Dysport® Adult Lower Limb Spasticity Follow-on Study

Study Overview
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Brief Summary
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The purpose of this research study is to assess the long term safety of Dysport® in hemiparetic subjects with lower limb spasticity due to stroke or traumatic brain injury over repeated treatment cycles.

Official Title
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A Phase III, Prospective, Multicentre, Open Label, Extension Study, to Assess the Long Term Safety and Efficacy of Repeated Treatment of Dysport® Intramuscular Injection in the Treatment of Lower Limb Spasticity in Adult Subjects With Spastic Hemiparesis Due to Stroke or Traumatic Brain Injury

Conditions
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Post-stroke Spasticity, Spasticity Post-Traumatic Brain Injury

Intervention / Treatment
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* Biological: Botulinum toxin type A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Completion of Dysport® Adult Lower Limb Spasticity Double Blind study Y-55-52120-140 (NCT01249404) Exclusion Criteria: Fixed contractures in lower limb

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dysport®<br>Dysport® is injected into lower limbs across 4 cycles of treatment, a minimum of 12 weeks between 2 injections. Doses vary from 1000 U to 1500 U. | Biological: Botulinum toxin type A<br>* I.M. (intramuscular) injection on day 1 of each treatment cycle.<br>* Other names: AbobotulinumtoxinA (Dysport®);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of the Long-Term Safety of Dysport® Through the Collection of Treatment Emergent Adverse Events (TEAEs) | Adverse events (AEs) were monitored from the time that the subject gave informed consent to the end of the study/early withdrawal (EOS/EW). An AE was reported as a TEAE if it was not present prior to study treatment administration in Study 140, or if it was present prior to study treatment in Study 140 but the intensity increased during the treatment phase of this study. Adverse events of special interest (AESIs) were identified as those assessed as being due to remote spread of effect of Dysport®, or any AE that was assessed as a hypersensitivity reaction. TEAEs, treatment related TEAEs, severe TEAEs, TEAEs leading to death, TEAEs leading to withdrawal, treatment emergent AESIs, and serious adverse events (SAEs) are summarised by treatment cycle. | Up to EOS (maximum duration of 52 weeks). | 
| Mean Change From Baseline to Week 4 in Systolic and Diastolic Blood Pressure (BP) | Systolic and diastolic BP were recorded at baseline and at each subsequent study visit. BP was measured with the subject in a sitting position after resting for 3 minutes. Mean change in BP from baseline at Week 4 is reported per cycle. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Heart Rate (HR) | HR was recorded at baseline and at each subsequent study visit. HR was measured with the subject in a sitting position after resting for 3 minutes. Mean change in HR from baseline at Week 4 is reported per cycle. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Red Blood Cell (RBC) Count | Blood samples for RBC count were taken at baseline, at Week 4, and at EOS/EW. Outcome measure is reported per cycle as change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Haemoglobin and Mean Corpuscular Haemoglobin Concentration (MCHC) | Blood samples for haemoglobin and MCHC were taken at baseline, at Week 4, and at the EOS/EW. Outcome measure is reported per cycle as change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Haematocrit | Blood samples for haematocrit were taken at baseline, at Week 4, and at the EOS/EW. Outcome measure is reported per cycle as change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Mean Corpuscular Haemoglobin (MCH) | Blood samples for MCH were taken at baseline, at Week 4, and at the EOS/EW. Outcome measure is reported per cycle as change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Mean Corpuscular Volume (MCV) | Blood samples for MCV were taken at baseline, at Week 4, and at the EOS/EW. Outcome measure is reported per cycle as change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in White Blood Cell (WBC) Count, Neutrophils, Lymphocytes and Platelets | Blood samples for WBC count with differentials (neutrophils, lymphocytes) and platelet count were taken at baseline, at Week 4, and at the EOS/EW. Outcome measure is reported per cycle as change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Alkaline Phosphatase (ALP), Gamma Glutamyl Transferase (GGT), Serum Glutamic Oxaloacetic Transaminase (SGOT) and Serum Glutamic Pyruvic Transaminase (SGPT) | Blood samples were taken at baseline, at Week 4, and at the EOS/EW for analysis of the following clinical chemistry parameters: ALP, GGT, SGOT and SGPT. Outcome measure is reported per cycle as change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Total Bilirubin and Creatinine | Blood samples for clinical chemistry