Soleus 75 (6 ml) 0 (6 ml) 75 (6 ml. Tibialis posterior 75 (6 ml) 0 (6 ml) 75 (6 ml) Total 300 (24 ml) 0 (24 ml) 300 (24 ml) Dose: U (solution volume)

Transcription

1 Study No.: BTX Title: A Multicenter Study to Evaluate the Efficacy and Safety in Patients with Post-Stroke lower Limb Spasticity Receiving a Double-Blind, -Controlled GSK Treatment Followed by an Open-Label GSK Treatment Rationale: This was a confirmatory study to evaluate the efficacy and safety of GSK (botulinum toxin type A, BTX) in subjects with post-stroke lower limb spasticity. This study was designed and conducted based on advice and comments from the Pharmaceuticals and Medical Devices Agency (PMDA) raised during the PMDA consultation meeting on September 1, Phase: III Study Period: May 22, 2007 to December 26, 2008 Study Design: The evaluation period consists of two parts: the double-blind (DB) phase followed by the open-label (OL) phase. Part 1 (DB phase): A multicenter, randomized, double-blind, parallel-group, placebo-controlled Part 2 (OL phase): A multicenter, uncontrolled, open-label The study period was from the time of obtaining informed consent to the completion of OL phase or the time of withdrawal, consisting of the screening phase up to 4 weeks and the evaluation period of 48 weeks (12-week DB phase and 36-week OL phase) for a maximum of 52 weeks. Centres: A total of 19 medical institutions in Japan Indication: post-stroke lower limb spasticity Treatment: [Investigational product] BTX: Each vial contained the following ingredients and was reconstituted before use: botulinum toxin type A, 100 Unit (U); human serum albumin, 0.5 mg; sodium chloride, 0.9 mg. (Control) : Each vial (unidentifiable from the investigational product) contained the following ingredients and was reconstituted before use; Sodium chloride, 0.9 mg. BTX or placebo was administered by intramuscular injection into 3 sites of each the gastrocnemius (medial and lateral), soleus and tibialis posterior muscles (i.e. muscles primarily involved in equinus symptoms) as specified in the table below (the BTX group [ group] and the placebo group).a single treatment of BTX or placebo was given in the DB phase, and up to 3 repeated treatments of BTX were given in the OL phase. Muscle DB phase OL phase Gastro-cnemius Medial 75 (6 ml) 0 (6 ml) 75 (6 ml) Lateral 75 (6 ml) 0 (6 ml) 75 (6 ml) Soleus 75 (6 ml) 0 (6 ml) 75 (6 ml Tibialis posterior 75 (6 ml) 0 (6 ml) 75 (6 ml) Total 300 (24 ml) 0 (24 ml) 300 (24 ml) Dose: U (solution volume) During the DB phase, the investigator (or sub-investigator) used an EMG or nerve stimulator, and an EMG needle to assist in proper muscle localization for injection. During the OL phase, the investigator (or sub-investigator) chose whether an EMG or nerve stimulator and an EMG needle were used to localize the muscle for injection. The subjects were re-administered whenever they met all of the following re-administration criteria: 1. Ankle flexor muscle tone of >= 2 on the MAS at pre-treatment. 2. At least 12 weeks (84 days) since the last injection. 3. Body weight of >= 50 kg. Objectives: To confirm the superior efficacy of a single treatment of BTX 300 U over placebo in subjects with equinus deformity (plantar flexion of the ankle) associated with post-stroke lower limb spasticity using the Modified Ashworth Scale (MAS) ankle score. Primary Outcome/Efficacy Variable: An area under the curve (AUC) for the change from baseline in MAS ankle score in the DB phase. Secondary Outcome/Efficacy Variable(s): 1

