS in the intervention groups was 0.21 lower (0.81 lower to 0.39 higher)	‐0.21 (‐0.81 to 0.39)	388 (3)	⊕⊕⊕⊕ high
Impairment ‐ change in CMTES at 24 months (0 to 28 points)	The mean change in CMTES ranged across control groups from ‐0.64 to 0.5 point	The mean change in CMTES in the intervention groups was 0.12 lower (0.67 lower to 0.42 higher)	‐0.12 (‐0.67 to 0.42)	337 (2)	⊕⊕⊕⊝ moderate¹
Change in timed 10‐m walk at 12 months (seconds (s))	The mean change in timed 10‐m walk ranged across control groups from ‐0.15 to 0.56 s	The mean change in timed 10‐m walk in the intervention groups was 0.02 lower (0.32 lower to 0.29 lower)	‐0.02 (‐0.32 to 0.29)	401 (3)	⊕⊕⊕⊕ high
Change in foot dorsiflexion at 12 months (N)	The mean change in foot dorsiflexion force ranged across control groups from ‐5.1 to 3 N	The mean change in foot dorsiflexion force in the intervention groups was 1.1 higher (3.47 lower to 5.67 higher)	1.1 (‐3.47 to 5.67)	423 (4)	⊕⊕⊕⊕ high
Change in 9‐hole peg test (HPT) at 12 months (seconds)	The mean change in 9‐HPT ranged across control groups from ‐3.5 to 0.43 s	The mean change in 9‐HPT in the intervention groups was 0.39 lower (0.76 lower to 0.02 lower)	‐0.39 (‐0.76 to ‐0.02)	286 (3)	⊕⊕⊕⊝ moderate¹
Serious adverse events (SAE; %)	The relative abundance of SAE was 12% in the placebo group ((number of SAE/number of participants)*100)	The relative abundance of SAE was 11.7% in the intervention groups ((number of SAE/number of participants)*100)	Not estimable	702 (6, including 1 study in children)	⊕⊕⊕⊕ high
The assumed risk* is based on the mean change or the range of mean change) across control groups in included studies.. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Key: 10‐m walk: 10‐metre walk; 9‐HPT: 9‐hole‐peg test; CMTES: CMT examination scale; CMTNS: CMT neuropathy scale; CI: confidence interval; RR: risk ratio; N: Newton; SAE: Serious adverse event
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Evidence downgraded because of number of studies and participants, which was lower than for other outcomes. Further research may thus have an impact on our confidence in the estimate of effect and may change the estimate.

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Comparison 1. Ascorbic acid versus placebo 12 months (adults)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Impairment ‐ CMTNS (scale 0 to 36 points) Show forest plot	5	533	Mean Difference (IV, Fixed, 95% CI)	‐0.37 [‐0.83, 0.09]

2 Impairment ‐ CMTES (scale 0 to 28 points) Show forest plot	3	460	Mean Difference (IV, Fixed, 95% CI)	‐0.15 [‐0.57, 0.27]

3 Impairment ‐ NIS (scale ‐26 to 26 points) Show forest plot	1	110	Mean Difference (IV, Fixed, 95% CI)	1.91 [‐2.24, 6.06]

4 Disability ‐ ODSS (scale 0 to 12 points) Show forest plot	2	134	Mean Difference (IV, Fixed, 95% CI)	‐0.09 [‐0.36, 0.18]

5 Disability ‐ ONLS (scale 0 to 12 points) Show forest plot	2	289	Mean Difference (IV, Fixed, 95% CI)	0.07 [‐0.02, 0.17]

6 Disability ‐ ALDS (scale 0 to 100 points) Show forest plot	1	11	Mean Difference (IV, Fixed, 95% CI)	‐1.3 [‐4.28, 1.68]

7 CMAP, ulnar nerve (abductor digiti minimi) Show forest plot	2	161	Mean Difference (IV, Fixed, 95% CI)	0.13 [‐0.34, 0.59]

8 CMAP, median nerve (abductor pollicis brevis) Show forest plot	1	11	Mean Difference (IV, Fixed, 95% CI)	‐0.18 [‐1.19, 0.83]

9 CMAP summatory from ulnar, median and peroneal nerves Show forest plot	1	217	Mean Difference (IV, Fixed, 95% CI)	0.23 [‐0.48, 0.94]

