Clinical Trial Results:
A PHASE III, PROSPECTIVE, MULTICENTRE, OPEN LABEL, EXTENSION STUDY ASSESSING THE LONG TERM SAFETY AND EFFICACY OF REPEATED TREATMENT WITH DYSPORT USED IN THE TREATMENT OF LOWER LIMB SPASTICITY IN CHILDREN WITH DYNAMIC EQUINUS FOOT DEFORMITY DUE TO CEREBRAL PALSY
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Summary
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EudraCT number |
2010-019102-17 |
Trial protocol |
FR PL |
Global end of trial date |
14 Jan 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Aug 2016
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First version publication date |
13 Aug 2016
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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-55-52120-147
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Ipsen Pharma SAS
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Sponsor organisation address |
65 Quai Georges Gorse, Boulogne-Billancourt, France, 92100
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Public contact |
Medical Director, Paediatric Neurology, Ipsen Pharma SAS, clinical.trials@ipsen.com
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Scientific contact |
Medical Director, Paediatric Neurology, Ipsen Pharma SAS, 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 |
01 Sep 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
14 Jan 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
14 Jan 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 is to assess the long term safety of repeated treatments with Dysport used in the treatment of lower limb spasticity in children with dynamic equinus foot deformity due to CP.
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Protection of trial subjects |
This clinical study was designed and implemented and reported in accordance with the International Conference on Harmonisation (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
05 Oct 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 |
Poland: 66
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Country: Number of subjects enrolled |
France: 2
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Country: Number of subjects enrolled |
Chile: 16
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Country: Number of subjects enrolled |
Mexico: 34
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Country: Number of subjects enrolled |
Turkey: 56
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Country: Number of subjects enrolled |
United States: 42
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Worldwide total number of subjects |
216
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EEA total number of subjects |
68
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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) |
193
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Adolescents (12-17 years) |
23
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was performed as a multicentre study at 27 investigational sites in France, Mexico, Turkey, Poland, Chile and the United States of America (USA). Twenty six sites recruited at least one subject and the other site was inactive. | ||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Of 216 subjects enrolled into this open label study from 141 Study, 203 subjects went straight into Cycle 1. 13 subjects were not considered eligible for retreatment at end of Study 141 (all of whom had received Dysport) and per study design they entered into observational phase of study 147. Of these 13, 4 subjects entered cycle 1 at a later date. | ||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Open Label Study (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 |
Dysport was injected into the affected gastrocnemius soleus complex (GSC) with / without Hamstring injections at doses ranging between 5U/kg to 20U/kg for one leg and 10U/kg to 30U/kg for both legs | ||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||
Investigational medicinal product name |
Dysport
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Investigational medicinal product code |
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Other name |
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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 |
Dysport was injected into the affected gastrocnemius soleus complex (GSC) with / without Hamstring injections at doses ranging between 5U/kg to 20U/kg for one leg and 10U/kg to 30U/kg for both legs
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| Notes [1] - 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: Of 207 subjects who started in cycle 1, only 175 subjects entered cycle 2. (8 subjects withdrew at cycle 1, 24 subjects completed study after cycle 1) [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: Of 207 subjects who started in cycle 1, only 86 subjects entered cycle 3. (16 subjects withdrew at cycles 1 and 2, 105 subjects completed study after cycles 1 and 2) [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: Of 207 subjects who started in cycle 1, only 11 subjects entered cycle 4. (19 subjects withdrew at cycles 1,2 and 3, 177 subjects completed study after cycles 1, 2 and 3) |
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Baseline characteristics reporting groups
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Reporting group title |
Open Label Study
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Total Dysport
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Reporting group description |
Dysport was injected into the affected gastrocnemius soleus complex (GSC) with / without Hamstring injections at doses ranging between 5U/kg to 20U/kg for one leg and 10U/kg to 30U/kg for both legs | ||
Subject analysis set title |
Treatment Cycle 1
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
ITT Population
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Subject analysis set title |
Treatment Cycle 2
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
ITT Population.
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Subject analysis set title |
Treatment Cycle 3
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
ITT Population.
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Subject analysis set title |
Dysport All Doses
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
ITT Population.
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End point title |
Number of subjects with Treatment Emergent Adverse Events Reported in the Double Blind (DB) + Open Label (OL) Period [1] | ||||||||||||||||||||||||||||||||||||||||||
End point description |
Safety Population.
