The statistical analysis plan (SAP) was finalised and agreed by the TSC before unblinding. Data analysis, using the statistical software R version 2.14.2 (The R Foundation for Statistical Computing, Vienna, Austria), was undertaken on an ITT basis. All tests were carried out at the 5% significance level, with no adjustments for multiple testing.
In models for each outcome, main effects of study site, baseline EDSS score, disease type, age at registration, sex and weight were considered, as well as treatment allocation.
Pre-specified analyses of primary clinical outcomes
Primary analysis of time to first Expanded Disability Status Scale score progression
Kaplan–Meier estimates were used to show probability of EDSS score progression in the two treatment groups and in groups defined in terms of baseline EDSS score. Analysis of time to first EDSS score progression used a Cox proportional hazards (PH) model. Primary analysis was based on EDSS data obtained according to trial schedule; losses to follow-up before confirmed progression were considered as missing data and treated as censored observations at the time of the last visit for which EDSS measurements were taken.
METHODS: MAIN STUDY AND MAGNETIC RESONANCE IMAGING SUBSTUDY
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Sensitivity analyses of time to first Expanded Disability Status Scale score progression
Sensitivity of conclusions from the main analysis of time to first EDSS score progression were assessed by repeating the analysis, considering all losses to follow-up as progression events at the time of the scheduled visit after the last visit for which EDSS measurements were taken.
Evidence for the sensitivity of conclusions to the effect of study sites with high losses to follow-up was assessed by repeating the analysis, under each way of dealing with losses to follow-up (censored
observations or progression events), sequentially removing study sites with high rates of loss to follow-up. Furthermore, sensitivity of conclusions to the decisions from the EPC review regarding EDSS score
progressions was assessed by repeating the analysis, under each way of dealing with losses to follow-up, incorporating the findings from the EPC review.
Subgroup analyses of time to first Expanded Disability Status Scale score progression
Hazard ratios (active : placebo) for EDSS score progression, in subgroups defined by sex, baseline EDSS score, disease type, weight and age, were estimated.
Primary analysis of change in Multiple Sclerosis Impact Scale-29 20-point physical subscale
Total MSIS-29phys scores were calculated using previously published methods.6Repeated measures data
on MSIS-29phys were analysed using multilevel models, which included time (visit) as well as the other pre-specified covariates. Individual differences in scores were incorporated using random coefficients.7
Backward elimination was used to identify a final, reduced model, including effects significant at the 5% level, as well as effects of time and treatment allocation.
Pre-specified analyses of secondary clinical outcomes
Multiple Sclerosis Functional Composite, Multiple Sclerosis Walking Scale-12, Rivermead Mobility Index, Short Form questionnaire-36 items (physical health subscale), Multiple Sclerosis Spasticity Scale-88
Scores for each MSFC component were calculated using previously published methods.8MSFC
component-wisez-scores9were computed using results from all participants at visit 2 as the reference
population.8MSFC composite scores were calculated from the mean of the component-wisez-scores.
Total scores for MSWS-12v2,10RMI,6SF-36v2 physical health subscale [SF-36(PH)]11and MSSS-8812were
calculated using an algorithm analogous to that used for MSIS-29phys for dealing with missing data. Repeated measures of MSFC (composite and component-wisez-scores), MSWS-12v2 (total score),
RMI (total score), SF-36(PH) (total score) and MSSS-88 [total score for each of three sections from the eight subscales, where MSSS-88 (1) combines subscales 1–3 and concerns muscle stiffness/spasms, pain and discomfort; MSSS-88 (2) combines subscales 4–6 and concerns activity, walking and body movements; and MSSS-88 (3) combines subscales 7 and 8 and concerns feelings and social functioning], were analysed using multilevel models, using the same covariates and variable selection procedure as for MSIS-29phys.
Investigation of adverse events and serious adverse events
Serious adverse events and the most common AEs (i.e. those which affected at least 10% of all participants) were summarised in terms of frequencies and relative frequencies.
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Category rating scales
Category rating scales, included in patient-completed questionnaires sent at 3 months, 1, 2 and 3 years from baseline (visits 5, 7, 9 and 11), consisted of 16 questions: 1–8 related to how the patient felt over the past week and 9–16 related to how the patient felt at the time of completing the questionnaire compared with just before the start of the study. Analysis focused on questions 9–16, which were on a 1–11 scale, where 1=very much better; 6=no difference; and 11=very much worse. Responses to these questions were grouped as 1–5=better; 6=no change; 7–11=worse and summarised in terms of frequencies and relative frequencies in the two treatment groups, at each follow-up. Chi-squared tests for trend were used to test for an association between treatment allocation and response to question, allowing for the ordered nature of the grouped responses. No adjustments were made for multiple comparisons.
Analysis of premature discontinuations of trial medication and losses to follow-up
Kaplan–Meier estimates were used to show probability of discontinuation of trial medication in the two treatment groups. Analyses of time to discontinuation of trial medication or loss to follow-up used Cox PH models, in order to investigate the effect of treatment allocation and any potential pre-randomisation variables, on the risk of discontinuation. A forward selection procedure was used to identify a suitable model, including effects significant at the 5% level.
Pre-specified analyses of magnetic resonance imaging substudy
A multilevel model was used to analyse repeated measures data on PBVC13,14from cranial MRI,
transformed to cumulative, relative PBVC on the log10scale.
Logistic regression models were used to examine the effect of treatment allocation and other pre-specified covariates on new T1 hypointense and new or enlarging T2 hyperintense lesions during follow-up.
Participants were classified as having either no, or at least one, new or enlarging lesion(s) during follow-up. Final models were identified using a forward selection procedure and included main effects and interactions significant at the 5% level, as well as the main effect of treatment.
Further analyses
Details of post-hoc exploratory analyses performed on outcomes from the main study and MRI substudy are presented inChapter 4.
One of the goals of the CUPID trial was to examine the contribution of advanced, but not widely used, methods, particularly rating scale psychometric methods. With this in mind we undertook a RMT-based analysis of data generation by the MSIS-29v2, MSWS-12v2 and MSSS-88. Specifically, when compared with traditional psychometric methods, RMT enables a more sophisticated evaluation of rating scale performance, the generation (contingent on appropriate findings) of interval-level measurements for analysis (rather than ordinal scores) and legitimate analyses of changes and differences at the individual person level. These methods are studied in detail inChapter 5. An economic evaluation is detailed in Chapter 6.