analysis of total bilirubin and creatinine were taken at baseline, at Week 4, and at the EOS/EW. Outcome measure is reported per cycle as change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Blood Urea Nitrogen (BUN) and Fasting Blood Glucose | Blood samples for analysis of BUN and fasting blood glucose levels were taken at baseline, at Week 4 and at the EOS/EW. Outcome measure is reported per cycle as change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Presence of Botulinum Toxin Type A (BTX-A) Neutralising Putative Antibodies (NAbs) Following Injection of Dysport® | Blood samples were collected at baseline, Week 4 and at EOS/EW to test for the presence of BTX-A antibodies. The number of subjects who were either NAb positive at baseline or negative at baseline but then positive following injection of Dysport® were reported. | At Week 4 | 
| Mean Change From Baseline to Week 4 in 12-Lead Electrocardiogram (ECG) | 12-lead ECG tracing was performed at baseline, at Week 4 of each cycle and at EOS/EW. The 12-lead ECG recordings were performed at a paper speed of 25 millimetres/second (mm/s), recorded with the subject in a supine position after 5 minutes rest. The ECG parameters; QT Duration, QT interval corrected with Fridericia's method (QTcF), QT interval corrected with Bazett's method (QTcB), QRS duration and PR duration were recorded and outcome measure is reported per cycle as change from baseline at Week 4. | Baseline and Week 4 of each cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline to Week 4 in the Modified Ashworth Scale (MAS) Score Measured in the Gastrocnemius-soleus Complex (GSC) (Knee Extended) | Muscle tone in the treated limb was assessed by MAS in the GSC (with the knee extended) at baseline, at Weeks 4 and 12, at discretionary visits at Weeks 16, 20 and 24 of each cycle, and at EOS/EW. The MAS consists of 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion (ROM)), 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion or extension), and can be applied to muscles of both the upper and lower limbs. Outcome measure is reported per cycle as mean change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in the MAS Measured in the Soleus Muscle (Knee Flexed) | Muscle tone in the treated limb was assessed by MAS in the soleus muscle (with the knee flexed) at baseline, at Weeks 4 and 12, at discretionary visits at Weeks 16, 20 and 24 of each cycle, and at EOS/EW. The MAS consists of 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the ROM), 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion or extension), and can be applied to muscles of both the upper and lower limbs. Outcome measure is reported per cycle as mean change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Percentage of Subjects With At Least a 1 or 2 Grade Reduction in the MAS Measured in the GSC (Knee Extended) at Week 4 | Muscle tone in the treated limb was assessed by MAS in the GSC (with the knee extended) at baseline, at Weeks 4 and 12, at discretionary visits at Weeks 16, 20 and 24 of each cycle, and at EOS/EW. The MAS consists of 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the ROM), 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion or extension), and can be applied to muscles of both the upper and lower limbs. Outcome measure is reported per cycle as the percentage of subjects with at least a 1 grade reduction or 2 grades reduction in MAS score at Week 4. | Week 4 of each cycle | 
| Percentage of Subjects With At Least a 1 or 2 Grade Reduction in the MAS Measured in the Soleus Muscle (Knee Flexed) at Week 4 | Muscle tone in the treated limb was assessed by MAS in the soleus muscle (with the knee flexed) at baseline, at Weeks 4 and 12, at discretionary visits at Weeks 16, 20 and 24 of each cycle, and at EOS/EW. The MAS consists of 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the ROM), 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion or extension), and can be applied to muscles of both the upper and lower limbs. Outcome measure is reported per cycle as the percentage of subjects with at least a 1 grade reduction or 2 grades reduction in MAS score at Week 4. | Week 4 of each cycle | 
| Physician's Global Assessment (PGA) of Treatment Response at Week 4 | An assessment of overall treatment response was conducted by the investigator at baseline, at Weeks 4 and 12, at discretionary visits at Weeks 16, 20 and 24 of each cycle and at EOS/EW. The investigator rated the response to treatment in the subject's lower limb after injection of Dysport® relative to the status at the baseline. Answers were made on a nine-point rating scale: -4=markedly worse, -3=much worse, -2=worse, -1=slightly worse, 0=no change, +1=slightly improved, +2=improved, +3=much improved, +4=markedly improved. The mean PGA scores per cycle at Week 4 were reported. | Week 4 of each cycle | 