N=216, One Subject received placebo in the double blind study and two treatment cycles of Dysport in this open label study. However, both Dysport treatments were outside of the ranges specified and therefore has been excluded from the tables since all Subjects with dosage outside of the ranges specified (i.e. Cycle 1: <=7.5 or >12.5 U/kg (1 leg), <=15 or >25 U/kg (2 legs), Cycles 2-4: <=7.5 or >17.5 U/kg (1 leg), <=15 or >35 U/kg (2 legs)) were to be excluded.
Treatment Emergent Adverse Event (TEAE); Serious Adverse Event (SAE)
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End point type |
Primary
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End point timeframe |
From baseline (Day 1) till end of study (week 40)
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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: No statistical analyses for this endpoint |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
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End point title |
Mean change from baseline (in the double blind study) in the MAS score in the GSC assessed at the ankle joint of the (most) affected lower limb | ||||||||||||||||||||||
End point description |
ITT (Intent to treat) Population.
The baseline value for the ‘change from cycle baseline in the open label study’ was defined as the baseline (Day 1) of the current treatment cycle.
n=number of subjects with data.
Modified Ashworth Scale (MAS): A 6-point scale which measures the intensity of muscle tone by measuring the resistance of the muscle to passive lengthening or stretching. Investigator will grade muscle tone in the Gastrocnemius-soleus complex (GSC) from 0 (no increase in tone) to 4 (affected parts rigid in flexion or extension).
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End point type |
Secondary
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End point timeframe |
At baseline (Day 1), week 4 and 12
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Mean change from baseline (prior to the first injection cycle in the hamstrings) in the MAS score in the knee flexors assessed at the knee joint of the (most) affected lower limb | ||||||||||||||||||||||
End point description |
ITT Population. Baseline: The baseline value used for this table was defined as the value obtained prior to the first injection in the hamstrings.
Modified Ashworth Scale (MAS): A 6-point scale which measures the intensity of muscle tone by measuring the resistance of the muscle to passive lengthening or stretching. Investigator will grade muscle tone in the Gastrocnemius-soleus complex (GSC) from 0 (no increase in tone) to 4 (affected parts rigid in flexion or extension).
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End point type |
Secondary
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End point timeframe |
At baseline (Day 1), week 4 and week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Mean change from baseline (prior to the first injection cycle in upper limb muscle groups) in the mean MAS score for all injected upper limb muscle groups from Treatment Cycle 2 onwards | ||||||||||||||||||||||||
End point description |
ITT Population.
The baseline value used for this table was defined as the value obtained prior to the first injection in the upper limb(s).
No subjects were treated in the upper limb in Treatment Cycle 4.
TC = Treatment Cycle.
n = number of subjects with data.
TC 3 - Elbow Flexors at week 12 - value for standard deviation is not applicable as number of subject is 1.
Modified Ashworth Scale (MAS): A 6-point scale which measures the intensity of muscle tone by measuring the resistance of the muscle to passive lengthening or stretching. Investigator will grade muscle tone in the Gastrocnemius-soleus complex (GSC) from 0 (no increase in tone) to 4 (affected parts rigid in flexion or extension).
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End point type |
Secondary
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End point timeframe |
At baseline (Day 1), week 4 and week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Mean PGA (Physician’s Global Assessment) score | ||||||||||||||||||||||
End point description |
ITT Population.
Physician’s Global Assessment (PGA) Scale of the Treatment Response: Global assessment of treatment response will be assessed by asking the Investigator the following question: “how would you rate the response to treatment in the subject’s lower limb(s) since the last injection?” Answers will be made on a 9 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).
Global assessment of treatment response is based on changes since the first injection in the double blind study.
Subjects with dosage outside of the ranges specified (i.e. ≤7.5 or >17.5 U/kg) were excluded from the table.
n=number of subjects with data.
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End point type |
Secondary
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End point timeframe |
At week 4 and week 12.
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Mean GAS (Goal Attainment Scale) score | ||||||||||||||||||||||
End point description |
ITT Population.
Goal Attainment Scale (GAS): A functional scale used to measure progress towards individual therapy goals. Individual goals will be defined for each subject by the physician, and the child's parents (caregiver) where applicable, prior to treatment. Post-baseline, the GAS for each goal will be rated using a defined scale (-2: Much less than expected outcome, -1: somewhat less than expected outcome, 0: expected outcome, 1: somewhat more than expected outcome, and 2: Much more than expected outcome).
Individual goals were defined prior to treatment in each treatment period. Subjects with dosage outside of the ranges specified (i.e. ≤7.5 or >17.5 U/kg) were excluded from the table.
n=number of subjects with data.
