Clinical Trial Results:
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.
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Summary
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EudraCT number |
2009-017723-26 |
Trial protocol |
BE CZ SK IT PT HU |
Global end of trial date |
14 Apr 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
31 Mar 2017
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First version publication date |
31 Mar 2017
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
Y-55-52120-142
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01251367 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Ipsen Pharma
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Sponsor organisation address |
65 quai Georges Gorse, Boulogne-Billancourt, France, 92100
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Public contact |
Medical Director, Neurology, Ipsen Pharma, clinical.trials@ipsen.com
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Scientific contact |
Medical Director, Neurology, Ipsen Pharma, clinical.trials@ipsen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
14 Apr 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
14 Apr 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
14 Apr 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary study objective was 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.
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Protection of trial subjects |
The clinical study was conducted in accordance with the International Conference on Harmonisation Consolidated Guideline on Good Clinical Practice, under the ethical principles laid down in the Declaration of Helsinki. In addition, this clinical study adhered to all local regulatory requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Jun 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Belgium: 16
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Country: Number of subjects enrolled |
Czech Republic: 17
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Country: Number of subjects enrolled |
France: 49
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Country: Number of subjects enrolled |
Hungary: 15
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Country: Number of subjects enrolled |
Italy: 22
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Country: Number of subjects enrolled |
Poland: 83
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Country: Number of subjects enrolled |
Russian Federation: 26
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Country: Number of subjects enrolled |
Australia: 35
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Country: Number of subjects enrolled |
Slovakia: 16
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Country: Number of subjects enrolled |
United States: 61
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Country: Number of subjects enrolled |
Portugal: 12
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Worldwide total number of subjects |
352
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EEA total number of subjects |
230
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
286
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From 65 to 84 years |
66
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was designed as a multicentre study and included 51 sites in Australia, Belgium, the Czech Republic, France, Hungary, Italy, Poland, Portugal, Russia, Slovakia and the United States of America that included at least one subject. The current study (Study 142) was an open label extension to the double blind Study 140 (Y-55-52120-140). | ||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 366 subjects completed Study 140, of which 352 subjects were enrolled in Study 142. Of these, 7 subjects entered an observational phase and never received open label treatment with Dysport in Study 142 and the remaining 345 subjects started treatment and received at least one open label injection of Dysport in Study 142. | ||||||||||||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
352 | ||||||||||||||||||||||||||||
Number of subjects completed |
345 | ||||||||||||||||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Entered Observational Phase: 7 | ||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||
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Arms
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Arm title
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Total Dysport | ||||||||||||||||||||||||||||
Arm description |
Subjects who had completed Study 140 were offered to continue to receive open label treatment with Dysport in Study 142 for a maximum of 4 additional treatment cycles, with a minimum interval of 12 weeks between treatment cycles. All subjects were administered an appropriate dosage of Dysport (1500 Units [U] or 1000 U) by intramuscular (i.m.) injection in the lower limb on Day 1 of treatment Cycle 1. In all cases, the administration of the Dysport injections was limited to a maximum dose of 1500 U every 12 weeks. Follow up visits were timed to assess the onset and progression of treatment response. From treatment Cycle 3 onwards, subjects with co-existing upper limb spasticity were able to receive concomitant injections of Dysport into at least one upper limb muscle at a dose not exceeding 500 U. | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Dysport
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Investigational medicinal product code |
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Other name |
Botulinum toxin type A haemagglutinin complex
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intramuscular use
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Dosage and administration details |
Vials containing 500 U of botulinum toxin type A haemagglutinin complex (Dysport) were reconstituted with 2.5 millilitre (mL) sodium chloride for injection (0.9 %). A total volume of 7.5 mL of the reconstituted product for any Dysport dose was injected.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Worldwide data is reported for safety population of 352 subjects (including all enrolled subjects who provided informed consent to participate in this open label extension study). Baseline data is reported for 345 subjects for intention to treat population (including all enrolled subjects who had received at least one injection of Dysport in this open label extension study). [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: 275 Subjects completed Cycle 2. 51 subjects completed the study at this point and 224 subjects progressed to Cycle 3. [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: 211 Subjects completed Cycle 3. 72 subjects completed the study at this point and 139 subjects progressed to Cycle 4. |
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Baseline characteristics reporting groups
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Reporting group title |
Overall Trial
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Reporting group description |
