Upper Limb Spasticity in Adult Patients

The efficacy and safety of XEOMIN for the treatment of upper limb spasticity in adult patients were evaluated in two Phase 3, randomized, multi-center, double-blind studies.

Study 1 (NCT01392300) and Study 2 (NCT00432666) were both prospective, double-blind, placebo-controlled, randomized, multi-center trials with an open-label extension period (OLEX) to investigate the efficacy and safety of XEOMIN in the treatment of post-stroke spasticity of the upper limb. For patients who had previously received botulinum toxin treatment in any body region, Study 1 and Study 2 required that ≥12 months and ≥4 months, respectively, had passed since the most recent botulinum toxin administration.

Study 1 consisted of a 12-week main phase followed by three 12-week OLEX treatment cycles for a total exposure duration of 48 weeks. The study included 317 treatment-naïve patients who were at least three months post-stroke in the main study period (210 XEOMIN and 107 placebo). During the main period, XEOMIN (fixed total dose of 400 Units) and placebo were administered intramuscularly to the defined primary target clinical pattern chosen from among the flexed elbow, flexed wrist, or clenched fist patterns and to other affected muscle groups. 296 treated patients completed the main phase and participated in the first OLEX cycle. Each OLEX cycle consisted of a single treatment session (XEOMIN 400 Units total dose, distributed among all affected muscles) followed by a 12-week observation period.

Study 2 consisted of a 12-to-20-week main phase followed by an OLEX period of 48 – 69 weeks, for up to 89 weeks of exposure to XEOMIN. The study included 148 treatment-naïve and pre-treated patients with a confirmed diagnosis of post-stroke spasticity of the upper limb who were at least six months post-stroke (73 XEOMIN and 75 placebo). During the main period, for each patient, the clinical patterns of flexed wrist and clenched fist were treated with fixed doses (90 Units and 80 Units, respectively). Additionally, if other upper limb spasticity patterns were present, the elbow, forearm and thumb muscles could be treated with fixed doses of XEOMIN per muscle. 145 patients completed the main phase and participated in the OLEX period, during which time the dosing of each involved muscle could be adapted individually. During the main and OLEX periods, the maximum total dose per treatment session and 12-week interval was 400 Units.

The average XEOMIN doses injected into specific muscles and the number of injection sites per muscle in Study 1 and Study 2 are presented in Table 19.

In Study 1, the primary efficacy variable was the change from baseline in Ashworth Scale (AS) score of the primary target clinical pattern determined by the investigator at the Week 4 visit. The Ashworth Scale is a clinical measure of the severity of spasticity by judging resistance to passive movement. The spasticity of the elbow flexors, wrist flexors, finger flexors, and thumb muscles as well as the forearm pronators was assessed on the 0 to 4-point Ashworth scale at each visit. The co-primary efficacy variable of Study 1 was the Investigator's Global Impression of Change Scales (GICS) after 4 Weeks of treatment with XEOMIN or placebo. The GICS is a global measure of a subject's functional improvement. Investigators were asked to evaluate the subject's global change in spasticity of the upper limb due to treatment, compared to the condition before the last injection. The response was assessed using a 7-point Likert scale that ranges from –3 (very much worse) to +3 (very much improved). XEOMIN was considered to be superior to placebo in Study 1 only if statistical significance was reached in both the AS and GICS variables.

The primary efficacy results are displayed in Table 20.

A greater percentage of XEOMIN-treated subjects (43%) than placebo-treated subjects (23%) reported 'very much improved' and 'much improved' in their spasticity (see Figure 8).

Figure 8: Investigator's GICS in Adult Upper Limb Spasticity Study 1

Upper Limb Spasticity in Pediatric Patients

Study 1 (NCT02002884) was a prospective, double-blind, dose-response, randomized, multi-center trial with an open-label extension period to evaluate the efficacy and safety of XEOMIN for the treatment of upper limb spasticity in pediatric patients. Study 1 enrolled a total of 350 pediatric patients 2 to 17 years of age with upper limb spasticity in one or both upper limbs. In the double-blind main period of Study 1, patients were randomized to one of three dosages of XEOMIN: 2 Units/kg (maximum 50 Units per upper limb), 6 Units/kg (maximum 150 Units per upper limb); or 8 Units/kg (maximum 200 Units per upper limb). The maximum dose, if both upper limbs were treated, respectively was 4 Units/kg (maximum 100 Units), 12 Units/kg (maximum 300 Units), or 16 Units/kg (maximum 400 Units). For treatment of flexed elbow, injection of biceps brachii was mandatory. The investigator could select 1 of the 2 other muscles contributing to spasticity of elbow flexion (i.e., brachialis and brachioradialis) for injection. For patients needing treatment for a flexed wrist, both the flexor carpi radialis and flexor carpi ulnaris were injected. Study 1 used a dose-response design, in which the two highest dosages of XEOMIN (8 Units/kg and 6 Units/kg) were compared to the lowest dosage (2 Units/kg), which served as control. In the absence of a placebo control, the efficacy of the 2 Units/kg dosage of XEOMIN could not be evaluated in Study 1.

The co-primary efficacy variables in Study 1 were the change from baseline on the Ashworth Scale for the primary clinical target pattern (i.e., elbow flexors or wrist flexors), and the Investigator's Global Impression of Change Scale (GICS), both at Week 4. The GICS is a global measure of a subject's functional improvement based on a 7-point Likert scale that ranges from -3 = very much worse to +3 = very much improved.

As displayed in Table 21, the change from baseline in Ashworth Scale score was significantly greater for patients treated with XEOMIN 8 Units/kg than for patients treated with XEOMIN 2 Units/kg. The difference in GICS score between patients treated with XEOMIN 8 Units/kg and those treated with XEOMIN 2 Units/kg did not reach statistical significance. However, the clinical meaningfulness of the difference in Ashworth Scale score change between patients treated with XEOMIN 8 Units/kg and those treated with XEOMIN 2 Units/kg was established by a responder analysis, in which the proportion of patients with a 1-point change or greater on the Ashworth Scale was examined. In that analysis, 86% of patients treated with XEOMIN 8 Units/kg met the responder definition, compared to 71% of patients treated with XEOMIN 2 Units/kg (nominal p value = 0.0099).

There was no significant difference in change from baseline in Ashworth Scale score, GICS score, or proportion of responders between patients treated with XEOMIN 6 Units/kg and those treated with XEOMIN 2 Units/kg. Therefore, the efficacy of a 6 Units/kg dosage of XEOMIN for the treatment of upper limb spasticity in pediatric patients was not established in Study 1.