Results: main study and magnetic resonance imaging substudy

Susan Ball; Jane Vickery; Jeremy Hobart; Dave Wright; Colin Green; James Shearer; Andrew Nunn; Mayam Gomez Cano; David MacManus; David Miller; Shahrukh Mallik; John Zajicek

Chapter 3Results: main study and magnetic resonance imaging substudy

Patients were randomised between May 2006 and July 2008 and the final follow-up data collection took place in January 2012.

Unblinding of randomised treatments

The treatment allocation was unblinded six times during the course of the trial at the request of the sponsor organisation to assist in the management of suspected unexpected serious adverse reactions (SUSARs). In addition, unblinding of four participants at four separate sites was carried out at the request of the local investigator, on clinical grounds.

Telephone-based assessment of Expanded Disability Status Scale score

Of 3812 assessments of EDSS score over the study period, 42 (1.1%) were by telephone, rather than face to face. These telephone assessments were carried out on a total of 39 patients (25 assigned to active; 14 assigned to placebo).

Figure 1 shows the trial profile and Table 3 shows discontinuations of trial medication and losses to follow-up. A total of 498 patients were randomly assigned to active treatment (n = 332) or matching placebo (n = 166). The data from three patients (two randomised to active, one to placebo) were removed from the trial because they withdrew their consent after randomisation. A further two patients (one randomised to active, one to placebo) were found to be ineligible after randomisation. Four hundred and ninety-three (329 active, 164 placebo) received their allocated intervention and were therefore included in an ITT analysis. Of the 493 randomised and treated participants, 415 (84%) completed follow-up, of whom 119 (29%) had prematurely discontinued trial medication (Figure 1).

FIGURE 1

The Consolidated Standards of Reporting Trials (CONSORT) flow diagram. a, Nine patients initially did not fulfil entry criteria, but did so on subsequent rescreening. DNA, did not attend; PEP, primary end point of EDSS score progression.

TABLE 3

Analysis set and study completion (all randomised patients)

Baseline comparability of randomised groups

Baseline patient and disease characteristics were similar in both treatment groups (Table 4). At baseline, 59% of participants were women, 61% had SPMS and 78% had an EDSS score of 6.0 or 6.5. There were no important differences in outcome measures assessed at baseline (Table 5).

TABLE 4

Baseline characteristics of patients by treatment group and overall

TABLE 5

Outcome variables at baseline for patients randomised to the two treatment groups

Prescribed dose of trial medication

Prescribed daily doses of trial medication at each 6-monthly follow-up are summarised in Table 6 for those patients not discontinuing trial medication and for all patients. Among those patients not withdrawing from trial medication (n = 178 active, n = 118 placebo), median prescribed daily dose during final year of follow-up was four capsules (25th–75th percentiles 2–6 capsules) in the active group compared with six (25th–75th percentiles 4–8 capsules) in the placebo group. Final year medians among all patients were four capsules (25th–75th percentiles 2.0–5.5) for active and six capsules (25th–75th percentiles 4–8 capsules) for placebo. Percentiles of prescribed daily dose among non-withdrawals, by treatment group and weight group, are shown in Figure 2.

TABLE 6

Prescribed daily dose of trial medication at each 6-monthly follow-up, by treatment group, among non-withdrawals and overall

FIGURE 2

Random urine testing to determine any illicit cannabis use

Results from urinalyses throughout the study are given in Table 7. These results showed little illicit cannabis use in the placebo group and an increasing proportion of negative test results within the active group over time.

TABLE 7

Frequency and relative frequency (%) of patients in each treatment group with a urine sample tested positive or negative for cannabinoid presence. The frequency and relative frequency of tests yielding no result is also given

The main results are summarised in Table 8 and detailed below.

TABLE 8

Summary of main results

Pre-specified analyses of primary clinical outcomes

Primary analysis of time to first confirmed Expanded Disability Status Scale score progression

Primary analysis using a Cox regression model showed no evidence of an effect of age (p = 0.36), disease type (p = 0.12), sex (p = 0.56), weight (p = 0.11) or treatment (p = 0.57; see Table 8) on time to confirmed EDSS score progression. The HR for first EDSS score progression event in patients randomly assigned to dronabinol compared with those assigned to placebo was 0.92 [95% confidence interval (CI) 0.68 to 1.23; see Table 8]. At trial completion, Kaplan–Meier estimates of the probability of EDSS score progression were 0.55 (95% CI 0.46 to 0.63) in the dronabinol group compared with 0.60 (95% CI 0.44 to 0.71) in the placebo group (Figure 3).

FIGURE 3

We noted evidence of some study site effects and of an effect of baseline EDSS score on time to confirmed progression (Figure 4). Most notably, relative to a baseline EDSS score of 4.0, there was an increased hazard of disease progression among those with a baseline EDSS score of 5.5 (HR 3.17, 95% CI 1.45 to 6.93; p = 0.004) and a reduced hazard among those with a baseline EDSS score of 6.5 (HR 0.49, 95% CI 0.24 to 0.98; p = 0.04). However, the numbers of participants in the individual EDSS groups are small (Figure 5), as are the numbers in some study sites (see Table 16 and Appendix 3).

FIGURE 4

Estimated HRs and 95% CIs for EDSS score progression from a Cox regression model. HRs for study sites are compared with site 01; HR for SPMS is compared with PPMS; active compared with placebo; each baseline EDSS is compared with a baseline EDSS score (more...)

FIGURE 5

TABLE 16

Premature discontinuations of trial medication and losses to follow-up, by study site

The global PH test gave no evidence that the PH assumption was violated (χ² = 36, 36 degrees of freedom; p = 0.47).

Sensitivity analyses of time to first confirmed Expanded Disability Status Scale score progression

Results of sensitivity analysis showed that when losses to follow-up were treated as progression events rather than censored observations, the estimated HR (active : placebo) for EDSS score progression changed to 1.11 (95% CI 0.86 to 1.44; see Table 8), but the estimated effect of treatment remained non-significant (p = 0.41). This change in HR might be because the dronabinol group had a higher proportion of losses to follow-up for EDSS assessment [56 of 71 (79%)] than the placebo group [15 of 71 (21%)] and represents a worst-case scenario in terms of patient deterioration and hence the potential benefit of dronabinol.

The EPC reviewed data on 95 patients [71 active (74.7%); 24 placebo (25.3%)], for which there were ambiguities regarding EDSS scores. The EPC considered 22 (12 active; 10 placebo) of these patients to have progressed. These patients had no confirmed progression according to the data collected from the trial schedule. A further four patients (three active; one placebo) were considered to have progressed prior to the time of progression determined from the trial schedule. Clinical information on the remaining 69 patients reviewed by the EPC either confirmed non-progression or was insufficient to draw any further conclusions over those made on the primary data. As a result, data derived following EPC review consisted of a total of 240 first progression events compared with 218 in the primary data (with losses to follow-up considered as censored observations in both).

Conclusions from the main analyses of time to first EDSS score progression were robust to sensitivity analyses in terms of whether or not conclusions from the EPC were considered in defining EDSS progressions under both approaches to dealing with losses to follow-up, that is treated as censored observations or as progression events (see Table 8).

Furthermore, estimated HRs (active : placebo) for EDSS score progression remained similar after sequential removal of study sites with high loss to follow-up rates, under each of the two ways of treating losses to follow-up and each of the two data sets, that is according to trial schedule or following EPC review (Figure 6).

FIGURE 6

Pre-specified subgroup analyses of time to first confirmed Expanded Disability Status Scale score progression

Pre-specified subgroup analyses of time to first EDSS score progression suggested a differential effect of treatment between participants with lower (4.0–5.5) and higher (6.0–6.5) baseline EDSS scores (Figure 7). There was little evidence of differential effects of treatment among subgroups defined in terms of sex, disease type, or age or weight at registration.

