Clinical Trial Results:
Open-label, non-controlled, multicenter long-term study to investigate the safety and efficacy of Xeomin® (incobotulinumtoxinA, NT 201) for the treatment of spasticity of the lower limb(s) or of combined spasticity of upper and lower limb in children and adolescents (age 2 - 17 years) with cerebral palsy
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Summary
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EudraCT number |
2012-005055-17 |
Trial protocol |
AT EE SK CZ Outside EU/EEA FR |
Global end of trial date |
16 Jan 2017
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Results information
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Results version number |
v2(current) |
This version publication date |
26 Nov 2017
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First version publication date |
15 Jul 2017
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Other versions |
v1 |
Version creation reason |
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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 |
MRZ60201_3071_1
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01905683 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Merz Pharmaceuticals GmbH
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Sponsor organisation address |
Eckenheimer Landstrasse 100, Frankfurt/M, Germany, 60318
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Public contact |
Public Disclosure Manager, Merz Pharmaceuticals GmbH, +49 69 1503 1, clinicaltrials@merz.de
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Scientific contact |
Public Disclosure Manager, Merz Pharmaceuticals GmbH, +49 69 1503 1, clinicaltrials@merz.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001039-PIP01-10 | ||
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? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
16 Jan 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Jan 2017
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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 purpose of this study is to determine whether injections of Botulinum toxin type A into muscles of the leg(s) or of leg(s) and one arm are safe in treating children/adolescents (age 2-17 years) long-term with increased muscle tension/uncontrollable muscle stiffness (spasticity) due to cerebral palsy.
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Protection of trial subjects |
High medical and ethical standards were followed in accordance with Good Clinical Practice and other applicable regulations. In addition, an independent data monitoring committee was in charge of monitoring patient safety while the study was ongoing.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Nov 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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: 67
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Country: Number of subjects enrolled |
Slovakia: 5
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Country: Number of subjects enrolled |
Austria: 1
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Country: Number of subjects enrolled |
Czech Republic: 1
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Country: Number of subjects enrolled |
Estonia: 5
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Country: Number of subjects enrolled |
Germany: 1
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Country: Number of subjects enrolled |
Turkey: 5
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Country: Number of subjects enrolled |
Russian Federation: 33
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Country: Number of subjects enrolled |
Israel: 1
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Country: Number of subjects enrolled |
Korea, Republic of: 59
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Country: Number of subjects enrolled |
Ukraine: 170
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Country: Number of subjects enrolled |
Romania: 22
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Worldwide total number of subjects |
370
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EEA total number of subjects |
102
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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) |
317
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Adolescents (12-17 years) |
53
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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 |
- | ||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 391 subjects were screened, of which 370 subjects were enrolled and treated in this study. Of these, 124 subjects were recruited from the lead-in study (62, 29 and 33 subjects from the IncobotulinumtoxinA high, mid and low dose group respectively of the study MRZ60201_3070_1 [2012-005054-30]) and 246 subjects were newly recruited. | ||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall period
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Is this the baseline period? |
Yes | ||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||||
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Arms
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Arm title
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16 - 20 U/kg Body Weight IncobotulinumtoxinA (Xeomin) | ||||||||||||||||||||||
Arm description |
Subjects received total doses of 16 to 20 unit per kilogram (U/kg) body weight of IncobotulinumtoxinA (Xeomin) with a maximum of 400 to 500 units per injection treatment via intramuscular injection into spastic muscles on Day 1 of 4 treatment cycles (12 to 16 weeks treatment per each cycle). The higher dose could only be administered to subjects with GMFCS-E&R levels I to III. | ||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||
Investigational medicinal product name |
IncobotulinumtoxinA
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Investigational medicinal product code |
NT 201
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Other name |
Xeomin; Botulinum toxin type A (150 kiloDalton) free from complexing proteins
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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 |
All subjects received 8U/kg per pes equinus into at least one pes equinus and 12 to 16U/kg total into their lower limb(s). Newly recruited subjects were eligible to receive additional 4U into their UL. Subjects who were enrolled after completion of the lead-in study MRZ60201_3070_1 (2012-005054-30) all received 16 U/kg (max. 400 U) per injection treatment into the same LL only treatment patterns chosen in the previous study.
