Results

In the RRMS group (n=31), on the initial scan 15 (48.4%) patients had enhancing lesions. During follow up, six patients showed no newly active lesions during the study period. The total number of scans with newly active lesions was 88 (47.3%). The mean number of newly active lesions/patient was 8.9 (median 4 (SE 2), range=0–39).

In the RRMS group, without the extra run-in scan, the demonstration of a 70% AIII efficacy with a power of 80 required 2×30 patients to be studied for six months or 2×40 patients for four months (table 4). When the extra run-in scan was added, 70% efficacy was demonstrated if 2×20 patients were studied for six months or 2×30 patients for four months (table 5).

In the SPMS group (n=28), on the initial scan 10 (35.7%) had enhancing lesions. During follow up, six patients showed no newly active lesions in the six months of the study. The total number of scans with newly active lesions was 75 (44.6%). The mean number of newly active lesions/patient was 12.2 (median 2.0 (SE 3.9), range=0−85).

In the SPMS group without the run-in scan, demonstration of a 70% AIII efficacy with a power of about 80 required 2×50 patients to be studied for six months (the actual power calculated was 78 for a homogeneous and 83 for heterogeneous response) or 2×75 for four months (table 6). When the extra run-in scan was added, 70% efficacy was demonstrated in 2×30 patients in four or six months, but not in 2×20 patients studied for six months (table 7): thus the SPMS sample sizes come closer to those seen in the RR group (figure).

Three groups of patients with different levels of new lesion activity were defined:

(1) Low activity—0–2 new active lesions during the six months of follow up:

(2) Moderate activity—3–30 new active lesions.

(3) High activity—greater than 30 new active lesions.

A higher proportion of SPMS patients exhibited low activity (14/28 (50%) v 10/31(32%) of RR patients), whereas a greater number of RR patients had moderate activity (18/31 (58%)v 9/28 (32%) of SP patients). High activity was seen in 18% of SP and 10% of RR patients. The two patients with the highest MRI activity (66 and 85 new active lesions) had SPMS (table8).

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Power calculations for subgroups with sample size 2×30 and 70% efficacy.

The sample size calculations for the two groups of patients were tabulated for the AIII response (tables 4-7). The calculations for a homogeneous or heterogeneous response were generally very similar: only the homogeneous response data are presented. Slightly smaller sample sizes were generally required for AIII than for AII data, in both RR and SP subgroups (AII data not shown).

Discussion

At present, the generally modest correlations between MRI findings and clinical status in MS means that new therapies are ultimately judged in large phase III trials in which a clinical outcome is the primary measure.4 Nevertheless, MRI is now widely used as the primary outcome measure of disease activity in exploratory Phase I/II trials in RRMS and SPMS, because the high frequency of asymptomatic disease activity detected by MRI in these subgroups makes it a powerful tool for small cohort and short duration studies.5-11 Furthermore, some correlations do exist between the activity seen on serial T2 weighted and gadolinium enhanced scans and clinical measures of disease activity or progression in both RR5 6 8-10 19 and SP8 20 subgroups, the most consistent being the higher frequency of enhancing lesions during clinical relapse. These correlations suggest that it is valid and clinically relevant to use MRI to determine efficacy in exploratory trials.

Some previous MRI studies of small cohorts have reported broadly similar mean rates of new lesion activity in RR and SP disease.5-11 Pronounced between patient variability in the level of MRI activity has, however, been readily apparent in both groups.5-12 21 In particular, higher rates of activity have been reported in RR and SP patients who continued to relapse, whereas lower rates were seen in RR patients in remission10 and SP patients who continue to progress, but without superimposed relapses.11 Such heterogenous patterns in reports involving small cohorts led us to the present study of larger and separate RR and SP cohorts on which to perform sample size calculations for exploratory MRI outcome treatment trials.

The number of patients that need to be enrolled into a trial, the number of hospital visits required, and the number of scans that need to be performed, must all be established to design a trial which minimises the burden on patients, is cost efficient, and has a high likelihood of showing the anticipated treatment effect. In the last respect, trials that are predicted to yield a statistical power less than 80 are generally deemed unacceptable. We employed well documented statistical techniques.12-14 In the RR subgroup we compared our results with other published studies, but have used a larger patient cohort. Our study also considered SPMS patients as a separate entity for the first time.

Our results showed significant differences between the two groups. When just the single pretreatment scan was obtained, substantially larger sample sizes were required for the SP group to show an equivalent therapeutic effect in a given period of time.

The addition of one extra run-in scan (but not more than one) before entry into an exploratory treatment trial was previously shown to reduce the sample sizes required.13 We again saw this effect in the present analysis, in both of our patient subgroups. For SPMS patients the effect was especially pronounced, and using the run-in scan the differences in sample sizes needed to show the same treatment effect in the same period of time were smaller (table 7).