FIGURE 7

Estimated HRs (active : placebo) and 95% CIs for EDSS score progression by subgroup.

Primary analysis of change in Multiple Sclerosis Impact Scale-29 20-point physical subscale

A multilevel model fitted to repeated measures of MSIS-29phys score showed no evidence of an effect of treatment [estimated between-group difference (active–placebo) −0.91 points, 95% CI −2.01 to 0.19 points; p = 0.11; see Table 8], or of disease type, sex, weight or study site (data not shown; p > 0.05 for all).

It was estimated that MSIS-29phys score reduced by a mean of 1.4 points (95% CI 0.3 to 2.5 points; p = 0.02) for every 10-year increase in age. In both treatment groups, mean MSIS-29phys score decreased from baseline to month 3, after which it tended to increase (Figure 8).

FIGURE 8

Estimated mean MSIS-29phys score, with 95% CIs, at each visit, separated by treatment group. The numbers of patients with total scores calculated at each visit, in each treatment group, are given directly above the CI for placebo and directly below the (more...)

With the exception of a small reduction in MSIS-29phys score in patients with a baseline EDSS score of 5.0 compared with those with a score of 4.0, MSIS-29phys score tended to increase with increasing baseline EDSS score (data not shown).

Results from the primary analysis of repeated measures of MSIS-29phys remained unchanged after removal of non-significant terms from the fitted model and under an alternative analysis based on comparison of treatment groups in terms of change from baseline to last valid observation [estimated between-group difference (active–placebo) –1.4 points, 95% CI –3.3 to 0.4 points; p = 0.13].

Pre-specified analyses of secondary outcomes

Results of multilevel models fitted to data on the secondary outcomes MSWS-12v2, MSFC, RMI, SF-36(PH) and MSSS-88 are summarised in Table 8 and detailed below.

Multiple Sclerosis Walking Scale-12

A multilevel model fitted to repeated measures of MSWS-12v2 score showed no evidence of an effect of treatment [estimated effect –0.19 (95% CI –0.97 to 0.60); p = 0.74; see Table 8], or of disease type, sex or weight (data not shown; p > 0.05 for all). There was some evidence of study site effects (data not shown) and of effects of baseline EDSS score. Compared with those with a baseline EDSS score of 4.0, MSWS-12v2 was estimated to be, on average, 5.7 (95% CI 2.3 to 9.0), 6.1 (95% CI 3.7 to 8.5) and 9.3 (95% CI 6.8 to 11.8) points higher in those with a baseline EDSS score 5.5, 6.0 and 6.5, respectively. In both treatment groups, mean MSWS-12v2 score decreased from baseline to month 3, after which it tended to increase (Figure 9).

FIGURE 9

Estimated mean MSWS-12v2, with 95% CIs, at each visit, separated by treatment group. The numbers of patients with total scores calculated at each visit, in each treatment group, are given directly above the CI for placebo and directly below the CI for (more...)

Multiple Sclerosis Functional Composite

A multilevel model fitted to repeated measures of MSFC composite z-score showed no evidence of an effect of treatment; estimated between-group difference (active–placebo) –0.03 (95% CI –0.19 to 0.09; p = 0.72; see Table 8). Multilevel models fitted to the MSFC component-wise z-scores each showed no evidence of an effect of treatment. Estimated between-group differences (active–placebo) were: T25-FW –0.08 (95% CI –0.25 to 0.09; p = 0.37); 9-HPT 0.05 (95% CI –0.04 to 0.13; p = 0.28); and PASAT –0.01 (95% CI –0.10 to 0.09; p = 0.92). Across both treatment groups, mean T25-FW, 9-HPT and composite z-scores increased from baseline to week 1, after which they tended to decrease. After an initial increase at week 1, PASAT z-scores remained relatively constant over the 3-year study period (Figure 10).

FIGURE 10

Estimated mean MSFC composite (a), T25-FW (b), 9-HPT (c) and PASAT (d) z-scores, with 95% CIs, at each visit, separated by treatment group. The numbers of patients with scores calculated at each visit, in each treatment group, are given directly above (more...)

Rivermead Mobility Index

A multilevel model fitted to repeated measures of RMI showed no evidence of an effect of treatment [the estimated between-group difference (active–placebo) was 0.04 (95% CI –0.24 to 0.32; p = 0.76; see Table 8)] or of disease type, sex or weight (data not shown; p > 0.05 for all). There was some evidence of study site effects (data not shown) and of effects of baseline EDSS score. Compared with those with a baseline EDSS score of 4.0, RMI was estimated to be, on average, 1.57 points (95% CI 0.38 to 2.76 points), 2.44 points (95% CI 1.59 to 3.30 points) and 4.99 points (95% CI 4.10 to 5.88 points) lower in those with a baseline EDSS score of 5.5, 6.0 and 6.5, respectively. In both treatment groups, RMI decreased from baseline to 30 months, after which it remained fairly constant (Figure 11).

FIGURE 11

Estimated mean RMI, with 95% CIs, at each visit, separated by treatment group. The numbers of patients with total scores calculated at each visit, in each treatment group, are given directly above the CI for placebo and directly below the CI for active. (more...)

Short Form questionnaire-36 items (physical health subscale)

A multilevel model fitted to repeated measures of SF-36(PH) showed no evidence of an effect of treatment [the estimated between-group difference (active–placebo) was –0.15 (95% CI –0.83 to 0.53; p = 0.67; see Table 8)], or of disease type, sex or weight (data not shown; p > 0.05 for all). In both treatment groups, mean SF-36(PH) score increased from baseline to month 3, after which it tended to decrease (Figure 12).

FIGURE 12

Estimated mean SF-36(PH), with 95% CIs, at each visit, separated by treatment group. The numbers of patients with total scores calculated at each visit, in each treatment group, are given directly above the CI for placebo and directly below the CI for (more...)

With the exception of a small increase in SF-36(PH) score in patients with a baseline EDSS score of 5.0 compared with those with a score of 4.0, SF-36(PH) score tended to decrease with increasing baseline EDSS score (data not shown).

Multiple Sclerosis Spasticity Scale-88

Figure 13 shows estimated mean MSSS-88 scores, with 95% CIs, by visit and treatment group, for each of the eight subscales.

FIGURE 13

For each of the physical components of the MSSS-88, subscales 1 to 6 inclusive, after an initial decrease from baseline to month 3, mean scores tended to increase. Estimated means were consistent across treatment groups, as seen by the overlapping CIs. For the two psychological components, subscales 7 and 8, after an initial decrease from baseline to month 3, mean scores remained relatively constant over the study period. Estimated mean scores for these components tended to be higher in the active group than in placebo, but any differences failed to reach statistical significance.

Multilevel models fitted to three groups of the MSSS-88, where MSSS-88 (1) combines subscales 1–3; MSSS-88 (2) combines subscales 4–6 and MSSS-88 (3) combines subscales 7 and 8 (as described in Chapter 2), each showed no evidence of an effect of treatment. Estimated between-group difference (active–placebo) for MSSS-88 (1) was 0.26 (95% CI –1.99 to 2.52; p = 0.82; see Table 8); for MSSS-88 (2) was –0.02 (95% CI –2.35 to 2.32; p = 0.99; see Table 8); and for MSSS-88 (3) was 1.00 (95% CI –0.70 to 2.70; p = 0.25; see Table 8). In both treatment groups, mean MSSS-88 (1) and mean MSSS-88 (2) decreased from baseline to month 3, after which they tended to increase (Figure 14). After an initial decrease from baseline to month 3, mean MSSS-88 (3) remained relatively constant over the study period (see Figure 14).

