Micallef 2009.
| Methods | Block‐randomised, double‐blind, placebo‐controlled, multicentre trial Duration: 12 months |
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| Participants | Participants were recruited from 3 hospital sites in France 195 patients were initially screened and 179 (110 women and 69 men) with a clinical diagnosis of CMT1A confirmed by genotyping with duplication in 17p11.2 were subsequently randomised prior to intervention Participants were aged between 18 and 70 years of age and had to have at least one motor symptom or sign (gait disorder, distal amyotrophy, foot deformation or muscle weakness). People with any cause of neuropathy other than CMT1A and other medical conditions: kidney stones, hypersensitivity or intolerance to ascorbic acid or lactose, uncorrected oxalosis, cardiovascular disease, poliomyelitis or radiotherapy, those for whom ascorbic acid supplementation was contra‐indicated, women of childbearing age who were pregnant, breastfeeding or not using adequate contraception, were excluded |
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| Interventions | Participants were randomised in a 1:1:1 ratio to ascorbic acid 1 g, (n = 56), ascorbic acid 3 g (n = 61) or placebo containing lactose (n = 62), all given as a single daily administration of 3 hard gelatine capsules for 12 months. | |
| Outcomes | Primary outcome: Charcot‐Marie‐Tooth neuropathy score (CMTNS) at 12 months after commencement of intervention Secondary outcomes
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| Funding | No indication of funding given | |
| Declarations of interest | One study author (MF) is one of the inventors of the patent for ascorbic acid for the treatment of CMT1A licensed to Murigenetics. Two of the study authors (MF and OB) are scientific advisers to Murigenetics and are 15% shareholders in the company. | |
| Notes | Participants were recruited from Sept 2005 to September 2007 | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Block randomisation stratified to site and sex for subgroup analyses with sequence generation using an independent contract research organisation |
| Allocation concealment (selection bias) | Low risk | Randomisation list sent to an independent research organisation for preparation of ascorbic acid and placebo capsule (identical hard gelatine capsules) |
| Blinding (performance bias and detection bias) All outcomes | Low risk | Ascorbic acid and placebo formulated from hard gelatine capsules (identical in weight, appearance and taste). Placebo contained lactose |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Analyses were on an intention‐to‐treat basis. Reporting of dropouts (total 16) was effective: 6 withdrew (1 in placebo, 4 in 1g ascorbic acid and 1 in 3 g ascorbic acid group) due to adverse events (cystitis, myalgia, gastralgia, depression, colitis and insomnia), 2 were lost to follow up (1 in placebo and 1 in 3 g ascorbic acid group), 6 withdrew consent (1 in placebo, 4 in 1 g ascorbic acid and 1 in 3 g ascorbic acid), 1 was non‐compliant with treatment in the placebo group and 1 placebo participant was missing a baseline CMTNS score |
| Selective reporting (reporting bias) | Low risk | All stated primary and secondary outcomes were fully reported |
| Other bias | Unclear risk | Intention‐to‐treat analysis meant sufficient sample size for adequate power. No indication of how missing data were dealt with for intention‐to‐treat analyses. Therefore difficult to determine risk of bias due to method |