The summary of baseline characteristics presented are from subjects completing Study 140 who were selected by the investigator for entry into Study 142 and received at least one injection of study treatment in this open label extension study. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Total Dysport
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Reporting group description |
Subjects who had completed Study 140 were offered to continue to receive open label treatment with Dysport in Study 142 for a maximum of 4 additional treatment cycles, with a minimum interval of 12 weeks between treatment cycles. All subjects were administered an appropriate dosage of Dysport (1500 Units [U] or 1000 U) by intramuscular (i.m.) injection in the lower limb on Day 1 of treatment Cycle 1. In all cases, the administration of the Dysport injections was limited to a maximum dose of 1500 U every 12 weeks. Follow up visits were timed to assess the onset and progression of treatment response. From treatment Cycle 3 onwards, subjects with co-existing upper limb spasticity were able to receive concomitant injections of Dysport into at least one upper limb muscle at a dose not exceeding 500 U. | ||
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End point title |
Assessment of the Long-Term Safety of Dysport Through the Collection of Treatment Emergent Adverse Events (TEAEs) [1] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
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End point type |
Primary
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End point timeframe |
Up to Week 24
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for this primary end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Mean Change from Baseline to Week 4 in Systolic and Diastolic Blood Pressure (BP) [2] | ||||||||||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
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End point type |
Primary
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End point timeframe |
At Week 4
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for this primary end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Mean Change from Baseline to Week 4 in Heart Rate (HR) [3] | ||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
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End point type |
Primary
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End point timeframe |
At Week 4
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for this primary end point. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Mean Change from Baseline to Week 4 in Red Blood Cell (RBC) Count [4] | ||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
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End point type |
Primary
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End point timeframe |
At Week 4
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for this primary end point. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Mean Change from Baseline to Week 4 in Haemoglobin and Mean Corpuscular Haemoglobin Concentration (MCHC) [5] | ||||||||||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
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End point type |
Primary
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End point timeframe |
At Week 4
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for this primary end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Mean Change from Baseline to Week 4 in Haematocrit [6] | ||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
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End point type |
Primary
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End point timeframe |
At Week 4
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for this primary end point. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Mean Change from Baseline to Week 4 in Mean Corpuscular Haemoglobin (MCH) [7] | ||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
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End point type |
Primary
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End point timeframe |
At Week 4
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for this primary end point. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Mean Change from Baseline to Week 4 in Mean Corpuscular Volume (MCV) [8] | ||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
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End point type |
Primary
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End point timeframe |
At Week 4
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| Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for this primary end point. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Mean Change from Baseline to Week 4 in White Blood Cell (WBC) Count, Neutrophils, Lymphocytes and Platelets [9] | ||||||||||||||||||||||||||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
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End point type |
Primary
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End point timeframe |
At Week 4
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| Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for this primary end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
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End point title |
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) [10] | ||||||||||||||||||||||||||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
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End point type |
Primary
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End point timeframe |
At Week 4
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| Notes [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for this primary end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
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End point title |
Mean Change from Baseline to Week 4 in Total Bilirubin and Creatinine [11] | ||||||||||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
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End point type |
Primary
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End point timeframe |
At Week 4
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| Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for this primary end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Mean Change From Baseline to Week 4 in Blood Urea Nitrogen (BUN) and Fasting Blood Glucose [12] | ||||||||||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
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End point type |
Primary
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End point timeframe |
At Week 4
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| Notes [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for this primary end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Presence of Botulinum Toxin Type A (BTX-A) Neutralising Putative Antibodies (NAbs) following Injection of Dysport [13] | ||||||||||
End point description |
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. Outcome measure is reported for subjects with data available for analysis.