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Baseline characteristics reporting groups
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Reporting group title |
16 - 20 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
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Reporting group description |
Subjects received total doses of 16 to 20 unit per kilogram (U/kg) body weight of IncobotulinumtoxinA (Xeomin) with a maximum of 400 to 500 units per injection treatment via intramuscular injection into spastic muscles on Day 1 of 4 treatment cycles (12 to 16 weeks treatment per each cycle). The higher dose could only be administered to subjects with GMFCS-E&R levels I to III. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
16 - 20 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
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Reporting group description |
Subjects received total doses of 16 to 20 unit per kilogram (U/kg) body weight of IncobotulinumtoxinA (Xeomin) with a maximum of 400 to 500 units per injection treatment via intramuscular injection into spastic muscles on Day 1 of 4 treatment cycles (12 to 16 weeks treatment per each cycle). The higher dose could only be administered to subjects with GMFCS-E&R levels I to III. | ||
Subject analysis set title |
Safety Evaluation Set (SES)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The SES included all subjects treated with investigational product (IP) at least once.
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Subject analysis set title |
Full Analysis Set (FAS)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The FAS included all subjects in the SES for whom at least a baseline value (Day 1 of the first cycle, Visit 2) of ashworth scale (AS) score of plantar flexors was available. For subjects from lead-in study at least one post-baseline value was available.
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End point title |
Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and Per Injection Cycle [1] | ||||||||||||||||
End point description |
TEAEs are events observed from the time point of first injection until end of study visit (Week 50-66). Values reported here refer to the number of subjects affected. Here, 'n' indicated number of subjects for which the variable was assessed at each of the injection cycles.
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End point type |
Primary
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End point timeframe |
From the timepoint of first injection up to end of study visit (Week 50-66)
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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 data was planned to be analyzed in this endpoint. |
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| Notes [2] - SES |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Occurrence of TEAEs of Special Interest (TEAESIs) Overall and Per Injection Cycle [3] | ||||||||||||||||
End point description |
TEAE occurring after treatment that were thought to possibly indicate toxin spread throughout the trial conduct are defined as TEAE of Special Interests. Values reported here refer to the number of subjects affected. Here, 'n' indicated number of subjects for which the variable was assessed at each of the injection cycles.
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End point type |
Primary
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End point timeframe |
From the timepoint of first injection until end of study visit (Week 50-66)
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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 data was planned to be analyzed in this endpoint. |
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| Notes [4] - SES |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Occurrence of Treatment-emergent Serious Adverse Events (TESAEs) Overall and Per Injection Cycle [5] | ||||||||||||||||
End point description |
TESAEs are events observed from the time point of first injection until end of study visit (Week 50-66). Values reported here refer to the number of subjects affected. Here, 'n' indicated number of subjects for which the variable was assessed at each of the injection cycles.
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End point type |
Primary
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End point timeframe |
From the timepoint of first injection until end of study visit (Week 50-66)
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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 data was planned to be analyzed in this endpoint. |
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| Notes [6] - SES |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Investigator’s Global Assessment of Tolerability at Day 99 (Week 14) Of Each Injection Cycle | ||||||||||||||||||||||||||||||||||||||||
End point description |
The investigator’s global assessment of tolerability was assessed on a 4-point ordinal scale where 1 = very good, 2 = good, 3 = moderate, and 4 = poor. Results for Day 99 (Week 14) of 4th injection cycles were collected at the end of study visit. Here, 'n' indicated number of subjects for which the variable was assessed at each of the injection cycles.
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End point type |
Secondary
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End point timeframe |
Day 99 (Week 14) of 1st, 2nd, 3rd and 4th injection cycle (IC)
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| Notes [7] - SES |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||
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End point title |
Changes in Ashworth Scale (AS) Score of Left and Right Plantar Flexors (PF) From Baseline to all Other Visits, From Day 1 of Each Injection Cycle to Day 29 (Week 4), Day 57 (Week 8, 1st IC Cycle Only) and Day 99 (Week 14) of the Respective Injection Cycle | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The AS is a well known and commonly used scale in clinical trials with spasticity. In spastic muscles the resistance to passive movement is assessed. It is a 5-point scale that ranges from 0 (= no increase in tone) to 4 (=limb rigid in flexion or extension). For subjects with bilateral pes equinus, the body side for efficacy analysis i.e. “primary body side” was decided by investigator at screening and was kept throughout the entire study. Here, 'n' indicated number of subjects for which the variable was assessed at each of the injection cycles. V3 = Week 4 of 1st IC; V4 = Week 8 of 1st IC; V5 = Day 1 of 2nd IC; V6 = Week 4 of 2nd IC; V7 = Day 1 of 3rd IC; V8 = Week 4 of 3rd IC; V9 = Day 1 of 4th IC; V10 = Week 4 of 4th IC; V11 = Week 14 of 4th IC = end of study visit.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, Visit[V] 2) to all other visits (V3, V4, V5, V6, V7, V8, V9, V10, and V11); From Day 1 of Each IC to Day 29 (Week 4), Day 57 (Week 8, 1st IC cycle only) and Day 99 (Week 14) of the respective IC
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| Notes [8] - FAS |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Investigator's, Child's/Adolescent's, and Parent's/Caregiver's Global Impression of Change Scale (GICS) at Day 29 (Week 4) of Each Injection Cycle | ||||||||||||||||||||||||||||||||
End point description |
The GICS are global outcomes to assess the impression of change due to treatment. GICS were assessed by the investigator, by the subject (if feasible) and by parents'/caregiver (if applicable). GICS are 7-Point Likert Scales ranging from +3 (very much improved function) to -3 (very much worse function). Here, 'n' indicates number of subjects exposed to each dose group for each injection cycle. Here, 'n' indicated number of subjects for which the variable was assessed at each of the injection cycles.
