Placebo effects in a multiple sclerosis spasticity enriched clinical trial with the oromucosal cannabinoid spray (THC/CBD): dimension and possible causes

Abstract

Regulatory authorities admit clinical studies with an initial enrichment phase to select patients that respond to treatment before randomization (Enriched Design Studies; EDSs). The trial period aims to prevent long-term drug exposure risks in patients with limited chances of improvement while optimizing costs. In EDSs for symptom control therapies providing early improvements and without a wash-out period, it is difficult to show further improvements and thus large therapeutic gains versus placebo. Moreover, in trials with cannabinoids, the therapeutic gains can be further biased in the postenrichment randomized phase because of carryover and other effects. The aims of the present review article are to examine the placebo effects in the enrichment and postenrichment phases of an EDS with Δ(9) -tetrahydrocannabinol and cannabidiol (THC/CBD) oromucosal spray in patients with multiple sclerosis (MS) spasticity and to discuss the possible causes of maintained efficacy after randomization in the placebo-allocated patients. The overall mean therapeutic gain of THC/CBD spray over placebo in resistant MS spasticity after 16 weeks can be estimated as a ~1.27-point improvement on the spasticity 0-10 Numerical Rating Scale (NRS; ~-20.1% of the baseline NRS score). We conclude that careful interpretation of the results of EDSs is required, especially when cannabinoid-based medications are being investigated.

Trial registration: ClinicalTrials.gov NCT00702468 NCT00711646 NCT01599234 NCT01610713 NCT06681538.

Keywords: Endocannabinoid system; Multiple sclerosis; Placebo; Spasticity; Δ9-tetrahydrocannabinol and cannabidiol.

Conflict of interest statement

Vincenzo Di Marzo receives research funds and acts as a consultant for GW Pharmaceuticals Ltd, UK. Diego Centonze has received honoraria for speaking or consultation fees from Almirall, Spain and GW Pharmaceuticals Ltd, UK.

© 2014 John Wiley & Sons Ltd.

Figures

Figure 1

Mean spasticity 0–10 Numerical Rating Scale (NRS) scores for an enriched design study 5 and estimated placebo response from pooled data. The dashed line in Phase A is the calculated placebo effect, based on an analysis of pooled data from RCTs. The dashed line in Phase B represents the actual placebo response seen in Phase B of the Enriched Design Studies (EDS). This illustrates the estimated therapeutic gain that would have been observed if it was a conventional, nonenriched design study conducted in treatment responders.