2 1. Throughout the evaluation period (DB and OL phases): Change from baseline in MAS ankle score, change from baseline in physician s rati ng scale (PRS) score, and change from baseline in clinical global impression (CGI) of functional disability. 2. If any change was made to permissible concomitant rehabilitation therapy during the OL phase: global impression of therapeutic benefit of BTX to rehabilitation. Statistical Methods: [Efficacy analysis methods] The full analysis set (FAS) was the primary population for efficacy analyses. The FAS consisted of all subjects randomized with the exception of those who did not receive any injection of the investigational product and those with no assessment of post-treatment MAS ankle score. For the primary efficacy endpoint (AUC for the change from baseline in MAS ankle score in the DB phase), a mean difference between the and placebo groups was analysed by t- test. If the p value was less than the two-sided significance level of 5%, the superiority of BTX 300 U over placebo was considered to be confirmed. Also a point estimate and 95% confidence interval (CI) for the mean difference between the two groups were calculated. For the secondary efficacy endpoints, the following analyses were performed: 1. MAS ankle score, PRS score, speed of gait and CGI score at each visit during the DB phase were summarized by treatment group using summary statistics and frequency tabulations. The changes from baseline in these variables at each follow-up visit after the injection were summarized by treatment group and mean differences between the and placebo groups was analysed by Wilcoxon test. 2. During the OL phase the variables mentioned above 1 were summarized with summary statistics up to 12 weeks after each repeated injection of BTX 300 U (first, second and third repeated injections) for each group in the DB phase and overall (combined treatment groups). The baseline (Visit 2) was used to calculate the change from baseline during the OL phase. 3. The presence or absence of any change to rehabilitation during the OL phase and if any change to rehabilitation was made, the global impression of therapeutic benefit of BTX to rehabilitation was summarized for each group in the DB phase and overall. [Safety analyses] The safety population (SP) was used for safety analyses. The SP consisted of all subjects who received at least one injection of the investigational product. The analyses of adverse events (AEs) during the OL phase use of the subgroup of the SP consisting subjects who received at least one injection of the investigational product during the OL phase. AEs were grouped by System Organ Class (SOC), Preferred Term (PT), severity, and relationship to the investigational product. The number (%) of subjects with AEs was summarized separately in the DB phase and OL phase. For clinical laboratory data, pulse rate, blood pressure, body weight, 12-lead ECG findings, summary statistics were calculated by treatment group and timepoint. Study Population: This study enrolled male or female subjects with equinus deformity (plantar flexion of the ankle) who met all of the following criteria at baseline (Visit 2): between 20 and 80 years of old; body weight of at least 50 kg; at least 6 months post stroke; and MAS ankle score of >= 3. Subjects with any of the following were excluded from the study: bilateral hemiplegia or quadriplegia; fixed contractures of the ankle (absence of range of motion); profound atrophy of the muscles to be injected; or previous botulinum toxin therapy. Number of Subjects: Planned, N Randomised, N DB phase completed, n (%) 52 (90) 61 (98) Withdrawn in the DB phase, n (%) 6 (10) 1 (2) Adverse Events 3 (5) 0 Protocol Violation 0 1 (2) Subject decided to withdraw from 3 (5) 0 2

3 study Study completed, n (%) 45 (78) 52 (84) Withdrawn in the OL phase, n (%) 7 (12) 9 (15) Adverse Events 1 (2) 6 (10) Subject decided to withdraw from 6 (10) 2 (3) study Other, specify 0 1 (2) Demographics: N (FAS/SP) Females: Males 8: 50 16: 46 Mean Age, years (SD) 62.4 (8.66) 62.5 (9.32) < 60 year, n (%) 16 (28) 19 (31) >= 60 year, n (%) 42 (72) 43 (69) Asian - Japanese, n (%) 58 (100) 62 (100) Primary Efficacy Results: AUC for Change from Baseline in MAS Ankle Score (Up to 12 weeks after the Injection in the DB Phase) (N=58) Mean (SD) (6.6904) (6.6496) Mean Difference between Treatments % Confidence Interval , p-value Secondary Outcome Variable(s): 1. Changes from Baseline in Secondary Outcome Variables by Treatment Cycle (Up to 12 weeks after the Injection) DB phase (N=58) OL phase 300U to 300U (n=50) to 300U (n=57) MAS ankle score Baseline, Mean (SD) 3.28 (0.451) 3.24 (0.432) DB phase 1 st treatment ~ ~ OL phase 2 nd treatment ~ ~ rd treatment ~ ~ th treatment ~ ~ PRS score Baseline, Mean (SD) 3.10 (2.352) 3.23 (2.020) DB phase 1 st treatment ~ ~ OL phase 2 nd treatment ~ ~ rd treatment ~ ~ th treatment ~ ~ Speed of Gait (Time [sec] to Walk 10 m) Baseline, Mean (SD) (49.688) (51.563) DB phase 1 st treatment ~ ~ OL phase 2 nd treatment ~ ~ rd treatment ~ ~ th treatment ~ ~ CGI of functional disability (by investigator) Baseline, Mean (SD) (1.690) (1.783) DB phase 1 st treatment ~ ~