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End point type |
Primary
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End point timeframe |
Up to Week 24
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| Notes [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for this primary end point. |
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| No statistical analyses for this end point | |||||||||||
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End point title |
Mean Change from Baseline to Week 4 in 12-Lead Electrocardiogram (ECG) [14] | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
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End point type |
Primary
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End point timeframe |
At Week 4
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| Notes [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive analysis was planned and performed for this primary end point. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Mean Change from Baseline to Week 4 in the Modified Ashworth Scale (MAS) Score measured in the Gastrocnemius-soleus Complex (GSC) (Knee Extended) | ||||||||||||||||
End point description |
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 six grades: 0, 1, 1+, 2, 3, or 4 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 (n = number of subjects with data available for analysis).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
At Week 4.
|
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|
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| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Mean Change from Baseline to Week 4 in the MAS measured in the Soleus Muscle (Knee Flexed) | ||||||||||||||||
End point description |
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 six grades: 0, 1, 1+, 2, 3, or 4 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 (n = number of subjects with data available for analysis).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Proportion of Subjects with At Least a 1 or 2 Grade Reduction in the MAS Measured in the GSC (Knee Extended) at Week 4 | ||||||||||||||||||||||||
End point description |
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 six grades: 0, 1, 1+, 2, 3, or 4 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 or 2 grades reduction in MAS score at Week 4 (n = number of subjects with data available for analysis).
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Proportion of Subjects with At Least a 1 or 2 Grade Reduction in the MAS Measured in the Soleus Muscle (Knee Flexed) at Week 4 | ||||||||||||||||||||||||
End point description |
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 six grades: 0, 1, 1+, 2, 3, or 4 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 or 2 grades reduction in MAS score at Week 4 (n = number of subjects with data available for analysis).
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||
End point title |
Physician's Global Assessment (PGA) of Treatment Response at Week 4 | ||||||||||||||||
End point description |
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 (n=subjects with data available for analysis).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Proportion of subjects with a score of at least +1 on the PGA scale at Week 4 | ||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
|
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End point type |
Secondary
|
||||||||||||||||
End point timeframe |
At Week 4
|
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|
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| No statistical analyses for this end point | |||||||||||||||||
|
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End point title |
Mean Change from Baseline to Week 4 in the Range of Active Ankle Dorsiflexion both with the Knee Flexed and with the Knee Extended | ||||||||||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||
|
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End point title |
Mean Change from Baseline to Week 4 in Lower Limb Pain | ||||||||||||||||
End point description |
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 representing the intensity of pain. 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 (n =number of subjects with data available for analysis).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Mean Change from Baseline to Week 4 in Short Form (36) Health Survey (SF-36) Quality of Life (QoL) | ||||||||||||||||||||||||
End point description |
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 dimensions, which are specific health domains such as physical functioning, social functioning and vitality. The mean change in the Physical Component Summary (PCS) and Mental Component Summary (MCS) from baseline to Week 4 are reported (n=subjects with data available for analysis).
|
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End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||
|
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End point title |
Mean Change from Baseline in European Quality of Life - 5 Dimensions (EQ-5D) QoL | ||||||||||||||||||||||||
End point description |
Subjects were asked to complete the EQ-5D QoL questionnaire prior to the study treatment at baseline, at Week 4 and at EOS/EW visit. The EQ-5D 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. The mean change in pain and discomfort and Visual Analogue Scale (VAS) scores from baseline to Week 4 are reported (n=subjects with data available for analysis).
|
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End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Mean Change from Baseline to Week 4 in Walking Speed (WS) | ||||||||||||||||||||||||||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||||||||||||||||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
|
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End point title |
Mean Change from Baseline to Week 4 in Step Length | ||||||||||||||||||||||||||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Mean Change from Baseline to Week 4 in Cadence | ||||||||||||||||||||||||||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis).
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
End point title |
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) | ||||||||||||||||||||||||||||||||
End point description |
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 (n=subjects with data available for analysis).