10 Sensation ‐ INCAT Sensory Sum score (scale 0 to 20 points) Show forest plot	1	10	Mean Difference (IV, Fixed, 95% CI)	‐2.0 [‐5.53, 1.53]

11 SNAP amplitude Show forest plot	1	123	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.42, 0.42]

12 Hand grip Show forest plot	3	412	Mean Difference (IV, Fixed, 95% CI)	1.39 [‐4.17, 6.95]

13 Three‐point pinch Show forest plot	3	300	Mean Difference (IV, Fixed, 95% CI)	0.60 [‐1.53, 2.73]

14 Foot dorsiflexion Show forest plot	4	423	Mean Difference (IV, Fixed, 95% CI)	1.10 [‐3.47, 5.67]

15 Quality of life ‐ SF36 ‐ physical functioning Show forest plot	4	522	Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐1.32, 1.22]

16 Quality of life ‐ SF36 ‐ bodily pain Show forest plot	3	401	Mean Difference (IV, Fixed, 95% CI)	‐0.53 [‐2.69, 1.62]

17 Quality of life ‐ SF36 ‐ energy Show forest plot	2	291	Mean Difference (IV, Fixed, 95% CI)	0.45 [‐2.84, 3.74]

18 Quality of life ‐ SF36 ‐ psychological Show forest plot	1	123	Mean Difference (IV, Fixed, 95% CI)	0.90 [‐2.65, 4.45]

19 Quality of life ‐ SF36 ‐ MCS Show forest plot	1	110	Mean Difference (IV, Fixed, 95% CI)	0.46 [‐3.80, 4.72]

20 Quality of life ‐ SF36 ‐ PCS Show forest plot	1	110	Mean Difference (IV, Fixed, 95% CI)	0.39 [‐2.98, 3.76]

21 9‐hole peg test Show forest plot	3	286	Mean Difference (IV, Fixed, 95% CI)	‐0.39 [‐0.76, ‐0.02]

22 Timed 10 m walk Show forest plot	3	401	Mean Difference (IV, Fixed, 95% CI)	‐0.02 [‐0.32, 0.29]

23 50 m walk Show forest plot	1	11	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐2.49, 1.89]

Comparison 1. Ascorbic acid versus placebo 12 months (adults)

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Comparison 2. Ascorbic acid versus placebo 24 months (adults)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Impairment ‐ CMTNS (scale 0 to 36 points) Show forest plot	3	388	Mean Difference (IV, Fixed, 95% CI)	‐0.21 [‐0.81, 0.39]

2 Impairment ‐ CMTES (scale 0 to 28 points) Show forest plot	2	337	Mean Difference (IV, Fixed, 95% CI)	‐0.12 [‐0.67, 0.42]

3 Disability ‐ ONLS (scale 0 to 12 points) Show forest plot	2	276	Mean Difference (IV, Fixed, 95% CI)	0.14 [‐0.05, 0.34]

4 CMAP, ulnar nerve (abductor digiti minimi) Show forest plot	2	161	Mean Difference (IV, Fixed, 95% CI)	0.06 [‐0.10, 0.23]

5 Hand grip Show forest plot	2	186	Mean Difference (IV, Fixed, 95% CI)	1.25 [‐3.86, 6.37]

6 Three‐point pinch Show forest plot	2	276	Mean Difference (IV, Fixed, 95% CI)	0.73 [‐3.62, 5.08]

7 Foot dorsiflexion Show forest plot	2	278	Mean Difference (IV, Fixed, 95% CI)	0.77 [‐7.21, 8.76]

8 Quality of life ‐ SF36 ‐ physical functioning Show forest plot	3	382	Mean Difference (IV, Fixed, 95% CI)	‐0.07 [‐2.41, 2.26]

9 Quality of life ‐ SF36 ‐ bodily pain Show forest plot	3	385	Mean Difference (IV, Fixed, 95% CI)	‐1.57 [‐4.93, 1.80]

10 Quality of life ‐ SF36 ‐ energy Show forest plot	2	267	Mean Difference (IV, Fixed, 95% CI)	0.71 [‐3.35, 4.77]

11 9‐hole peg test Show forest plot	2	275	Mean Difference (IV, Fixed, 95% CI)	‐1.16 [‐1.96, ‐0.37]