FIGURE 14

Investigation of adverse events and serious adverse events

The number of participants experiencing at least one SAE was 114 (35%) in the Δ⁹-THC group and 46 (28%) in the placebo group, the most common SAE being admission to hospital for MS-related events and infections. The number and nature of SAEs experienced was similar across treatment groups (Table 9).

TABLE 9

Occurrences of SAEs and the most common AEs

There were numerous non-serious AEs in both groups, consistent with the effects of MS and the known safety profile of cannabinoids. The median number of events per participant in the active group was 11 (25th–75th percentiles 7–17) compared with 10 (25th–75th percentiles 6–14) in the placebo group. Of those events judged to be either moderate or severe, the most frequent are documented in Table 9. Among these AEs, there was some suggestion that those participants on active treatment were more likely to experience dizziness or light-headedness and dissociative and thinking or perception disorders. On the other hand, a higher proportion of patients in the placebo group experienced musculoskeletal pain and aches than in the active group.

Six SAEs were classified as potential SUSARs in accordance with European clinical trials legislation. Three events occurred in each of the active and placebo groups. Trial treatment was discontinued in three participants as a result of the SAE. Three SAEs were classified as nervous system disorders: two were psychiatric events and one related to the gastrointestinal tract.

Category rating scales

Responses to questions 9–16 of the category rating scales, relating to how the patient felt at the time of completing the questionnaire, compared with just before the start of the study, have been grouped (as described in Chapter 2) and summarised, in terms of frequencies and relative frequencies in the two treatment groups, at each follow-up (Tables 10–13). Unadjusted p-values from chi-squared tests for trend are given.

TABLE 10

Frequencies and relative frequencies (%) of responses to category rating scale questions 9–16, by treatment group, at 3 months after baseline. Percentages are taken with respect to total number of patients in the corresponding treatment group (more...)

TABLE 13

Frequencies and relative frequencies (%) of responses to category rating scale questions 9–16, by treatment group, at 3 years after baseline. Percentages are taken with respect to total number of patients in the corresponding treatment group

Generally, a higher proportion of patients on active treatment than on placebo reported being more forgetful at the time of follow-up compared with before the study. At 3 months from baseline, there was an approximately twofold increase in proportion of responses classified as ‘worse’ in the active group compared with placebo (32% active, 15% placebo; p = 0.0067; see Table 10). These proportions were similar across treatment groups at 1-year follow-up (49% active, 42% placebo; p = 0.25; see Table 11), at 2 years there was an approximately 30% increase in ‘worse’ responses in the active group compared with placebo (57% active, 44% placebo; p = 0.037; see Table 12) and similarly at 3 years, with a 33% increase (60% active, 45% placebo; p = 0.11; see Table 13). Responses to the remaining questions were similar across treatment groups.

TABLE 11

Frequencies and relative frequencies (%) of responses to category rating scale questions 9–16, by treatment group, at 1 year after baseline. Percentages are taken with respect to total number of patients in the corresponding treatment group

TABLE 12

Frequencies and relative frequencies (%) of responses to category rating scale questions 9–16, by treatment group, at 2 years after baseline. Percentages are taken with respect to total number of patients in the corresponding treatment group

Analysis of premature discontinuations of trial medication and losses to follow-up

Of the 493 patients included in the ITT analysis, 119 (24.1%; 89 active, 30 placebo) prematurely discontinued trial medication but remained in follow-up. Seventy-eight patients (15.8%; 62 active, 16 placebo) were lost to follow-up, meaning that 296 (60%) patients completed the study on trial treatment.

There was evidence of an increased risk of discontinuation of trial medication in the active group compared with placebo (p < 0.001, log-rank test) (Figure 15).

FIGURE 15

Kaplan–Meier estimates of the probability of discontinuation of trial medication in the two treatment groups. Those patients who were lost to follow-up during the trial, without previous discontinuation of trial medication, are marked by +. Those (more...)

Reasons for discontinuation of trial medication or loss to follow-up were dominated by AEs, accounting for 65% of all early discontinuations (Table 14). Reasons for loss to follow-up are summarised in Table 15. The most common reasons were reported as ‘MS or other health issues’ and ‘other’, accounting for 50% (39 out of 78) of all losses to follow-up. ‘Travel or burden of the trial’ accounted for 22% (17 out of 78) of reasons for loss to follow-up and accounted for a larger proportion of losses in placebo patients [5 out of 16 (31%) compared with 12 out of 62 (19%) of the losses in the active group].

TABLE 14

Frequencies and relative frequencies (%) of reasons for discontinuation of trial medication or loss to follow-up, by treatment group, disease type, baseline EDSS, sex and overall

TABLE 15

Frequencies and relative frequencies (%) of reasons for loss to follow-up, by treatment group, disease type, baseline EDSS, sex and overall

Rates of discontinuations from trial medication or loss to follow-up varied across study sites (Table 16).

Following a forward selection procedure, a Cox regression model fitted to data on time to discontinuation of trial medication or loss to follow-up showed evidence of effects of treatment allocation, sex and study site on the risk of withdrawal or loss to follow-up. The risk of withdrawal or loss to follow-up was estimated to be higher in men than in women [HR (men : women) 1.37, 95% CI 1.02 to 1.84] and higher in the active group than in the placebo group [HR (active : placebo) 1.97, 95% CI 1.41 to 2.76].

Pre-specified analyses of magnetic resonance imaging substudy

Two hundred and seventy-four patients from 13 study sites were allocated to the MRI substudy. Of these, one patient was excluded at baseline visit (as baseline scan was deemed problematic, due to patient tremor).

Baseline data on demographic and disease characteristics were similar across treatment groups (Table 17). Fifty-nine per cent of patients were women, 64% had SPMS and 76% had an EDSS score of 6.0 or 6.5.

TABLE 17

Baseline characteristics of patients in the MRI substudy, by treatment group and overall

Forty-seven of the 182 patients (25.8%) on active treatment and 17 of the 91 patients (18.7%) on placebo were lost to follow-up during the study period. Figure 16 shows the flow of patients over the 3-year follow-up period.

FIGURE 16

Flow of participants through the MRI substudy.

Between-treatment-group comparisons of PBVC and numbers of new or enlarging T2 and new T1 lesions at each annual follow-up showed little evidence of an association between treatment allocation and these outcomes (Table 18).

TABLE 18

Descriptive statistics and between-treatment-group comparisons for MRI outcome measures at years 1, 2 and 3

A multilevel model fitted to cumulative PBVC showed no evidence of an effect of active treatment on brain atrophy compared with placebo over the course of the study [estimated between-group difference in PBVC (active–placebo) was −0.01%, 95% CI −0.26% to 0.24%; p = 0.94; see Table 8]. However, brain atrophy did change significantly over time (p < 0.0001); using a fitted model, cumulative PBVC was estimated to be a mean of −0.58% at year 1, −1.20% at year 2 and −2.02% at year 3 (Figure 17).

FIGURE 17

Estimated mean cumulative PBVC (%), and 95% CI, by treatment group, measured at yearly MRI visits. Green points, active treatment; black points, placebo. n, number of patients with cumulative PBVC calculated at each visit, given directly above the CI (more...)

There was evidence of an effect of baseline normalised brain volume (NBV) on brain atrophy. Using a fitted model, it was estimated that, for a 100-unit reduction in baseline NBV, brain atrophy increased by a mean of 0.21% (95% CI 0.08% to 0.34%; p = 0.003).

