title: Assessment of blinding to treatment allocation in studies of a cannabis-based medicine (Sativex®) in people with multiple sclerosis: a new approach.
abstract: BACKGROUND
  Maintenance of the blind-to-treatment allocation is one of the most important means of avoiding bias in randomised controlled clinical trials. Commonly used methodologies to determine whether patients have become unblinded to treatment allocation are imperfect. This may be of particular concern in studies where outcomes are patient-reported, and with products which have a characteristic adverse event profile. We report the results of an evidence-based statistical approach to exploring the possible impact of unblinding to a cannabis-based medicine (Sativex®) in people with muscle spasticity due to multiple sclerosis.
  
  
  METHODS
  All 666 patients included in three Phase III placebo-controlled studies were included in this analysis. The relationship between factors that might permit patients to identify their treatment allocation and the effect of treatment on the self-reported primary outcome measure was investigated using a general linear model where the dependent variable was the change from baseline in patient self-reported spasticity severity, and the various possible explanatory factors were regarded as fixed factors in the model.
  
  
  RESULTS
  There was no significant relationship between the effect of Sativex® on spasticity and the prior use of cannabis or the incidence of 'typical' adverse events. Nor was there any significant relationship between the prior use of cannabis and the incidence of 'typical' adverse events, nor between prior use of cannabis and dose of Sativex®.
  
  
  CONCLUSIONS
  There is no evidence to suggest that there was widespread unblinding to treatment allocation in these three studies. If any patients did become unblinded, then there is no evidence that this led to bias in the assessment of the treatment difference between Sativex® and Placebo for efficacy, adverse events or study drug dosing. This methodology may be suitable for assessment of the integrity of the blind in other randomized clinical trials.
authors.affiliation: GW Pharma, Ltd, Porton Down Science Park, Salisbury, Wiltshire, SP4 0JQ, UK. swright@gwpharm.com
authors.forename: Stephen
authors.initials: S
authors.lastname: Wright
authors.forename: Paul
authors.initials: P
authors.lastname: Duncombe
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Altman
mesh_terms: D015982:Bias; D002185:Cannabidiol; D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D004311:Double-Blind Method; D013759:Dronabinol; D004338:Drug Combinations; D006801:Humans; D016014:Linear Models; D008385:Marijuana Smoking; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D009128:Muscle Spasticity / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D009465:Neuromuscular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D010936:Plant Extracts / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design; D057566:Self Report; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D004338:Drug Combinations; D009465:Neuromuscular Agents; D010936:Plant Extracts; D002185:Cannabidiol; D013759:Dronabinol; C587251:nabiximols