Extrakt aus Cannabis Sativa (2) – Sativex®

• Clinical trials
  • The benefit assessment is based on the direct comparative trials SAVANT and GWSP0604.
  • Both studies are Phase III trials comprising a single-blind, single-arm Phase A and a randomised, double-blind, placebo-controlled Phase B.

Adult patients with moderate to severe spasticity due to multiple sclerosis (MS) who have not responded adequately to other antispastic drug therapies, in which at least two different oral antispastic drugs, including at least one medicinal product containing baclofen or tizanidine, which have been used at optimised doses, and which have demonstrated a major improvement in spasticity-related symptoms during an initial treatment trial

• mortality
  • No events occurred in the SAVANT study for the endpoint of all-cause mortality.
  • In the GWSP0604 study, 2 events occurred in the intervention arm.
  • There is no statistically significant difference between the treatment groups.
  • Additional benefit is therefore not proven for the mortality category.
• Morbidity – spasticity: NRS response
  • The degree of spasticity was recorded by patients daily throughout the study duration at bedtime using an 11-point scale (Numerical Rating Scale [NRS]) in the electronic patient diary (in the SAVANT study) or via an Interactive Voice Response System (IVRS; in the GWSP0604 study).
  • In the SAVANT study, a statistically significant difference in favour of Cannabis sativa extract was observed regarding the proportion of patients showing an improvement in spasticity of at least 18% and at least 30%.
  • 41 out of 48 patients (85.4%) showed an improvement in spasticity of at least 18% and at least 30% whilst being treated with Cannabis sativa extract; in the control group, 19 out of 46 patients (41.3 per cent) showed an improvement of at least 18 per cent, whilst 17 out of 46 patients (37 per cent) showed an improvement of at least 30 per cent.
  • The GWSP0604 study also showed a statistically significant difference in favour of Cannabis sativa extract.
  • An improvement of at least 18% in spasticity was observed in 26 out of 28 patients (92.9%) treated with Cannabis sativa extract and in 19 out of 29 patients (65.5%) in the control group.
  • 23 out of 28 patients (82.1%) showed an improvement of at least 30% whilst taking Cannabis sativa extract; in the control group, the figure was 16 out of 29 patients (55.2%).
  • The difference between the treatment groups was minor in the GWSP0604 study (27.4% and 26.9% respectively) compared to the SAVANT study (44.1% and 48.4% respectively).
• Quality of life – 36-item Short Form Health Survey (SF-36)
  • In the SAVANT study, a statistically significant difference in favour of Cannabis sativa extract was observed for the physical pain subscale.
  • However, the confidence interval for the standardised mean difference (Hedges’ g) does not lie entirely outside the irrelevance range [−0.2; 0.2]. It cannot therefore be concluded that the effect is clinically relevant.
  • In the GWSP0604 study, there is also no statistically significant difference between the treatment groups for the physical pain subscale.
  • Neither the SAVANT study nor the GWSP0604 study shows a statistically significant difference between the treatment groups with regard to the other subscales of the SF-36.
  • An additional benefit is therefore not proven for the quality of life category.
• Side effects – overall rate of AEs
  • In the SAVANT study and the GWSP0604 study, there was no statistically significant difference between the treatment groups for either adverse events (AEs) or the endpoint of discontinuation due to AEs.
  • In the GWSP0604 study, no statistically significant difference was observed between the treatment groups.
  • For the endpoint ‘dizziness’, no usable data are available for either study, as it remains unclear whether, in addition to the operationalisations listed by the pharmaceutical manufacturer (feeling of dizziness and vertigo), other operationalisations that occurred – such as balance disorders, should be included under the endpoint ‘dizziness’.
  • An additional benefit for the category of side effects is therefore not proven.
• Overall assessment
  • In the morbidity category, both studies show an additional benefit for Cannabis sativa extract compared with optimised standard therapy in terms of the number of patients experiencing an improvement in spasticity of at least 18% and at least 30%.
  • However, there is uncertainty regarding the severity of spasticity in the study participants.
  • For the endpoints ‘severity of spasms’ and ‘pain due to spasticity’ (for women), additional benefit is evident only in the SAVANT study, as neither endpoint was assessed in the GWSP0604 study.
  • The majority of patients did not exhibit severe spasticity or pain caused by spasticity at the start of the study.
  • With regard to the morbidity endpoints ‘sleep disturbance due to spasticity’ and ‘health status’ (assessed using the SGIC), it is not possible to conclude with the requisite certainty that there is an additional benefit, as although the endpoints were assessed in both studies, statistically significant results were observed in only one study in each case.
  • In determining the extent of the additional benefit, account is taken of the fact that the number of endpoints showing a significant advantage from Cannabis sativa extract is higher in the SAVANT study than in the GWSP0604 study.
  • Similarly, the significant effect for the endpoint ‘improvement in spasticity by at least 18 per cent’ or ‘by at least 30 per cent’ is greater in the SAVANT study than in the GWSP0604 study.
  • However, due to the study design, the SAVANT study may overestimate the actual effect size.
  • In the quality of life category, there is no significant advantage of Cannabis sativa extract compared with the appropriate comparator therapy; likewise, the data on the side effects recorded provide no indications of greater harm or greater benefit from Cannabis sativa extract compared with the appropriate comparator therapy.
  • The G-BA classifies the extent of the additional benefit of Cannabis sativa extract as minor, based on the criteria in Section 5(7) of the AM-NutzenV, taking into account the severity of the condition and the therapeutic objective in the treatment of the condition.
  • Compared with the appropriate comparator therapy, this constitutes, in accordance with Section 5(7) in conjunction with § 2(3) of the AM-NutzenV, taking into account the uncertainties regarding the effect size of the results of the SAVANT study and the current severity of the spasticity, this represents a moderate—and not merely minor—improvement in health status that has not yet been achieved.

Courtesy translation only, please refer to the German original.