Treatment did not significantly affect the occurrence of new or newly enlarging T2 lesions [estimated odds ratio (OR) (active : placebo) 0.89, 95% CI 0.50 to 1.58; p = 0.70; see Table 8] or new T1 lesions [estimated OR (active : placebo) 1.05, 95% CI 0.59 to 1.88; p = 0.87; see Table 8].

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Copyright © Queen’s Printer and Controller of HMSO 2015. This work was produced by Ball et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

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NLM Citation

Ball S, Vickery J, Hobart J, et al. The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis. Southampton (UK): NIHR Journals Library; 2015 Feb. (Health Technology Assessment, No. 19.12.) Chapter 3, Results: main study and magnetic resonance imaging substudy.

FIGURE 1

TABLE 3

Analysis set and study completion (all randomised patients)

Analysis population and scenarios for follow-up	All randomised patients (N = 498)
Analysis population and scenarios for follow-up	Active (n = 329; 66.7%)		Placebo (n = 164; 33.3%)		All (n = 493)
Analysis population, n (%)
Full analysis set	329	(99.1)	164	(98.8)	493	(99.0)
Scenarios for follow-up, n (%) of full analysis set
Completed follow-up on trial treatment	178	(54.1)	118	(72.0)	296	(60.0)
Completed follow-up having prematurely discontinued trial medication	89	(27.1)	30	(18.3)	119	(24.1)
Discontinued trial medication and subsequently lost to follow-up	51	(15.5)	10	(6.1)	61	(12.4)
Lost to follow-up without previous discontinuation of trial medication	11	(3.3)	6	(3.7)	17	(3.4)

: Percentages may not sum to 100 due to rounding.

TABLE 4

Baseline characteristics of patients by treatment group and overall

Patient baseline characteristics	Randomised patients (N = 493;^a 100%)
Patient baseline characteristics	Active (n = 329; 66.7%)		Placebo (n = 164; 33.3%)		All (n = 493)
Age in years, mean (SD)	52.29	(7.6)	51.97	(8.2)	52.19	(7.8)
Weight in kg, mean (SD)	74.54	(16.5)	75.93	(16.5)	75.00	(16.5)
Men, n (%)	133	(40.4)	68	(41.5)	201	(40.8)
Women, n (%)	196	(59.6)	96	(58.5)	292	(59.2)
Disease type, n (%)^b
PPMS	126	(38.3)	65	(39.6)	191	(38.7)
SPMS	203	(61.7)	99	(60.4)	302	(61.3)
EDSS score, n (%)^b
4.0	20	(6.1)	9	(5.5)	29	(5.9)
4.5	18	(5.5)	7	(4.3)	25	(5.1)
5.0	22	(6.7)	10	(6.1)	32	(6.5)
5.5	16	(4.9)	8	(4.9)	24	(4.9)
6.0	169	(51.4)	85	(51.8)	254	(51.5)
6.5	84	(25.5)	45	(27.4)	129	(26.2)
Median (25th–75th percentiles)	6.0	(6.0–6.5)	6.0	(6.0–6.5)	6.0	(6.0–6.5)
Mean (SD)	5.83	(0.69)	5.88	(0.67)	5.85	(0.69)

a: Excluding five post-randomisation exclusions.

b: Stratification/minimisation variable.

: Percentages may not sum to 100 due to rounding.

TABLE 5

Outcome variables at baseline for patients randomised to the two treatment groups

Outcome measures at baseline	Randomised patients (N = 493;^a 100%)
Outcome measures at baseline	Active (n = 329; 66.7%)		Placebo (n = 164; 33.3%)		All (n = 493)
EDSS score^b
Mean (SD)	5.83	(0.69)	5.88	(0.67)	5.85	(0.69)
Median (25th–75th percentiles)	6.0	(6.0–6.5)	6.0	(6.0–6.5)	6.0	(6.0–6.5)
MSIS-29phys score^c
Mean (SD)	55.03	(10.81)	55.19	(10.96)	55.08	(10.85)
Median (25th–75th percentiles)	55	(47.00–63.00)	56	(47.25–63.00)	55.78	(47.00–63.00)
Not reported, n (%)	3	(0.9)	2	(1.2)	5	(1.0)
MSFC components^d
T25-FW
Time in seconds,^e mean (SD)	20.34	30.16	15.25	13.41	18.64	25.9
Median (25th–75th percentiles)	10.95	(7.95–18.60)	10.85	(7.85–16.55)	10.90	(7.90–17.54)
Not reported, n (%)	4	(1.2)	1	(0.6)	5	(1.0)
9-HPT (dominant hand)
Time in seconds, mean (SD)	36.74	(41.68)	38.65	(43.42)	37.37	(42.23)
Median (25th–75th percentiles)	27.27	(22.39–34.1)	27.4	(22.89–35.34)	27.33	(22.55–34.79)
Not reported, n (%)	1	(0.3)	0	(0.0)	1	(0.2)
9-HPT (non-dominant hand)
Time in seconds, mean (SD)	41.79	(49.31)	34.82	(27.13)	39.46	(43.3)
Median (25th–75th percentiles)	28.08	(23.25–36.94)	28.62	(24.74–35.45)	28.12	(23.44–36.55)
Not reported, n (%)	1	(0.3)	0	(0.0)	1	(0.2)
9-HPT (standard score)^f
Mean (SD)	0.04	(0.01)	0.03	(0.01)	0.04	(0.01)
Median (25th–75th percentiles)	0.04	(0.03–0.04)	0.04	(0.03–0.04)	0.04	(0.03–0.04)
Not reported, n (%)	1	(0.3)	0	(0.0)	1	(0.2)
PASAT score^g
Mean (SD)	41.43	(13.75)	41.02	(13.42)	41.29	(13.63)
Median (25th–75th percentiles)	43	(30–53)	42	(31–53)	43	(31–53)
Not reported, n (%)	2	(0.6)	3	(1.8)	5	(1.0)
MSWS-12v2^h
Mean (SD)	45.51	(6.96)	45.26	(7.14)	45.42	(7.01)
Median (25th–75th percentiles)	47	(42–51)	47	(41–51)	47	(41–51)
Not reported, n (%)	3	(0.9)	5	(3.0)	8	(1.6)
RMIⁱ
Mean (SD)	11.40	2.51	11.64	2.20	11.48	2.41
Median (25th–75th percentiles)	12	(10–13)	12	(10–13)	12	(10–13)
Not reported, n (%)	1	(0.3)	0	(0.0)	1	(0.2)
SF-36(PH)^j
Mean (SD)	44.31	6.08	44.18	5.76	44.26	5.97
Median (25th–75th percentiles)	44	(40.5–48.0)	44	(40.25–47.00)	44	(40–48)
Not reported, n (%)	2	(0.6)	2	(1.2)	4	(0.8)
MSSS-88
Section 1^k
Mean (SD)	71.97	21.14	73.60	22.10	72.51	21.45
Median (25th–75th percentiles)	70	(55–84)	71	(56–88)	70	(55.26–85.00)
Not reported, n (%)	2	(0.61)	1	(0.61)	3	(0.61)
Section 2^l
Mean (SD)	77.96	20.78	80.30	20.90	78.73	20.83
Median (25th–75th percentiles)	77	(63.5–93.0)	81	(66.00–94.97)	78.23	(64–94)
Not reported, n (%)	2	(0.61)	3	(1.83)	5	(1.00)
Section 3^m
Mean (SD)	44.29	15.13	45.19	15.67	44.59	15.30
Median (25th–75th percentiles)	42	(32–55)	44	(32.25–56.75)	43	(32.0–55.5)
Not reported, n (%)	8	(2.43)	2	(1.22)	10	(2.00)

a: Excluding five post-randomisation exclusions.

b: Higher score indicates greater disability.

c: Total score, calculated according to standard procedure for dealing with missing data, with a possible range from 20 to 80; a higher score indicates a greater physical impact of MS.