| Percentage of Subjects With a Score of at Least +1 on the PGA Scale at Week 4 | An assessment of overall treatment response was conducted by the investigator at baseline, at Weeks 4 and 12, at discretionary visits at Weeks 16, 20 and 24 of each cycle and at EOS/EW. The investigator rated the response to treatment in the subject's lower limb after injection of Dysport® relative to the status at the baseline. Answers were made on a nine point rating scale: -4=markedly worse, -3=much worse, -2=worse, -1=slightly worse, 0=no change, +1=slightly improved, +2=improved, +3=much improved, +4=markedly improved. The percentage of responders with a PGA score of +1 or greater are reported at Week 4. | Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in the Range of Active Ankle Dorsiflexion Both With the Knee Flexed and With the Knee Extended | Range of active dorsiflexion of the ankle joint of the treated limb, measured using a goniometre, both with the knee flexed (90°) and extended, was used to assess treatment response. The measurements were obtained at the end of baseline, at Weeks 4 and 12, at discretionary visits at Weeks 16, 20 and 24 of each cycle and at EOS/EW. Outcome measure is reported per cycle as mean change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Lower Limb Pain | The intensity of lower limb pain in the treated limb was evaluated by the subject using the Scale of Pain Intensity (SPIN) which provided a pictorial representation of pain in a 6-point graphic scale with the degree of red shading inside a circle representing the intensity of pain. The bottom and top of the scale are anchored by two extremes: 'no pain' (circle with no red shading and scored as 0) and 'pain as bad as it could be' (circle completely red and scored as 5), marked with either verbal or visual cues. The intervening points are represented by red circles increasing proportionally in size. The subject marks the circle that best indicates their pain intensity. The SPIN assessments were obtained at baseline, Weeks 4 and 12 after each Dysport® injection, at discretionary visits at Weeks 16, 20 and 24 of each cycle and at the EOS/EW. The mean changes from baseline in subjects with a baseline SPIN Score >0 at Week 4 was reported per cycle. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Short Form (36) Health Survey (SF-36) Quality of Life (QoL) | Subjects were asked to complete the SF-36 health surveys prior to the study treatment at baseline, at Week 4 and at the EOS/EW visit. The SF-36 is a generic non preference based health status measure. This instrument assessed subject health across 8 variable dimensions, which are specific health domains such as physical functioning, social functioning and vitality. Each variable item score is coded and turned into a 0-100 scale where 0 indicates the worst and 100 indicates the best possible health state for both the Physical Component Summary (PCS) and Mental Component Summary (MCS) of the questionnaire. The mean change in the PCS and MCS from baseline to Week 4 are reported. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline in European Quality of Life - 5 Dimensions, 5 Level (EQ-5D-5L) QoL | Subjects were asked to complete the EQ-5D-5L QoL questionnaire prior to the study treatment at baseline, at Week 4 and at EOS/EW visit. The EQ-5D-5L index is a generic preference based measure of health related QoL producing utility scores that represent subject preferences for particular health states. This instrument rated subject health state looking at 5 specific dimensions such as mobility, self-care, usual activity, pain/discomfort and anxiety/ depression and scored their general health state. Each dimension has 5 levels of severity: no problems, slight problems, moderate problems, severe problems and extreme problems, rated from 1 to 5 (best to worst). In addition, a visual analogue scale (VAS) ranging from 0 to 100 was also included for the patients to summarize their overall health status, where 0 is the worst and 100 the best possible health state. The mean change in pain and discomfort and VAS scores from baseline to Week 4 are reported. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Walking Speed (WS) | All WS tests were conducted without walking aids over a distance of 10 metres at both a comfortable WS and at maximal WS. Evaluations of WS were made barefoot and with shoes on, at baseline, at Weeks 4 and 12, at discretionary visits at Weeks 16, 20 and 24 of each cycle, and at EOS/EW. Outcome measure is reported per cycle as mean change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Step Length | All WS tests were conducted without walking aids over a distance of 10 metres at both a comfortable WS and at maximal WS. Evaluations of step length were made barefoot and with shoes on, at baseline, at Weeks 4 and 12, at discretionary visits at Weeks 16, 20 and 24 of each cycle, and at EOS/EW. Outcome measure is reported per cycle as mean change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Cadence | All WS tests were conducted without walking aids over a distance of 10 metres at both a comfortable WS and at maximal WS. Evaluations of cadence were made barefoot and with shoes on, at baseline, at Weeks 4 and 12, at discretionary visits at Weeks 16, 20 and 24 of each cycle, and at EOS/EW. Outcome measure is reported per cycle as mean change from baseline at Week 4. