Evaluate symptomatic therapy in MS: can clinical trials be fine‐tuned?

Multiple Sclerosis is a chronic autoimmune disease with diffuse damage of the central nervous system. During the course of the disease several symptoms may occur, and spasticity is one of the most common, disabling and unmet treatment needs [1,2]. The efficacy of current oral medications for treating spasticity show modest effects as stated in a recent review [3]. Cannabinoids have been used to treat a wide variety of disorders for thousands of years with renewed interest as viable medications in the last 10 years. In a meta-analysis Nabixomols (Sativex R), a tetrahydrocannaboinol (THC)cannabidiol (CBD) 1:1 fixed ratio, for oromucosal use, was found to be well tolerated and able to reduce spasticity in MS patients [4]. In this current issue of the European Journal of Neurology Novotna et al. provide a contribution on refractory spasticity management in patients with MS (who had insufficient benefit from current medication regimen) [5]. They describe a double-blind, placebocontrolled, enriched-design study using Nabixomols delivered with a oromucosal spray. Five hundred seventy-two MS subjects were treated for 4 weeks in a single-blind phase with Nabixomols. Out of 272 patients who experienced an improvement in spasticity of >20%, 241 were randomized to the second phase of the study, 12 weeks during which subjects received placebo or active treatment. In the current study, based on previous results, the authors proposed a 20% selfreported improvement at Numerical Rating Scale (NRS) as significant and define responders as subjects who experience 30% variation between baseline and the end of the study on the NRS. Clinical response was assessed using a self-reported 0–10 point NRS. Therefore, only subjects who experienced a 20% reduction on the NRS scale were selected as potential responders and randomized to the second phase of the study during which half continued the active treatment and half were given placebo. The active arm was found to be superior to placebo with a mean difference of 0.84 points on NRS. In the first phase of the study 272 out of 572 (47%) were considered as responders in term of efficacy experiencing no side effects; in the second 12-week phase, 74% of randomized subjects on Nabixomols vs. 51% in the placebo arm reported improvement of spasticity compared to baseline. Several discussion points are of interest regarding this report. Researchers encounter several difficulties in designing clinical trials of symptomatic therapy, not only in MS. As stated by the authors, a conventional, parallel group, randomized, controlled study identifies the average of improvement seen in a group of patients but not the clinical reliance of the average improvement . As is the case for many MS symptoms, assessment of the benefits of any intervention depends on subjective reporting. Given this, it is necessary to identify at what point clinical improvement is significant for the patient, by identifying at what point minimal change is relevant. Conventional clinical trials tell us about the average performance of a therapy. In evaluating pain, the setting and other variables can influence how some patients show very limited response to a drug while others seem to benefit significantly from the same drug, although in these types of studies an average response loses its meaningfulness. These observations suggest the need for proposing new trial designs to capture the reality of the range of responses in clinical practice, meaning the ability to detect desirable efficacy in a subgroup. The enriched enrolment with randomized withdrawal (EERW) may be such a design. During phase I subjects are treated with a medication and those who experience adverse effects or who do not achieve the outcome are withdrawn from the study and only potential responders are randomized to phase II (see Fig. 1 of Ref. (5)]. A crucial point is how to define responders. The major difficulty of this design is that the primary end-point relies on a subjective measure. The authors selected subjects with spasticity severity >4 on the NRS (group mean score of 6.5). Although we do not know if the sample is representative of the MS population typically treated in a clinical setting, it is remarkable to find a such significant effect in patients with relatively severe spasticity. The secondary endpoint provided contrasting results. There was an effect on the Bartel Index, a measure for independence, but negative results on the Ashworth Scale, which has largely been used to rate spasticity. The scale is lacking in specificity and unfortunately remains the only objective measure used in clinical trials on spasticity. In line with this point, the authors do not report in the text if efficacy is related to the NRS score at baseline in order to understand if the Nabixomols is useful for all levels of spasticity or if the effect is more evident in subjects with more or less severe spasticity.