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End point type |
Secondary
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End point timeframe |
Day 29 (Week 4) of 1st, 2nd, 3rd and 4th IC
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| Notes [9] - FAS |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||
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End point title |
Investigator's Global Impression of Change of Plantar Flexor Spasticity Scale (GICS-PF) of Left and Right Plantar Flexors at Day 29 (Week 4) of Each Injection Cycle | ||||||||||||||||||||||||
End point description |
The GICS are global outcomes to assess the impression of change due to treatment. GICS were assessed by the investigator, by the subject(if feasible) and by parents'/caregiver (if applicable). GICS are 7-Point Likert Scales ranging from +3 (very much improved function) to -3 (very much worse function). For subjects with bilateral pes equinus, the body side for efficacy analysis i.e. “primary body side” was decided by investigator at screening and was kept throughout the entire study. Here, 'n' indicated number of subjects for which the variable was assessed at each of the injection cycles.
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End point type |
Secondary
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End point timeframe |
Day 29 (Week 4) of 1st, 2nd, 3rd and 4th IC
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| Notes [10] - FAS |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Changes in Modified Tardieu Scale (MTS) of Left and Right Plantar Flexors From Baseline to all Other Visits, From Day 1 of Each Injection Cycle to Day 29 (Week 4), Day 57 (Week 8, 1st IC Cycle Only) and Day 99 (Week 14) of the Respective Injection Cycle | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The Modified Tardieu Scale (MTS) assesses spastic muscle tone by subtraction of two angles measured at different conditions of passive muscle stretch. R2 is the angle of passive range of motion with a passive movement at slow speed. R1 is the angle where a "catch-and-release" or clonus can be triggered at the fastest possible speed. Score values represent the measured (R2-R1) difference, i.e. the dynamic tone component of the examined muscle(s). Decreases of (R2-R1) represent reductions in the dynamic component of spasticity, i.e. improvement of dynamic muscle spasticity. Here, 'n' indicated number of subjects for which the variable was assessed at each of the injection cycles. V3 = Week 4 of 1st IC; V4 = Week 8 of 1st IC; V5 = Day 1 of 2nd IC; V6 = Week 4 of 2nd IC; V7 = Day 1 of 3rd IC; V8 = Week 4 of 3rd IC; V9 = Day 1 of 4th IC; V10 = Week 4 of 4th IC; V11 = Week 14 of 4th IC = end of study visit.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, Visit[V] 2) to all other visits (V3, V4, V5, V6, V7, V8, V9, V10, and V11); From Day 1 of Each IC to Day 29 (Week 4), Day 57 (Week 8, 1st IC cycle only) and Day 99 (Week 14) of the respective IC
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| Notes [11] - FAS |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Change in Scores of Pain Intensity (From Subjects) and Frequency (From Parent/Caregiver) From Baseline to all Visits, From Day 1 of Each Injection Cycle to Day 29 (Week 4), Day 57 (Week 8, 1st IC Cycle Only) and Day 99 (Week 14) of Respective Injection | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The QPS is a patient-reported outcome for children and adolescents (2-17 years) with cerebral palsy on spasticity-related pain. Pain intensity (from participants) and pain frequency (from parent/caregiver) to be assessed with 'Questionnaire on Pain caused by Spasticity [QPS]'. The QPS Total Score for pain intensity ranges from 0 ('No Hurt') to 10 ('Hurt Worst'). The QPS Total Score for the observed pain frequency ranges from 0 (Never) to 4 (Always). Here, 'n' indicated number of subjects for which the variable was assessed at each of the injection cycles. V3 = Week 4 of 1st IC; V4 = Week 8 of 1st IC; V5 = Day 1 of 2nd IC; V6 = Week 4 of 2nd IC; V7 = Day 1 of 3rd IC; V8 = Week 4 of 3rd IC; V9 = Day 1 of 4th IC; V10 = Week 4 of 4th IC; V11 = Week 14 of 4th IC = end of study visit.