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Angle of Arrest (XV1), Angle of Catch (XV3) and Spasticity Angle (X) in the GSC (Knee Extended) | Spasticity in the treated limb was assessed using the Tardieu Scale (TS) for the GSC (knee extended). The TS is administered by applying passive stretch to a muscle group at two velocities. Slow speed of muscle stretch measures the range of passive motion. During a slow stretching movement, the examiner determines the angle of movement arrest, either due to subject discomfort or a mechanical resistance. The same movement is repeated at high velocity (as fast as possible) to determine the angle of catch and release. The angle of movement arrest at slow velocity (XV1) and the angle of catch at fast speed (XV3) were recorded at baseline, at Weeks 4 and 12 after each Dysport® injection, at discretionary visits at Weeks 16, 20 and 24 of each cycle and at EOS/EW. The spasticity angle (X) was calculated as the difference between XV1 and XV3. Mean changes in Angles XV1, XV3 and X from baseline to Week 4 are reported per cycle. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Spasticity Grade (Y) in the GSC (Knee Extended) | Spasticity in the treated limb was assessed using the TS for the GSC (knee extended). The TS is administered by applying passive stretch to a muscle group. The spasticity grade (Y) assesses quality of muscle reaction on a 5-point scale (measured at fast speed): 0 =No resistance throughout passive movement, 1=slight resistance throughout passive movement, 2=clear catch at precise angle, interrupting passive movement, followed by release, 3=fatigable clonus (less than 10 seconds when maintaining pressure) occurring at a precise angle, followed by release. 4=unfatigable clonus (more than 10 seconds when maintaining pressure) occurring at precise angle. Spasticity grade (Y) was recorded at baseline, at Weeks 4 and 12 after each Dysport® injection, at discretionary visits at Weeks 16, 20 and 24 of each cycle and at EOS/EW. Mean changes in spasticity grade (Y) from baseline to Week 4 are reported per cycle. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Angle of Arrest (XV1), Angle of Catch (XV3) and Spasticity Angle (X) in the Soleus Muscle (Knee Flexed) | Spasticity in the treated limb was assessed using the TS for the soleus muscle (knee flexed). The TS is administered by applying passive stretch to a muscle group at two velocities. Slow speed of muscle stretch measures the range of passive motion. During a slow stretching movement, the examiner determines the angle of movement arrest, either due to subject discomfort or a mechanical resistance. The same movement is repeated at high velocity (as fast as possible) to determine the angle of catch and release. The angle of movement arrest at slow velocity (XV1) and the angle of catch at fast speed (XV3) were recorded at baseline, at Weeks 4 and 12 after each Dysport® injection, at discretionary visits at Weeks 16, 20 and 24 of each cycle and at EOS/EW. The spasticity angle (X) was calculated as the difference between XV1 and XV3. Mean changes in Angles XV1, XV3 and X from baseline to Week 4 are reported per cycle. | Baseline and Week 4 of each cycle | 
| Mean Change From Baseline to Week 4 in Spasticity Grade (Y) in the Soleus Muscle (Knee Flexed) | Spasticity in the treated limb was assessed using the TS for the soleus muscle (knee flexed). The TS is administered by applying passive stretch to a muscle group. The spasticity grade (Y) assesses quality of muscle reaction on a 5-point scale (measured at fast speed): 0 =No resistance throughout passive movement, 1=slight resistance throughout passive movement, 2=clear catch at precise angle, interrupting passive movement, followed by release, 3=fatigable clonus (less than 10 seconds when maintaining pressure) occurring at a precise angle, followed by release. 4=unfatigable clonus (more than 10 seconds when maintaining pressure) occurring at precise angle. Spasticity grade (Y) was recorded at baseline, at Weeks 4 and 12 after each Dysport® injection, at discretionary visits at Weeks 16, 20 and 24 of each cycle and at EOS/EW. Mean changes in spasticity grade (Y) from baseline to Week 4 are reported per cycle. | Baseline and Week 4 of each cycle | 
| Use of Walking Aids/Orthoses at Baseline and Week 4 | Subjects were assessed on their use of walking aids and orthoses at baseline, at Weeks 4 and 12 after each Dysport® injection, at discretionary visits at Weeks 16, 20 and 24 of each cycle and at the EOS/EW visit. Outcome measure is reported per cycle at baseline and Week 4. Number of subjects with no walking aid/orthoses were included in the 'No Walking Aid' category and number of subjects with any kind of walking aid/orthosis (including single point cane, tripod cane, ankle foot orthosis or other type of walking aid/orthosis) were combined into the 'Walking Aid' category. | Baseline and Week 4 of each cycle |