12 Timed 10 m walk Show forest plot	2	278	Mean Difference (IV, Fixed, 95% CI)	0.09 [‐0.64, 0.82]

13 PMP22 mRNA (skin biopsy) Show forest plot	2	114	Mean Difference (IV, Fixed, 95% CI)	‐0.05 [‐0.13, 0.03]

Comparison 2. Ascorbic acid versus placebo 24 months (adults)

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Comparison 3. Ascorbic acid vs placebo (children)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 CMAP amplitude (M. abductor pollicis brevis) Show forest plot	1	80	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐0.75, 1.35]

2 Hand grip Show forest plot	1	80	Mean Difference (IV, Fixed, 95% CI)	9.80 [‐18.10, 37.70]

3 Finger pinch Show forest plot	1	80	Mean Difference (IV, Fixed, 95% CI)	1.60 [‐1.84, 5.04]

4 Foot dorsiflexion Show forest plot	1	80	Mean Difference (IV, Fixed, 95% CI)	‐1.0 [‐11.90, 9.90]

5 Foot plantar flexion Show forest plot	1	80	Mean Difference (IV, Fixed, 95% CI)	‐10.20 [‐36.29, 15.89]

6 Median nerve motor conduction velocity Show forest plot	1	80	Mean Difference (IV, Fixed, 95% CI)	2.0 [‐0.89, 4.89]

7 9‐hole peg test Show forest plot	1	78	Mean Difference (IV, Fixed, 95% CI)	‐0.80 [‐2.85, 1.25]

8 6 min walk Show forest plot	1	65	Mean Difference (IV, Fixed, 95% CI)	‐3.0 [‐32.34, 26.34]

9 Balance Show forest plot	1	74	Mean Difference (IV, Fixed, 95% CI)	‐1.30 [‐4.62, 2.02]

10 Agility Show forest plot	1	72	Mean Difference (IV, Fixed, 95% CI)	‐1.70 [‐5.43, 2.03]

11 Long jump Show forest plot	1	72	Mean Difference (IV, Fixed, 95% CI)	2.20 [‐11.10, 15.50]

12 Speed Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐9.33, 8.93]

13 Cadence Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	0.80 [‐6.54, 8.14]

14 Step time Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.05, 0.05]

15 Step length Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	‐0.90 [‐4.97, 3.17]

16 Stride length Show forest plot	1	53	Mean Difference (IV, Fixed, 95% CI)	‐1.80 [‐9.58, 5.98]

Comparison 3. Ascorbic acid vs placebo (children)

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Referencias

References to studies included in this review

Burns 2009 {published data only}

Lewis 2013 {published data only}

Mazanec 2013 [pers comm] {unpublished data only}

Micallef 2009 {published data only}

Pareyson 2011 {published data only}

Verhamme 2009a {published data only}

References to studies excluded from this review

Toth 2009 {published data only}

Additional references

Anderson 1996

Auer‐Grumbach 2013

Baets 2014

Baxter 2002

Bird 2014

Braathen 2012

Burns 2012

Chance 1993

Cornblath 1999

d'Ydewalle 2012

Dyck 2005b

Eldridge 1987

Gabreels‐Festen 1993

Gess 2010

Gess 2011

Gess 2013

GRADEpro 2015 [Computer program]

Grandis 2005

Hahn 2001

Harding 1980

Hayasaka 1993a

Hayasaka 1993b

Hayasaka 1993c

Higgins 2011

Jenkinson 1993

Komyathy 2013

Krajewski 1999

Krajewski 2000

Kurihara 2002

Liu 2014

Lupski 1991

Mannil 2014

Martini 2001

Merkies 2000

Murphy 2011

Murphy 2012

Nelis 1996

Nicholson 1993

Nobbio 2014

Pareyson 2014

Passage 2004

Raeymakers 1991

Reilly 2006

Review Manager 2014 [Computer program]

Rossor 2012

Rossor 2013

Saporta 2011

Senderek 2003

Shy 2005a

Shy 2005b

Timmerman 1992

Vallat 2013

van Swieten 1988

Verhamme 2009b

Verhoeven 2006

Young 2001

Zimon 2012

Zuchner 2004

References to other published versions of this review

Young 2006

Young 2008

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Characteristics of excluded studies [ordered by study ID]

Data and analyses

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