d: Measured during visit 2 (visit 1 was a practice visit).

e: A longer time indicates worse mobility and leg function.

f: Standard score, calculated as the mean of the reciprocal of the mean of the dominant hand score and the reciprocal of the mean of the non-dominant hand score; a higher score indicates greater finger dexterity.

g: Standard score, corresponding to the number of correctly answered questions out of 60; a higher score indicates greater capacity and rate of information processing.

h: Total score, calculated according to standard procedure for dealing with missing data, with a possible range from 12 to 52; a higher score indicates a greater walking impairment.

i: Total score, calculated according to standard procedure for dealing with missing data, with a possible range from 0 to 15; a lower score indicates worse mobility.

j: Total score for the physical component, calculated according to standard procedure for dealing with missing data, with a possible range from 12 to 112; a lower score indicates greater disability.

k: Total score from subscales 1–3, calculated according to standard procedure for dealing with missing data, with a possible range from 35 to 140; a higher score indicates greater distress.

l: Total score from subscales 4–6, calculated according to standard procedure for dealing with missing data, with a possible range from 32 to 128; a higher score indicates greater distress.

m: Total score from subscales 7–8, calculated according to standard procedure for dealing with missing data, with a possible range from 21 to 84; a higher score indicates greater distress.

TABLE 6

Prescribed daily dose of trial medication at each 6-monthly follow-up, by treatment group, among non-withdrawals and overall

Prescribed daily dose (number of capsules) of trial medication	Visit
	Week 5	Week 13	Month 7	Month 13	Month 19	Month 25	Month 31
Non-withdrawals (n = 296)
Active (n = 178)
n	177	176	177	178	178	177	177
Missing	1	2	1	0	0	1	1
Mean	5	4.48	4.26	4.06	4.05	3.99	3.91
SD	1.91	1.97	2.02	2	2.02	1.98	1.93
Median	5	4	4	4	4	4	4
25th percentile	4	3	3	2	2	2	2
75th percentile	6	6	6	6	6	6	5
Minimum	1	1	1	1	1	1	1
Maximum	8	8	8	8	8	8	8
Placebo (n = 118)
n	117	118	118	118	118	118	118
Missing	1	0	0	0	0	0	0
Mean	6.32	6.14	5.97	5.92	5.85	5.85	5.85
SD	1.57	1.67	1.81	1.91	1.92	1.92	1.92
Median	6	6	6	6	6	6	6
25th percentile	6	5.25	4	4	4	4	4
75th percentile	8	8	8	8	8	8	8
Minimum	2	1	1	1	1	1	1
Maximum	8	8	8	8	8	8	8
All patients (n = 493)
Active (n = 329)
n	315	290	260	235	215	198	189
Missing	14	39	69	94	114	131	140
Mean	4.98	4.31	4.08	3.94	3.91	3.94	3.91
SD	1.96	2	2.03	2.02	2.02	1.97	1.95
Median	5	4	4	4	4	4	4
25th percentile	4	3	2	2	2	2	2
75th percentile	6	6	6	6	6	6	5
Minimum	1	1	1	1	1	1	1
Maximum	8	8	8	8	8	8	8
Placebo (n = 164)
n	161	157	146	138	131	125	123
Missing	3	7	18	26	33	39	41
Mean	6.2	6.05	5.93	5.9	5.91	5.92	5.92
SD	1.57	1.68	1.76	1.89	1.89	1.91	1.92
Median	6	6	6	6	6	6	6
25th percentile	6	5	4	4	4	4	4
75th percentile	8	8	8	8	8	8	8
Minimum	2	1	1	1	1	1	1
Maximum	8	8	8	8	8	8	8

FIGURE 2

Percentiles of prescribed daily dose of trial medication among non-withdrawals at each visit, by treatment group and weight group. (a) Active, weight < 60 kg; (b) active, weight 60–80 kg; (c) active, weight > 80 kg; (d) placebo, weight < 60 kg; (e) placebo, weight 60–80 kg; and (f) active, weight > 80 kg. Heavy solid line, median; narrow solid lines, 25th and 75th percentiles; dashed lines, 5th and 90th percentiles. The maximum weight-related daily dose is superimposed in green.

TABLE 7

Visit	1 (N = 493)		2 (N = 16)		3 (N = 100)		4 (N = 117)		5 (N = 220)		6 (N = 215)		7 (N = 196)		8 (N = 217)		9 (N = 209)		10 (N = 194)		11 (N = 210)		AFU (N = 51)
Treatment group	Active	Placebo	Active	Placebo	Active	Placebo	Active	Placebo	Active	Placebo	Active	Placebo	Active	Placebo	Active	Placebo	Active	Placebo	Active	Placebo	Active	Placebo	Active	Placebo
n	329	164	10	6	60	40	71	46	155	65	142	73	133	63	136	81	136	73	119	75	131	79	34	17
Positive	1 (0.3)	0 (0.0)	0 (0.0)	0 (0.0)	59 (98.3)	1 (2.5)	67 (94.4)	1 (2.2)	138 (89.0)	0 (0.0)	114 (80.3)	0 (0.0)	103 (77.4)	0 (0.0)	105 (77.2)	4 (4.9)	108 (79.4)	3 (4.1)	91 (76.5)	2 (2.7)	93 (71.0)	1 (1.3)	3 (8.8)	3 (17.6)
Negative	328 (99.7)	164 (100.0)	10 (100.0)	6 (100.0)	1 (1.7)	38 (95.0)	3 (4.2)	45 (97.8)	17 (11.0)	65 (100.0)	28(19.7)	73 (100.0)	29 (21.8)	63 (100.0)	31 (22.8)	77 (95.1)	28 (20.6)	70 (95.9)	26 (21.8)	73 (97.3)	38 (29.0)	78 (98.7)	31 (91.2)	14 (82.4)
No result	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (2.5)	1 (1.4)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (0.8)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	2 (1.7)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)

: AFU, additional follow-up; N, total number of urine samples collected; n, number of urine samples within each treatment group.