The beneficial effect of the addition of the extra run-in scan is that it reduces some of the between patient variation in MR activity. The appreciably larger sample sizes in the SP patients when such a scan was omitted suggests a greater between patient variability among these patients . There were indeed notable differences between RRMS and SPMS groups when the new lesion activity over the six months was divided into those patients who showed low, moderate, and high levels of new lesion activity. Half of the SPMS group had low levels of activity compared with only one third of RRMS patients. By contrast, most RR patients (58%) displayed moderate new lesion activity. High levels of activity occurred in a small proportion in each group but if anything slightly more in the SPMS group, a few of whom were extremely active. The occurrence of more low activity scans in the SPMS patients will reduce the statistical power in this group as there will be fewer lesions to “treat”. The occurrence of more extreme highs in the same group will also reduce the power of the study as there is a greater degree of between patient variability. These factors probably account for the larger sample sizes calculated for SPMS than for RRMS patients in the present study.

The present study provides tables (tables 4-7) of the power estimates for a range of sample sizes at treatment efficacies of 60%, 70%, and 80%. The efficacy of an experimental treatment is, for example 70%, if an average of 70% fewer active lesions are seen when a treatment is given compared with placebo. Treatment efficacies of less than 60% can be calculated by adapting the computer program in such a way that the user can enter any desired efficacy and run it with any data set they wish (the data set on which this article is based is included as a demonstration set ( table 2 and table 3)). However, treatment efficacies lower than 60% may need to be interpreted with more caution. The experience from trials of β-interferon and other immunomodulatory therapies suggests that a major impact on MRI may be associated with more modest clinical effects.22 23 24Because the correlation between MRI and clinical disability in MS is modest, it may be prudent to demand a relatively high level of efficacy on MRI activity in phase II trials as a requirement for proceeding to phase III clinical outcome studies, especially if the therapy under investigation is expensive and has significant side effects.

The differences we have noted between the RR and SP subgroups are of practical importance when planning treatment trials in the future. They warrant consideration in choosing the appropriate sample size and cohort. Based on the similar patterns of activity reported in small cohorts,5-11 some pilot MRI studies have combined RRMS and SPMS subgroups15 22; an obvious advantage of this approach is that patient recruitment is easier, especially now that disease modifying therapies are being increasingly used, particularly in RR patients. Our present data suggest that such a combination may be problematic if only a single pretreatment scan is obtained: in this instance a substantially larger cohort of SP patients are needed, and randomisation errors which result in uneven proportions of RR and SP patients in the treated and placebo groups could lead to spurious results. If an extra run-in scan is added, combining RR and SP cohorts may be more acceptable as the differences in sample size are smaller.

When steroids were given to treat relapses during the natural history studies from which the present clinical and MRI data were taken, an attempt was often made to perform the enhanced MRI before starting treatment, to minimise any effect on MRI activity. A three day (1g/day) course of intravenous methyl prednisolone is the usual regime for treating relapses at our centres. Uncontrolled studies suggest that intravenous methyl prednisolone causes a temporary reduction in the number of enhancing lesions for periods ranging from one week to two months.25 26 However, in one of these studies there was a total of 53 new enhancing lesions among 10 patients one month after a course of 1g intravenous methyl prednisolone/day for three days.25 This suggests that the effect of this particular regime on the formation of new lesions is likely to be modest and transient.

The results also have implications for our understanding of the pathophysiology of MS. As new lesions in RRMS and SPMS usually display an initial phase of gadolinium enhancement, the concept has emerged that breakdown of the blood-brain barrier is a necessary event in the development of new pathology and, by inference, ongoing clinical deterioration.27 However, we found that over a half of our SP cohort had a minimal amount of enhancing lesion activity despite the fact that they were in a phase of the disease with a poorer clinical prognosis, characterised by a steady accumulation of disability.28 29 This discordance between lack of enhancement and clinical progression is already well recognised in the smaller cohort of MS patients who have a progressive and non-relapsing illness from onset (primary progressive MS)7 Our findings suggest that the pathophysiology of secondary progression is not necessarily dependent on blood-brain barrier abnormality at least as seen using standard dose gadolinium enhanced MRI.

To further optimise the design of MRI outcome treatment trials, more studies are needed to elucidate factors which may influence or predict MRI activity—for example, the frequency of relapses before and during the study, entry expanded disability status scale, age, sex, disease duration, and pre-existing MRI activity. Such studies will need to examine larger cohorts of patients. Some work in this area has already been published with RR patients.21 We are currently performing such an analysis in SP patients.