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End point type |
Secondary
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End point timeframe |
At week 4 and week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Mean change from treatment cycle baseline (cycle Day 1) in XV1 derived from the TS, in the GSC assessed at the ankle joint of the (most) affected lower limb | ||||||||||||||||||||||
End point description |
ITT Population.
The DB (Double blind) baseline is presented for each treatment cycle as it represents the baseline data just for the subjects entering into each treatment cycle. Subjects with dosage outside of the ranges specified (i.e. ≤7.5 or >17.5 U/kg) were excluded from the table.
n=number of subjects with data.
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End point type |
Secondary
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End point timeframe |
At baseline (Day 1), week 4 and week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Mean change from treatment cycle baseline (cycle Day 1) in XV3 derived from the TS, in the GSC assessed at the ankle joint of the (most) affected lower limb | ||||||||||||||||||||||
End point description |
ITT Population.
The DB baseline is presented for each treatment cycle as it represents the baseline data just for the subjects entering into each treatment cycle. Subjects with dosage outside of the ranges specified (i.e. ≤7.5 or >17.5 U/kg) were excluded from the table.
n=number of subjects with data.
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End point type |
Secondary
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End point timeframe |
At baseline (Day 1), week 4 and week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Mean change from treatment cycle baseline (cycle Day 1) in X derived from the TS, in the GSC assessed at the ankle joint of the (most) affected lower limb | ||||||||||||||||||||||
End point description |
ITT Population.
The DB baseline is presented for each treatment cycle as it represents the baseline data just for the subjects entering into each treatment cycle. Subjects with dosage outside of the ranges specified (i.e. ≤7.5 or >17.5 U/kg) were excluded from the table.
n=number of subjects with data.
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End point type |
Secondary
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End point timeframe |
At baseline (Day 1), week 4 and week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Mean change from treatment cycle baseline (cycle Day 1) in Y, derived from the TS, in the GSC assessed at the ankle joint of the (most) affected lower limb | ||||||||||||||||||||||
End point description |
ITT Population.
The DB baseline is presented for each treatment cycle as it represents the baseline data just for the subjects entering into each treatment cycle. Subjects with dosage outside of the ranges specified (i.e. ≤7.5 or >17.5 U/kg) were excluded from the table.
n=number of subjects with data.
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End point type |
Secondary
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End point timeframe |
At baseline (Day 1), week 4 and week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Mean change from baseline (prior to the first injection cycle in the hamstrings) in XV1, derived from the TS, in the knee flexors assessed at the knee joint of the (most) affected lower limb | ||||||||||||||||||||||
End point description |
ITT Population.
Subjects with dosage outside of the ranges specified (i.e. ≤3 or >12.5 U/kg) were excluded from the table, including the Dysport all doses.
n=number of subjects with data.
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End point type |
Secondary
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End point timeframe |
At baseline (Day 1), week 4 and week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Mean change from baseline (prior to the first injection cycle in the hamstrings) in XV3, derived from the TS, in the knee flexors assessed at the knee joint of the (most) affected lower limb | ||||||||||||||||||||||
End point description |
ITT Population.
Subjects with dosage outside of the ranges specified (i.e. ≤3 or >12.5 U/kg) were excluded from the table, including the Dysport all doses.
n=number of subjects with data.
DB = Double blind.
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End point type |
Secondary
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End point timeframe |
At baseline (Day 1), week 4 and week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Mean change from baseline (prior to the first injection cycle in the hamstrings) in X, derived from the TS, in the knee flexors assessed at the knee joint of the (most) affected lower limb | ||||||||||||||||||||||
End point description |
ITT Population.
Subjects with dosage outside of the ranges specified (i.e. ≤3 or >12.5 U/kg) were excluded from the table, including the Dysport all doses.
n=number of subjects with data.
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End point type |
Secondary
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End point timeframe |
At baseline (Day 1), week 4 and week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Mean change from baseline (prior to the first injection cycle in the hamstrings) in Y, derived from the TS, in the knee flexors assessed at the knee joint of the (most) affected lower limb | ||||||||||||||||||||||
End point description |
ITT Population.
Subjects with dosage outside of the ranges specified (i.e. ≤3 or >12.5 U/kg) were excluded from the table, including the Dysport all doses.
n=number of subjects with data.
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End point type |
Secondary
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End point timeframe |
At baseline (Day 1), week 4 and week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Mean change from treatment cycle baseline (cycle Day 1) in the OGS total score of the (most) affected leg | ||||||||||||||||||||||
End point description |
ITT Population.