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
|
|||||||||||||||||
End point title |
Mean Change from Baseline to Week 4 in Spasticity Grade (Y) in the GSC (Knee Extended) | ||||||||||||||||
End point description |
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 (n=subjects with data available for analysis).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||||||||||||||||||
End point title |
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) | ||||||||||||||||||||||||||||||||
End point description |
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 (n=subjects with data available for analysis).
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
|
|||||||||||||||||
End point title |
Mean Change from Baseline to Week 4 in Spasticity Grade (Y) in the Soleus Muscle (Knee Flexed) | ||||||||||||||||
End point description |
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 (n=subjects with data available for analysis).
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
At Week 4
|
||||||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||||||
|
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End point title |
Use of Walking Aids/Orthoses at Baseline and Week 4 | ||||||||||||||||||||||||||||||||||||||
End point description |
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 (n = number of subjects with data available for analysis). 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.
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline and Week 4
|
||||||||||||||||||||||||||||||||||||||
|
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||
|
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Adverse events information
|
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Timeframe for reporting adverse events |
From baseline to Week 24 +/- 2 weeks
|
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Adverse event reporting additional description |
An AE was reported as a TEAE if it arose or the intensity increased during the treatment phase of this study.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.0
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Reporting groups
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Reporting group title |
Total Dysport
|
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Reporting group description |
Subjects who had completed Study 140 continued to receive open label treatment with Dysport in Study 142 for a maximum of 4 additional treatment cycles, with a minimum interval of 12 weeks between treatment cycles. All subjects were administered an appropriate dosage of Dysport (1500 Units [U] or 1000 U) by intramuscular (i.m.) injection in the lower limb on Day 1 of treatment Cycle 1. Subjects requiring retreatment were treated during follow up visits, in accordance with meeting pre-specified criteria and investigator judgement. From treatment Cycle 3 onwards, subjects with co-existing upper limb spasticity were able to receive concomitant injections of Dysport into at least one upper limb muscle at a dose not exceeding 500 U. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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09 Feb 2012 |
Protocol Amendment 2 - Made the following changes:
• The study exclusion criteria were clarified to exclude subjects who had undergone previous surgery to treat spasticity of the affected lower limb (instead of those who had received previous surgery on muscles and ligaments, tendons or nerve trunks of the treated lower limb).
• A new exclusion criterion was added to exclude treatment with intrathecal baclofen during the course of the study.
• Subjects not requiring a new treatment cycle at the Week 24 follow up visit of treatment Cycle 1 or 2 (instead of Cycle 1 and potentially Cycles 2 and 3) were required to have follow up visits every 4 weeks until a new treatment cycle was required or they reached 12 months follow up.
• The Central Laboratory for putative antibody testing was changed from Ipsen Pharma SA (Barcelona, Spain) to Kymos Pharma Services SL (Barcelona, Spain); however, the bioanalytical test remained the same.
• The 12 Lead ECG was to be recorded with the subject in a supine position after 5 minutes rest instead of in a prone position after 30 minutes rest.
• Oral baclofen was added to the permitted concomitant medications.
• The sponsor’s Medically Responsible Person was changed. |
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10 Jan 2014 |
Protocol Amendment 5 - Made the following changes:
• The pharmacovigilance emergency contacts and telephone numbers were updated.
• Subjects were allowed to receive a fourth treatment cycle in Study 142 after the 12 month total follow up duration (including Study 140) in order to complement the long-term safety database. In order to receive the fourth treatment cycle in Study 142, subjects must have received 3 open label treatment cycles within the total 12 month follow up period (including Study 140) and be eligible for retreatment no later than Week 16 of treatment Cycle 3.
• The follow up duration was extended to a maximum of 18 months to ensure that the subjects receiving a fourth treatment cycle after Week 52 were monitored for 12 weeks following their last treatment.
• The EOS visit was amended to the Week 12 visit of the last treatment cycle administered.
• The overall EOS definition was amended to incorporate the change in EOS visit to Week 12.
• It was clarified that measurement of the passive range of motion at the affected hip, knee and ankle must be performed on Day 1 of Study 142.
• A time window was added to the study visits in the observational phase.
• Interim descriptive analyses were allowed, if required. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