TABLE 8

Summary of main results

Outcome measure	Summary statistics	Treatment group		Analysis	Estimated treatment effect (95% CI)	p-value
Main study		Active (n = 329)	Placebo (n = 164)
EDSS (all participants)	No. of first progression events	145	73	Primary: HR (active : placebo) from Cox regression analysis (losses to follow-up considered as censored observations)	0.92 (0.68 to 1.23)	0.57
	No. of first progression events per patient-year^a	0.24	0.23		0.92 (0.68 to 1.23)	0.57
	No. of first progression events	201	88	Sensitivity: HR (active : placebo) from Cox regression analysis (losses to follow-up considered as progression events)	1.11 (0.86 to 1.44)	0.41
	No. of first progression events per patient-year^a	0.34	0.27		1.11 (0.86 to 1.44)	0.41
	No. of first progression events	157	83	Sensitivity: HR (active : placebo) from Cox regression analysis (EPC derived data, losses to follow-up considered as censored observations)	0.88 (0.67 to 1.17)	0.39
	No. of first progression events per patient-year^a	0.26	0.26		0.88 (0.67 to 1.17)	0.39
	No. of first progression events	204	90	Sensitivity: HR (active : placebo) from Cox regression analysis (EPC-derived data, losses to follow-up considered as progression events)	1.11 (0.86 to 1.43)	0.42
	No. of first progression events per patient-year^a	0.34	0.28		1.11 (0.86 to 1.43)	0.42
				Subgroup analyses: HR (active : placebo) from Cox regression analysis	Baseline EDSS score of 4.0–5.5: 0.52 (0.32 to 0.85)	0.01
					Baseline EDSS score of 6.0: 1.15 (0.76 to 1.73)	0.51
					Baseline EDSS score of 6.5: 1.63 (0.85 to 3.10)	0.14
MSIS-29phys	Mean (SD) annual change	0.62 (3.29)	1.03 (3.74)	Multilevel model: estimated between-group difference (active–placebo)	–0.91 (–2.01 to 0.19)	0.11
MSFC composite (z-score)	Mean (SD) annual change	–0.17 (0.28)	–0.16 (0.30)	Multilevel model: estimated between-group difference (active–placebo)	–0.03 (–0.19 to 0.09)	0.72
T25-FW (z-score)	Mean (SD) annual change	–0.37 (0.73)	–0.41 (0.74)	Multilevel model: estimated between-group difference (active–placebo)	–0.08 (–0.25 to 0.09)	0.37
Main study		Active (n = 329)	Placebo (n = 164)
9-HPT (z-score)	Mean (SD) annual change	–0.13 (0.23)	–0.14 (0.27)	Multilevel model: estimated between-group difference (active–placebo)	0.05 (–0.04 to 0.13)	0.28
PASAT (z-score)	Mean (SD) annual change	–0.025 (0.21)	–0.0074 (0.20)	Multilevel model: estimated between-group difference (active–placebo)	–0.01 (–0.10 to 0.09)	0.92
MSWS-12v2	Mean (SD) annual change	0.37 (2.33)	0.52 (2.68)	Multilevel model: estimated between-group difference (active–placebo)	–0.19 (–0.97 to 0.60)	0.74
RMI	Mean (SD) annual change	–0.58 (0.96)	–0.72 (1.08)	Multilevel model: estimated between-group difference (active–placebo)	0.04 (–0.24 to 0.32)	0.76
SF-36(PH)	Mean (SD) annual change	–0.58 (2.07)	–0.49 (2.06)	Multilevel model: estimated between-group difference (active–placebo)	–0.15 (–0.83 to 0.53)	0.67
MSSS-88 (1)	Mean (SD) annual change	0.20 (6.25)	0.54 (7.42)	Multilevel model: estimated between-group difference (active–placebo)	0.26 (–1.99 to 2.52)	0.82
MSSS-88 (2)	Mean (SD) annual change	1.27 (6.71)	1.30 (6.50)	Multilevel model: estimated between-group difference (active–placebo)	–0.02 (–2.35 to 2.32)	0.99
MSSS-88 (3)	Mean (SD) annual change	–0.34 (4.88)	–0.97 (5.03)	Multilevel model: estimated between-group difference (active–placebo)	1.00 (–0.70 to 2.70)	0.25
MRI substudy		Active (n = 182)	Placebo (n = 91)
PBVC	Mean (SD) annual change	–0.68 (0.95)	–0.66 (0.98)	Multilevel model: estimated between-group difference (active–placebo)	–0.01 (–0.26 to 0.24)	0.94
Occurrence of new or enlarging T2 lesions	n (%)	60 (37)	34 (40)	Logistic regression model: estimated OR (active : placebo)	0.89 (0.50 to 1.58)	0.70
Occurrence of new or enlarging T1 lesions	n (%)	54 (34)	28 (33)	Logistic regression model: estimated OR (active : placebo)	1.05 (0.59 to 1.88)	0.87

: CI, confidence interval; OR, odds ratio.

a: Assuming progression events occur at the mid-point of the 6 month period between follow-ups.

FIGURE 3

Kaplan–Meier estimates of the probability of progression on the EDSS in the two treatment groups, confirmed after 6 months within the study period. The numbers at risk (cumulative number of censored observations) are given. Those patients who were lost to follow-up during the trial are marked by +. Those who reached the end of the trial without progressing are marked by x.

FIGURE 4

FIGURE 5

Kaplan–Meier estimates of the probability of progression on the EDSS, by baseline EDSS score, confirmed after 6 months within the study period. The numbers at risk (cumulative number of censored observations) are given. Those patients who were lost to follow-up during the trial are marked by +. Those who reached the end of the trial without progressing are marked by x. BL, baseline.

FIGURE 6

Estimated HRs (active : placebo) for EDSS score progression, with 95% CIs and p-values from Cox regression models, sequentially removing study sites with high loss to follow-up for each of the two data sets and each of the two ways of dealing with losses to follow-up. (a) Data = according to trial schedule, losses to follow-up = censored observations; (b) data = according to trial schedule, losses to follow-up = progression events; (c) data = following EPC review, losses to follow-up = censored observations; and (d) data = following EPC review, losses to follow-up = progression events. The two rows of n (%) on horizontal axes show top row = number of sites removed (% losses to follow-up in remaining data); bottom row = site number removed (within-site % losses to follow-up). n, number of participants included in each fitted model.

FIGURE 7

Estimated HRs (active : placebo) and 95% CIs for EDSS score progression by subgroup.

FIGURE 8

FIGURE 9

FIGURE 10

FIGURE 11

FIGURE 12

FIGURE 13

Estimated mean MSSS-88 subscales 1–8 scores, with 95% CIs, at each visit, separated by treatment group. The numbers of patients with total scores calculated at each visit, in each treatment group, are given directly above the CI for placebo and directly below the CI for active. Subscales relate to how bothered the patient has been by their spasticity in the past 2 weeks, where 1 = muscle stiffness; 2 = pain and discomfort; 3 = muscle spasms; 4 = effect of spasticity on daily activities; 5 = effect of spasticity on ability to walk; 6 = effect of spasticity on body movements; 7 = effect of spasticity on feelings; and 8 = effect of spasticity on social functioning. Green points, active treatment; black points, placebo.

FIGURE 14

Estimated mean MSSS-88 (1) total score from subscales 1–3, concerning muscle stiffness/spasms, pain and discomfort; MSSS-88 (2) total score from subscales 4–6, concerning activity, walking and body movements; and MSSS-88 (3) total score from subscales 7 and 8, concerning feelings and social functioning, with 95% CIs, at each visit, separated by treatment group. The numbers of patients with total scores calculated at each visit, in each treatment group, are given directly above the CI for placebo and directly below the CI for active. Green points, active treatment; black points, placebo.

TABLE 9

Occurrences of SAEs and the most common AEs

Classification or description of event	Number of patients (% of group)
Classification or description of event	Active (n = 329)	Placebo (n = 164)	All (n = 493)
SAEs
Death	6 (1.8)	1 (0.6)	7 (1.4)
Admission to hospital	106 (32)	44 (27)	150 (30)
Life-threatening or important medical event	10 (3.0)	4 (2.4)	14 (2.8)
At least one of the above	114 (35)	46 (28)	160 (32)
Most common AEs
Falls and injuries	101 (31)	51 (31)	152 (31)
Mobility, balance and co-ordination problems	108 (33)	43 (26)	151 (31)
Infections (excluding urinary tract)	95 (29)	47 (29)	142 (29)
Fatigue and tiredness	81 (25)	38 (23)	119 (24)
Dizziness and light-headedness	105 (32)	12 (7)	117 (24)
Muscle disorders (spasticity, stiffness, spasms or tremor)	78 (24)	38 (23)	116 (24)
Muscle disorders (weakness)	74 (22)	32 (20)	106 (22)
Dissociative and thinking or perception disorders	98 (30)	6 (4)	104 (21)
Mood disorders (depression)	66 (20)	26 (16)	92 (19)
Musculoskeletal pain and aches	49 (15)	41 (25)	90 (18)
Constipation, diarrhoea, faecal incontinence	56 (17)	22 (13)	78 (16)
Joint disorders	47 (14)	28 (17)	75 (15)
Urinary tract infections	44 (13)	28 (17)	72 (15)