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End point type |
Secondary
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End point timeframe |
Baseline (Day 1, Visit[V] 2) to all other visits (V3, V4, V5, V6, V7, V8, V9, V10, and V11); From Day 1 of Each IC to Day 29 (Week 4), Day 57 (Week 8, 1st IC cycle only) and Day 99 (Week 14) of the respective IC
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| Notes [12] - FAS |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Changes in Gross Motor Function Measure (GMFM)-66 Score From Baseline to All Injection Visits and End of Study | ||||||||||||||||
End point description |
The GMFM-66 is a standardized observational 66-item instrument designed and validated to measure change in gross motor function over time in participants with cerebral palsy. Score values represent the total GMFM-66 score. Total GMFM scores range from 0 (worst) to 100 (best). Here, 'n' indicated number of subjects for which the variable was assessed at each of the injection cycles.
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End point type |
Secondary
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End point timeframe |
Baseline to Day 1 of 2nd (V5), 3rd (V7), 4th (V9) IC and End of study (Week 44-68) (V11)
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| Notes [13] - FAS |
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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 the timepoint of first injection up to end of study visit (Week 50-66)
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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 |
19
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Reporting groups
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Reporting group title |
16 - 20 U/kg Body Weight IncobotulinumtoxinA (Xeomin)
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Reporting group description |
Newly enrolled subjects received 16 to 20 U/kg body weight of IncobotulinumtoxinA (Xeomin) with a maximum of 400 to 500 units per injection treatment and subjects who were enrolled after completion of the lead-in study MRZ60201_3070_1 (2012-005054-30) received 16 U/kg body weight of IncobotulinumtoxinA (Xeomin) with a maximum of 400 units per injection treatment via intramuscular injection into spastic muscles on Day 1 of the 4 treatment cycles (12 to 16 weeks treatment cycle each). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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12 Jul 2013 |
The following changes were made with relevance to safety:
1) Clarification that occurrence of severe AESI of respiratory function or severe swallowing disorders were criteria for premature study discontinuation of subjects without any further re-exposure to investigational product.
2) Addition of swallowing disorders to respiratory disorders as AESI category that could lead to premature termination of the study.
3) Clarification that hospitalization for analgosedation starting one day before or on the day of injection treatments was not regarded as a serious adverse event (SAE), if performed for organizational reasons only.
The following changes were made with relevance to assessment:
1) Addition of the estimated glomerular filtration rate (eGFR) to assess subjects’ renal function based on the height and creatinine levels.
2) Clarification that in case of casting of the target limb(s), casts were to be removable to allow for scheduled study assessments on visit days.
3) Clarification of regulation to keep clinical patterns of spasticity treatment throughout participation in MRZ60201_3071_1 and to keep the patterns also in subjects rolling-over from MRZ60201_3070_1.
4) Clarification of the calculation of the visit window in case of visits where the GMFM could be performed one day prior to all other assessments.
5) Correction of ranges for injection sites for the gastrocnemius muscle and for all other muscles in Appendix 16.5 of the CSP to be in line with the regulation of maximum of 25 units per injection site in subjects <25 kg BW and maximum of 50 units in subjects with BW >=25 kg.
6) Description how confidential data were handled on the GMFM-66 source form. |
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24 Apr 2015 |
The following changes were made:
1)Addition of a new safety assessment to prospectively monitor suicidality: the columbia suicide severity rating scale C-SSRS was to be considered as the most important source of information considering suicidality.
2) Addition of a new safety variable (classified as other safety variable) based on the results of the C-SSRS.
3) Addition of an exclusion criterion specifying that subjects with significant risk of suicidality at the baseline assessment were to be excluded.
4) Addition of a new discontinuation criterion: subjects were to be discontinued if there was a positive report on suicidality based on the C-SSRS.
5) Modification of data management procedures clarifying documentation of the C-SSRS results.
6) Modification of the definition of SAEs further specifying suicidal ideation (a response of “yes” to questions 4 or 5) or any suicidal behavior as “medically important condition”.
7) Description of the analysis of C-SSRS data.
8) Changes to the risk-benefit assessment. |
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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 | |||
