A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex(®) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis.

BACKGROUND: Spasticity is a disabling complication of multiple sclerosis, affecting many patients with the condition. We report the first Phase 3 placebo-controlled study of an oral antispasticity agent to use an enriched study design. METHODS: A 19-week follow-up, multicentre, double-blind, randomized, placebo-controlled, parallel-group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy. Subjects were treated with nabiximols, as add-on therapy, in a single-blind manner for 4weeks, after which those achieving an improvement in spasticity of ≥20% progressed to a 12-week randomized, placebo-controlled phase. RESULTS: Of the 572 subjects enrolled, 272 achieved a ≥20% improvement after 4weeks of single-blind treatment, and 241 were randomized. The primary end-point was the difference between treatments in the mean spasticity Numeric Rating Scale (NRS) in the randomized, controlled phase of the study. Intention-to-treat (ITT) analysis showed a highly significant difference in favour of nabiximols (P=0.0002). Secondary end-points of responder analysis, Spasm Frequency Score, Sleep Disturbance NRS Patient, Carer and Clinician Global Impression of Change were all significant in favour of nabiximols. CONCLUSIONS: The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice, by limiting exposure to those patients who are likely to benefit from it. Hence, the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment.

A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis.

BACKGROUND: Muscle spasticity is common in multiple sclerosis (MS), occurring in more than 60% of patients. OBJECTIVE: To compare Sativex with placebo in relieving symptoms of spasticity due to MS. METHODS: A 15-week, multicenter, double-blind, randomized, placebo-controlled, parallel-group study in 337 subjects with MS spasticity not fully relieved with current anti-spasticity therapy. RESULTS: The primary endpoint was a spasticity 0-10 numeric rating scale (NRS). Intention-to-treat (ITT) analysis showed a non-significant improvement in NRS score, in favor of Sativex. The per protocol (PP) population (79% of subjects) change in NRS score and responder analyses (> or =30% improvement from baseline) were both significantly superior for Sativex, compared with placebo: -1.3 versus -0.8 points (change from baseline, p=0.035); and 36% versus 24% (responders, p=0.040). These were supported by the time to response (ITT: p=0.068; PP: p=0.025) analyses, carer global impression of change assessment (p=0.013) and timed 10-meter walk (p=0.042). Among the subjects who achieved a > or =30% response in spasticity with Sativex, 98, 94 and 73% reported improvements of 10, 20 and 30%, respectively, at least once during the first 4 weeks of treatment. Sativex was generally well tolerated, with most adverse events reported being mild-to-moderate in severity. DISCUSSION AND CONCLUSIONS: The 0-10 NRS and responder PP analyses demonstrated that Sativex treatment resulted in a significant reduction in treatment-resistant spasticity, in subjects with advanced MS and severe spasticity. The response observed within the first 4 weeks of treatment appears to be a useful aid to prediction of responder/non-responder status.

[Granulomatous myopathy in patients with sarcoidosis and myasthenia gravis]. / Granulomatózní myopatie u pacientu se sarkoidózou a myasthenia gravis.

Granulomatous myopathies are extremely rare. The finding of epithelioid granulomas in muscle biopsy indicates mostly an involvement of the skeletal muscle in systemic sarcoidosis. In this report we provide description of five patients with previously diagnosed sarcoidosis (pulmonary or cutaneous), in which a clinically significant muscle weakness developed. We aim at demonstrating the value of muscle biopsy for further treatment of the patients, since clinically indistinguishable myopathies can arise not due to the involvement of muscles in the granulomatous process, but due to the corticosteroid-induced changes (chronic steroid myopathy). The demonstration of a selective atrophy of type II muscle fibers can provide the clue for distinguishing the patients, in which the corticosteroid treatment should continue, from those, in which the treatment should be modified. Further, we discuss a rare finding of granulomas in muscle biopsies of two patients with myasthenia gravis (MG) associated with thymoma. Although it is difficult to explain the pathogenesis of this event, MG should be considered in the differential diagnosis of granulomatous myopathies. Moreover, the finding of granulomas along with lymphocytic infiltration in MG muscle should lead to a search for an underlying thymic neoplasm.

[Activation tests in the diagnosis of myasthenia gravis using repetitive stimulation]. / Aktivacní testy pri diagnostice myasthenie gravis repetitivní stimulací.

145 patients with confirmed myasthenia gravis were examined by repetitive stimulation at a frequency of 2-3 s-1. A decrement of the proximal muscles at rest was demonstrated in 116 (80%) of the patients and the deltoid muscle was most sensitive. In 29 patients without a significant decrement at rest activation test were supplemented. Prolonged maximum isometric contraction for a period of 1 minute revealed a subsequent decrement in 13 patients. The ischaemic test was positive in 5, incl. 1 where activation by isometric contraction was negative. The total number of patients, where impaired neuromuscular transmission was diagnosed by repetitive stimulation, increased to 130 (90%) when activation tests were used. The described activation tests are technically unpretentious, non-invasive and can be used in routine practice of any EMG laboratory.

[Recurrent hemorrhage into the mesencephalon]. / Recidivující krvácení do mesencefala.

The author described the case of a 19-year-old man, normotensive, who developed after a blunt injury of the head haemorrhage into the left part of the mesencephalon with the symptomatology Weber's stem syndrome. Manifestation of focal symptoms was recorded three days after the injury. The cerebrospinal fluid examined on the fourth day was normal, cerebrospinal fluid one week later was blood stained. Fourteen months after this primary haemorrhage after almost complete clinical recovery a spontaneous relapse of haemorrhage occurred at the original site with the same symptomatology. Angiography was normal, haemorrhage was proved by CT and its cause was not elucidated. Haemorrhage into the brain stem of normotensive subjects is a rare and special group with a favourable prognosis and it must be differentiated from haemorrhage in hypertonic subjects.