TABLE 10

Visit 5 (3 months after baseline)	Better (scores 1–5)		No change (score 6)		Worse (scores 7–11)		p-value^a
Visit 5 (3 months after baseline)	Active	Placebo	Active	Placebo	Active	Placebo	p-value^a
Fatigue (n = 422; n_a = 276; n_p = 146)	58 (21)	27 (18)	118 (43)	67 (46)	100 (36)	52 (36)	0.80
Forgetfulness (n = 386; n_a = 254; n_p = 132)	32 (13)	18 (14)	141 (56)	94 (71)	81 (32)	20 (15)	0.0067
Sensory loss or numbness (n = 394; n_a = 254; n_p = 140)	40 (16)	21 (15)	152 (60)	74 (53)	62 (24)	45 (32)	0.21
Co-ordination (n = 445; n_a = 290; n_p = 155)	188 (65)	107 (69)	35 (12)	19 (12)	67 (23)	29 (19)	0.29
Irritability (n = 370; n_a = 238; n_p = 132)	43 (18)	22 (17)	130 (55)	80 (61)	65 (27)	30 (23)	0.65
Depression (n = 356; n_a = 238; n_p = 118)	43 (18)	27 (23)	130 (55)	67 (57)	65 (27)	24 (20)	0.12
Tremor (n = 438; n_a = 284; n_p = 154)	34 (12)	20 (13)	103 (36)	64 (42)	147 (52)	70 (45)	0.29
Bladder problems (n = 412; n_a = 270; n_p = 142)	56 (21)	30 (21)	129 (48)	72 (51)	85 (31)	40 (28)	0.61

: n, total number of patients; n_a, total number of patients in active treatment group; n_p, total number of patients in the placebo group.

a: From chi-squared test for trend (with 1 degree of freedom), with no adjustments for multiple comparisons.

TABLE 11

Visit 7 (1 year after baseline)	Better (scores 1–5)		No change (score 6)		Worse (scores 7–11)		p-value^a
Visit 7 (1 year after baseline)	Active	Placebo	Active	Placebo	Active	Placebo	p-value^a
Fatigue (n = 385; n_a = 250; n_p = 135)	32 (13)	25 (19)	80 (32)	39 (29)	138 (55)	71 (53)	0.29
Forgetfulness (n = 340; n_a = 222; n_p = 118)	18 (8)	12 (10)	96 (43)	56 (47)	108 (49)	50 (42)	0.25
Sensory loss or numbness (n = 348; n_a = 222; n_p = 126)	25 (11)	15 (12)	95 (43)	58 (46)	102 (46)	53 (42)	0.55
Co-ordination (n = 368; n_a = 239; n_p = 129)	23 (10)	9 (7)	98 (41)	61 (47)	118 (49)	59 (46)	0.89
Irritability (n = 349; n_a = 225; n_p = 124)	29 (13)	16 (13)	116 (52)	58 (47)	80 (36)	50 (40)	0.52
Depression (n = 335; n_a=225; n_p =110)	29 (13)	19 (17)	116 (52)	45 (41)	80 (36)	46 (42)	0.81
Tremor (n = 274; n_a = 117; n_p = 97)	22 (12)	23 (24)	78 (44)	43 (44)	77 (44)	31 (32)	0.011
Bladder problems (n = 380; n_a = 246; n_p = 134)	41 (17)	30 (22)	80 (33)	53 (40)	125 (51)	51 (38)	0.023

: n, total number of patients; n_a, total number of patients in active treatment group; n_p, total number of patients in the placebo group.

a: From chi-squared test for trend (with 1 degree of freedom), with no adjustments for multiple comparisons.

TABLE 12

Visit 9 (2 years after baseline)	Better (scores 1–5)		No change (score 6)		Worse (scores 7–11)		p-value^a
Visit 9 (2 years after baseline)	Active	Placebo	Active	Placebo	Active	Placebo	p-value^a
Fatigue (n = 358; n_a = 232; n_p = 126)	30 (13)	15 (12)	51 (22)	31 (25)	151 (65)	80 (63)	0.94
Forgetfulness (n = 327; n_a = 218; n_p = 109)	18 (8)	12 (11)	75 (34)	49 (45)	125 (57)	48 (44)	0.037
Sensory loss or numbness (n = 339; n_a = 220; n_p = 119)	25 (11)	9 (8)	91 (41)	48 (40)	104 (47)	62 (52)	0.25
Co-ordination (n = 344; n_a = 222; n_p = 122)	18 (8)	7 (6)	70 (32)	36 (30)	134 (60)	79 (65)	0.34
Irritability (n = 320; n_a = 207; n_p = 113)	37 (18)	15 (13)	83 (40)	45 (40)	87 (42)	53 (47)	0.26
Depression (n = 316; n_a = 207; n_p = 109)	37 (18)	19 (17)	83 (40)	43 (39)	87 (42)	47 (43)	0.86
Tremor (n = 276; n_a = 117; n_p = 99)	27 (15)	9 (9)	76 (43)	45 (45)	74 (42)	45 (45)	0.25
Bladder problems (n = 357; n_a = 233; n_p = 124)	39 (17)	18 (15)	63 (27)	32 (26)	131 (56)	74 (60)	0.50

: n, total number of patients; n_a total number of patients in active treatment group; n_p, total number of patients in the placebo group.

a: From chi-squared test for trend (with 1 degree of freedom), with no adjustments for multiple comparisons.

TABLE 13

Visit 11 (3 years after baseline)	Better (scores 1–5)		No change (score 6)		Worse (scores 7–11)		p-value^a
Visit 11 (3 years after baseline)	Active	Placebo	Active	Placebo	Active	Placebo	p-value^a
Fatigue (n = 332; n_a = 209; n_p = 123)	33 (16)	10 (8)	44 (21)	30 (24)	132 (63)	83 (67)	0.14
Forgetfulness (n = 301; n_a = 191; n_p = 110)	22 (12)	11 (10)	54 (28)	49 (45)	115 (60)	50 (45)	0.11
Sensory loss or numbness (n = 315; n_a = 201; n_p = 114)	25 (12)	8 (7)	80 (40)	46 (40)	96 (48)	60 (53)	0.19
Co-ordination (n = 321; n_a = 203; n_p = 118)	21 (10)	5 (4)	65 (32)	44 (37)	117 (58)	69 (58)	0.35
Irritability (n = 296; n_a = 185; n_p = 111)	29 (16)	10 (9)	87 (47)	58 (52)	69 (37)	43 (39)	0.31
Depression (n = 283; n_a = 185; n_p = 98)	29 (16)	18 (18)	87 (47)	42 (43)	69 (37)	38 (39)	0.89
Tremor (n = 252; n_a = 161; n_p = 91)	24 (15)	9 (10)	54 (34)	38 (42)	83 (52)	44 (48)	0.84
Bladder problems (n = 330; n_a = 209; n_p = 121)	38 (18)	21 (17)	46 (22)	32 (26)	125 (60)	68 (56)	0.75

: n, total number of patients; n_a, total number of patients in active treatment group; n_p, total number of patients in the placebo group.

a: From chi-squared test for trend (with 1 degree of freedom), with no adjustments for multiple comparisons.

