Clinical trials of multiple sclerosis monitored with enhanced MRI: new sample size calculations based on large data sets.(Statistical Data Included)

Abstract

Objective--A new parametric simulation procedure based on the negative binomial (NB) model was used to evaluate the sample sizes needed to achieve optimal statistical powers for parallel groups (with (PGB) and without (PG) a baseline correction scan). It was also used for baseline versus treatment (BVT) design clinical trials in relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS), when using the number of new enhancing lesions seen on monthly MRI of the brain as the measure of outcome.

Methods--MRI data obtained from 120 untreated patients with RRMS selected for the presence of MRI activity at baseline, 66 untreated and unselected patients with RRMS, and 81 untreated and unselected patients with SPMS were fitted using an NB distribution. All these patients were scanned monthly for at least 6 months and were all from the placebo arms of three large scale clinical trials and one natural history study. The statistical powers were calculated for durations of follow up of 3 and 6 months.

Results--The frequency of new enhancing lesions in patients with SPMS was lower, but not significantly different, from that seen in unselected patients with RRMS. As expected, enhancement was more frequent in patients with RRMS selected for MRI activity at baseline than in the other two patient groups. As a consequence, the estimated sample sizes needed to detect treatment efficacy in selected patients with RRMS were smaller than those of unselected patients with RRMS and those with SPMS. Baseline correction was also seen to reduce the sample sizes of PG design trials. An increased number of scans reduced the sample sizes needed to perform BVT trials, whereas the gain in power was less evident in PG and PGB trials.

Conclusion--This study provides reliable estimates of the sample sizes needed to perform MRI monitored clinical trials in the major MS clinical phenotypes, which should be useful for planning future studies.

(J Neurol Neurosurg Psychiatry 2001;70:494-499)

Keywords: multiple sclerosis; magnetic resonance imaging; sample size calculations; treatment trials

At present, the number of new gadolinium enhancing lesions on monthly MRI of the brain is one of the most used measures of outcome to monitor multiple sclerosis (MS) activity. [1-4] New MS enhancing lesions are, however, not normally distributed and, therefore, standard approaches for sample size calculations are not desirable. Considerable effort has already been devoted to deal with the issue of sample size calculations for MRI monitored clinical trials in MS. The first paper on this topic was by Nauta et al, [5] who proposed an algorithm based on a non-parametric resampling procedure. This statistical methodology, although limited by a significant overestimation of power, [6] was adopted in three subsequent studies. [7-9] More recently, a parametric model based on the negative binomial (NB) distribution has been proposed [6] to describe better than the conventional model (the Poisson model) the distribution of new enhancing lesions across patients with MS. The NB distribution is useful for modelling counts in all those situations in which the Poisson model is not able to account for a large variability of the data. In addition to offering relatively easy computation and interpretability of the data, [6] the NB distribution model allows a better fitting of the raw data, [6] thus giving the possibility of using parametric tests to assess new treatment efficacy and to have a more powerful tool for the sample size simulations.

Another limitation of previous work is the relatively few patients studied, [5-8] which inevitably results in less reliable estimates. [9] To increase the sizes of their samples, some of the previous investigators considered together patients with relapsing-remitting MS (RRMS) and secondary progressive MS(SPMS). [5] This is again a relevant limitation, as virtually all the modern clinical trials treat individual MS phenotypes separately. [10 11] This is based on the increasing perception that different factors are responsible for determining the clinical manifestations of the disease in the different clinical phenotypes. [12 13] As a consequence, it is likely that in the near future different treatment options will be tested in different MS phenotypes, thus suggesting the need for calculating sample sizes for RRMS and SPMS separately.

Earlier studies [5-9] had a limited availability of patients because they were based on data coming from natural history studies conducted in one or only a few centres. This is not the present situation any more, as several large scale, placebo controlled, MRI monitored clinical trials have been conducted on patients with RRMS [10 14-18] and SPMS. [11 19-21] In this study, we used data of the patients with RRMS and those with SPMS enrolled in the placebo arms of three of these trials [18 19 21] as well as those from a relatively large group of patients …