The DB baseline is presented for each treatment cycle as it represents the baseline data just for the subjects entering into each treatment cycle. Subjects with dosage outside of the ranges specified (i.e. ≤7.5 or >17.5 U/kg) were excluded from the table.
The OGS is a measurement tool that objectively measures to quantify positive and negative features (impairments) of the upper motor neurone syndrome [27]. The OGS is useful when children are too young or insufficiently cooperative for instrumented gait analysis. It is based on the Physicians Rating Scale but has some modifications to improve its sensitivity to detect changes following administration of BTX-A (Botulinum Toxin Type A).
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End point type |
Secondary
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End point timeframe |
At baseline (Day 1), week 4 and week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Mean change from treatment cycle baseline (cycle Day 1) in the PedsQL score (Cerebral Palsy Module Scores) at each study visit except Week 4 | ||||||||||||||||||||||||||||||||||||||||||||
End point description |
ITT Population.
The PedsQL is a validated quality of life questionnaire, designed for children from 2 to 18 years of age. It has a disease specific CP module that is relevant to the study population and complements the core modules.
Open Label (Dysport All Doses) - Treatment Cycle 1, 2 and 3
Baseline is baseline data from the double blind study.
S and C = Speech and communication.
n=number of subjects with data.
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End point type |
Secondary
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End point timeframe |
At baseline (Day 1), week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Mean change from treatment cycle baseline (cycle Day 1) in the PedsQL score (Generic Core Scores) at each study visit except Week 4 | ||||||||||||||||||||||||||||
End point description |
ITT Population.
The PedsQL is a validated quality of life questionnaire, designed for children from 2 to 18 years of age. It has a disease specific CP module that is relevant to the study population and complements the core modules.
Open Label (Dysport All Doses) - Treatment Cycle 1, 2 and 3.
Baseline is baseline data from the double blind study.
PhHS = Physical health summary
PHS = Psychosocial health summary.
n=number of subjects with data.
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End point type |
Secondary
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End point timeframe |
At baseline (Day 1), week 12
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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 Day 1 to end of study (week 40)
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Adverse event reporting additional description |
DB+OL Period Safety Popln N=216. Subjects with dosage outside specified ranges[Cycle 1:<=7.5 or>12.5U/kg(1 leg),<=15 or>25U/kg(2 legs),Cycles 2-4:<=7.5 or>17.5U/kg(1 leg),<=15 or>35U/kg (2 legs)] were to be excluded.One Subject who received placebo in DB & 2 cycles Dysport in OL was excluded from tables as both Dysport treatments were outside range
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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 |
17.1
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Reporting groups
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Reporting group title |
Dysport All Doses
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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07 Mar 2011 |
• The GAS was changed from a 7-point scale to the validated 5-point scale.
• Question 8 was omitted from the OGS, as central assessors were to evaluateand score each video in an independent manner and would not have thebaseline videos for comparison to score Question 8 which assesses change from baseline.
• The injection technique was modified to add the use of ultrasound as a complimentary muscle localisation method to electrical stimulation.
• Injection volume for the lower quadrant of gastrocnemius changed to optional and this volume could be utilised in other lower limb injection sites according to clinical presentation of spasticity. This change was based on a publication on neuromuscular endplate concentration in lower limb.
• Clarification was added to the study rationale in response to French Central Ethics Committee's request.
• A new contact number was added due to change of office reception number. |
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12 Jul 2012 |
• The pharmacovigilance/emergency contact details for the USA and Latin America were updated.
• Exclusion criterion 1 was modified to clarify the terminology for the exclusion of subjects based on the assessment of fixed myocontracture.
• Exclusion criterion 3 was modified to clarify the exclusion of subjects with a need for surgery due to spasticity.
• Written informed consent details were modified to clarify that either one or both parent(s)/guardian(s) would sign the ICF according to local legislation.
• Study treatment was to be administered within 24 hours of Day 1 visit assessments of each treatment cycle.
• Ipsen Pharma was replaced by Kymos Pharma as the central laboratory used for processing antibody samples.
• The wording of Section 9.5 was amended to clarify the meaning and take into account all possibilities regarding used and unused treatments and empty boxes for destruction.
• References to Sponsor’s Clinical Development Data Sciences Department were amended to Statistics Department. |
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18 Nov 2013 |
• The Sponsor’s Co-ordinating and Monitoring Office details were updated.
• The pharmacovigilance/emergency contact details for the UK, USA and Latin America were updated.
• Deleted informed consent information in Section 4.1.3 to be consistent with Section 5.2.
• To allow an interim analyses, if required, for registration purposes. |
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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 | |||