FIGURE 15

TABLE 14

Frequencies and relative frequencies (%) of reasons for discontinuation of trial medication or loss to follow-up, by treatment group, disease type, baseline EDSS, sex and overall

Patient characteristics	Total	Reason for discontinuation of trial medication or loss to follow-up
Patient characteristics	Total	AE	Death	Lack of efficacy	Other
Treatment group
Active	151	113 (74.8)	3 (2.0)	20 (13.2)	15 (9.9)
Placebo	46	14 (30.4)	1 (2.2)	22 (47.8)	9 (19.6)
Disease type
PPMS	80	48 (60.0)	4 (5.0)	20 (25.0)	8 (10.0)
SPMS	117	79 (67.5)	0 (0.0)	22 (18.8)	16 (13.7)
Baseline EDSS score
4.0–5.5	44	29 (65.9)	1 (2.3)	7 (15.9)	7 (15.9)
6.0	102	71 (69.6)	1 (1.0)	20 (19.6)	10 (9.8)
6.5	51	27 (52.9)	2 (3.9)	15 (29.4)	7 (13.7)
Sex
Women	107	68 (63.6)	2 (1.9)	24 (22.4)	13 (12.1)
Men	90	59 (65.6)	2 (2.2)	18 (20.0)	11 (12.2)
Overall	197	127 (64.5)	4 (2.0)	42 (21.3)	24 (12.2)

: Percentages may not sum to 100 due to rounding.

TABLE 15

Frequencies and relative frequencies (%) of reasons for loss to follow-up, by treatment group, disease type, baseline EDSS, sex and overall

Patient characteristics	Total	Reason for loss to follow-up
Patient characteristics	Total	Death	Moved out of area	AE	MS or other health issue	Travel or burden of the trial	Ineligible	Other
Treatment group
Active	62	7 (11.3)	5 (8.1)	6 (9.7)	17 (27.4)	12 (19.4)	1 (1.6)	14 (22.6)
Placebo	16	1 (6.3)	1 (6.3)	0 (0.0)	3 (18.8)	5 (31.3)	1 (6.3)	5 (31.3)
Disease type
PPMS	32	4 (12.5)	2 (6.3)	3 (9.4)	8 (25.0)	4 (12.5)	1 (3.1)	10 (31.2)
SPMS	46	4 (8.7)	4 (8.7)	3 (6.5)	12 (26.1)	13 (28.3)	1 (2.2)	9 (19.6)
Baseline EDSS score
4.0–5.5	15	2 (13.3)	1 (6.7)	2 (13.3)	3 (20.0)	1 (6.7)	0 (0.0)	6 (40.0)
6.0	41	3 (7.3)	3 (7.3)	3 (7.3)	10 (24.4)	11 (26.8)	1 (2.4)	10 (24.4)
6.5	22	3 (13.6)	2 (9.1)	1 (4.5)	7 (31.8)	5 (22.7)	1 (4.5)	3 (13.6)
Sex
Women	42	4 (9.5)	2 (4.8)	3 (7.1)	7 (16.7)	11 (26.2)	1 (2.4)	14 (33.3)
Men	36	4 (11.1)	4 (11.1)	3 (8.3)	13 (36.1)	6 (16.7)	1 (2.8)	5 (13.9)
Overall	78	8 (10.3)	6 (7.7)	6 (7.7)	20 (25.6)	17 (21.8)	2 (2.6)	19 (24.4)

: Percentages may not sum to 100 due to rounding.

TABLE 16

Premature discontinuations of trial medication and losses to follow-up, by study site

Participant group	Study site
Participant group	01	02	04	05	06	07	08	10	11	12	13	14	15	18	19	20	21	22	23	24	25	26	27	28	31	32	33
Total recruited, n	77	11	11	18	4	16	10	12	8	6	19	14	22	19	21	14	22	26	12	21	21	30	11	40	10	8	10
Premature discontinuation of trial medication or loss to follow-up, n (%)	23 (29.9)	8 (72.7)	5 (45.5)	7 (38.9)	1 (25.0)	4 (25.0)	3 (30.0)	8 (66.7)	5 (62.5)	0 (0.0)	8 (42.1)	2 (14.3)	12 (54.5)	7 (36.8)	8 (38.1)	4 (28.6)	6 (27.3)	11 (42.3)	1(8.3)	12 (57.1)	12 (57.1)	17 (56.7)	2 (18.2)	17 (42.5)	7 (70.0)	3 (37.5)	4 (40.0)

TABLE 17

Baseline characteristics of patients in the MRI substudy, by treatment group and overall

Patient baseline characteristics	Treatment group		All (N = 273)
Patient baseline characteristics	Active (N = 182; 66.7%)	Placebo (N = 91; 33.3%)	All (N = 273)
Age in years at registration, mean (SD)	52.4 (7.3)	52.2 (8.1)	52.3 (7.6)
Weight in kg at registration, mean (SD)	74.3 (16.1)	75.7 (17.5)	74.8 (16.6)
Men, n (%)	80 (44.0)	31 (34.1)	111 (40.7)
Women, n (%)	102 (56.0)	60 (65.9)	162 (59.3)
PPMS, n (%)	60 (33.0)	38 (41.8)	98 (35.9)
SPMS, n (%)	122 (67.0)	53 (58.2)	175 (64.1)
EDSS score at baseline, n (%)
4.0	14 (7.7)	6 (6.6)	20 (7.3)
4.5	12 (6.6)	5 (5.5)	17 (6.2)
5.0	12 (6.6)	6 (6.6)	18 (6.6)
5.5	8 (4.4)	3 (3.3)	11 (4.0)
6.0	95 (52.2)	47 (51.6)	142 (52.0)
6.5	41 (22.5)	24 (26.4)	65 (23.8)
Normalised brain volume, mean (SD)	1422 (91.0)	1417 (85.1)	1420 (88.9)
Not reported, n (%)	24 (13.2)	8 (8.8)	32 (11.7)

: Percentages may not sum to 100 due to rounding.

FIGURE 16

Flow of participants through the MRI substudy.

TABLE 18

Descriptive statistics and between-treatment-group comparisons for MRI outcome measures at years 1, 2 and 3

Outcome measures	Year 1		Year 2		Year 3
Outcome measures	Active (n = 159)	Placebo (n = 84)	Active (n = 146)	Placebo (n = 79)	Active (n = 135)	Placebo (n = 74)
PBVC
Mean (SD)	–0.60 (0.99)	–0.59 (0.95)	–0.58 (0.96)	–0.65 (0.95)	–0.88 (0.87)	–0.76 (1.04)
Median (25th–75th percentiles)	–0.60 (–1.32, –0.05)	–0.47 (–1.03, –0.08)	–0.52 (–1.21, –0.06)	–0.78 (–1.17, –0.10)	–0.78 (–1.43, –0.44)	–0.81 (–1.42, 0.20)
Not reported, n (%)	3 (1.9)	1 (1.2)	5 (3.4)	2 (2.5)	7 (5.2)	2 (2.7)
p-value^a	0.9		0.6		0.4
New or newly enlarging T2 lesions, n (%)
0	118 (74.2)	56 (66.7)	111 (76.0)	71 (89.9)	113 (83.7)	61 (82.4)
1	20 (12.6)	15 (17.9)	23 (15.8)	5 (6.3)	16 (11.9)	9 (12.2)
≥ 2	21 (13.2)	13 (15.5)	12 (8.2)	3 (3.8)	6 (4.4)	4 (5.4)
Not reported	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
p-value^b	0.40		0.05		0.96
New T1 lesions, n (%)
0	123 (77.4)	64 (76.2)	122 (83.6)	74 (93.7)	118 (87.4)	62 (83.8)
1	20 (12.6)	12 (14.3)	16 (11.0)	3 (3.8)	13 (9.6)	10 (13.5)
≥ 2	16 (10.1)	8 (9.5)	8 (5.5)	2 (2.5)	4 (3.0)	2 (2.7)
Not reported	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
p-value^b	0.9		0.1		0.7

a: From two-sample t-test, with no adjustments for multiple comparisons.

b: From Fisher’s exact test, with no adjustments for multiple comparisons.

: Percentages may not sum to 100 due to rounding.