4 OL phase 2 nd treatment ~ ~ rd treatment ~ ~ th treatment ~ ~ CGI of functional disability (by subject) Baseline, Mean (SD) (1.890) (2.051) DB phase 1 st treatment ~ ~ OL phase 2 nd treatment ~ ~ rd treatment ~ ~ th treatment ~ ~ CGI of functional disability (by physiotherapist/occupational therapist) Baseline, Mean (SD) (1.996) (2.044) DB phase 1 st treatment ~ ~ OL phase 2 nd treatment ~ ~ rd treatment ~ ~ th treatment ~ ~ Global impression of therapeutic benefit of BTX to rehabilitation Changed Rehabilitation in the OL 13 (27) 10 (18) phase, n(%) Considered Benefit of BTX to 13 (100) 8 (80) Rehabilitation, n (% of n Changed Rehabilitation) Safety Results: Adverse Events - On-Therapy 1. Adverse Events Reported by Two or More Subjects in Group in the DB phase (N=58) Subjects with any AE(s), n(%) 26 (45) 27 (44) Nasopharyngitis 8 (14) 12 (19) Myalgia 3 (5) 2 (3) Injection site pain 3 (5) 1 (2) Eczema 2 (3) 1 (2) Angina pectoris 2 (3) 0 2. Adverse Events Reported by 3% or More Subjects in Total in the OL phase 300U to 300U to (n=50) 300U Total (N=107) (n=57) Subjects with any AE(s), n(%) 35 (70) 40 (70) 75 (70) Nasopharyngitis 15 (30) 6 (11) 21 (20) Contusion 5 (10) 4 (7) 9 (8) Eczema 3 (6) 3 (5) 6 (6) Arthralgia 1 (2) 3 (5) 4 (4) Back pain 2 (4) 2 (4) 4 (4) Tinea pedis 3 (6) 0 3 (3) Muscle spasms 3 (6) 0 3 (3) Myalgia 3 (6) 0 3 (3) Pyrexia 3 (6) 0 3 (3) Constipation 2 (4) 1 (2) 3 (3) Upper respiratory tract inflammation 2 (4) 1 (2) 3 (3) Gait disturbance 1 (2) 2 (4) 3 (3) Blood creatine phosphokinase 1 (2) 2 (4) 3 (3) increased Hepatic function abnormal 1 (2) 2 (4) 3 (3) 4

5 Urinary tract infection 0 3 (5) 3 (3) Serious Adverse Events - On-Therapy,n (%) [n considered to be related to the investigational product by the investigator] 1. Serious Adverse Events in the DB phase (N=58) Subjects with non-fatal SAEs, n (%) 5 (9) [1] 1 (2) [0] Angina pectoris 2 (3) [0] 0 Gastric ulcer haemorrhage 1 (2) [0] 0 Fibula fracture 1 (2) [0] 0 Myalgia 1 (2) [1] 0 Convulsion 0 1 (2) [0] Subjects with fatal SAEs, n (%) Serious Adverse Events in the OL Phase 300U to 300U (n=50) to 300U (n=57) Total (N=107) Subjects with non-fatal SAEs, n (%) 3 (6) [0] 8 (14) [0] 11 (10) [0] Epilepsy 1 (2) [0] 0 1 (<1) [0] Depression 1 (2) [0] 0 1 (<1) [0] Gastroenteritis 1 (2) [0] 0 1 (<1) [0] Facial bones fracture 0 1 (2) [0] 1 (<1) [0] Femoral neck fracture 0 1 (2) [0] 1 (<1) [0] Femur fracture 0 1 (2) [0] 1 (<1) [0] Spinal compression fracture 0 1 (2) [0] 1 (<1) [0] Convulsion 0 1 (2) [0] 1 (<1) [0] Mania 0 1 (2) [0] 1 (<1) [0] Colonic polyp 0 1 (2) [0] 1 (<1) [0] Gastric polyps 0 1 (2) [0] 1 (<1) [0] Calculus ureteric 0 1 (2) [0] 1 (<1) [0] Subjects with fatal SAEs, n (%) Conclusion: The treatment of BTX 300U injection intramuscular to lower limb improved the spasticity, and the improvement continued for about 3 months after the injection. 5