Clinical Trial Results:
Multi-center Open Comparative Randomized Trial of Clinical and Neurophysiological Efficacy and Safety of Xeomin (Botulinum Toxin Type A) vs. Botox (Complex of Botulinum Toxin Type A and Hemagglutinin) in Children With Spastic Equine and Equinovarus Foot Deformation in Pediatric Cerebral Palsy
|
Summary
|
|
EudraCT number |
2016-005049-21 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
15 Dec 2016
|
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
29 Jun 2017
|
First version publication date |
29 Jun 2017
|
Other versions |
|
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
|
Trial identification
|
|||
Sponsor protocol code |
MRZ-R-201212_01001_N_2
|
||
|
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT02188277 | ||
WHO universal trial number (UTN) |
- | ||
|
Sponsors
|
|||
Sponsor organisation name |
Merz Pharmaceuticals GmbH
|
||
Sponsor organisation address |
Eckenheimer Landstrasse 100, Frankfurt/M, Germany, 60318
|
||
Public contact |
Public Disclosure Manager, Merz Pharmaceuticals GmbH, +49 69 1503 1, clinicaltrials@merz.de
|
||
Scientific contact |
Public Disclosure Manager, Merz Pharmaceuticals GmbH, +49 69 1503 1, clinicaltrials@merz.de
|
||
|
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
No
|
||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
|
||
|
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
15 Dec 2016
|
||
Is this the analysis of the primary completion data? |
No
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
15 Dec 2016
|
||
Was the trial ended prematurely? |
No
|
||
|
General information about the trial
|
|||
Main objective of the trial |
The main purpose of this study was to assess the clinical and neurophysiological efficacy of Xeomin vs. Botox in children with spastic equine and equinovarus foot deformation in pediatric cerebral palsy.
|
||
Protection of trial subjects |
“High medical and ethical standards were followed in accordance with Good Clinical Practice and other applicable regulations.”
|
||
Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
08 Jul 2014
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
No
|
||
|
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Russian Federation: 64
|
||
Worldwide total number of subjects |
64
|
||
EEA total number of subjects |
0
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
64
|
||
Adolescents (12-17 years) |
0
|
||
Adults (18-64 years) |
0
|
||
From 65 to 84 years |
0
|
||
85 years and over |
0
|
||
|
|||||||||||||||||||
|
Recruitment
|
|||||||||||||||||||
Recruitment details |
The study was conducted at 3 sites located in Russia. | ||||||||||||||||||
|
Pre-assignment
|
|||||||||||||||||||
Screening details |
A total of 64 subjects who were suffering from spastic paraplegia or hemiparesis in pediatric cerebral palsy were enrolled and randomized into Xeomin or Botox groups in a 1:1 ratio (32 subjects in each group). | ||||||||||||||||||
|
Period 1
|
|||||||||||||||||||
Period 1 title |
Overall study Period (overall period)
|
||||||||||||||||||
Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
|
||||||||||||||||||
Blinding used |
Not blinded | ||||||||||||||||||
|
Arms
|
|||||||||||||||||||
Are arms mutually exclusive |
Yes
|
||||||||||||||||||
|
Arm title
|
IncobotulinumtoxinA (Xeomin) | ||||||||||||||||||
Arm description |
Subjects received 4 (8) units per kilogram (U/kg) body weight incobotulinumtoxinA (Xeomin) | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
IncobotulinumtoxinA
|
||||||||||||||||||
Investigational medicinal product code |
NT 201
|
||||||||||||||||||
Other name |
Xeomin; Botulinum toxin type A (150 kiloDalton) free from complexing proteins
|
||||||||||||||||||
Pharmaceutical forms |
Powder for solution for injection
|
||||||||||||||||||
Routes of administration |
Intramuscular use
|
||||||||||||||||||
Dosage and administration details |
Subjects received 4 U/kg body weight incobotulinumtoxinA (Xeomin) treatment via intramuscular injection into gastrocnemius muscles for one leg and 8 U/kg body weight incobotulinumtoxinA (Xeomin) for both legs on Day 0.
|
||||||||||||||||||
|
Arm title
|
Onabotulinumtoxin A (Botox) | ||||||||||||||||||
Arm description |
Subjects received 4 (6) units per kilogram (U/kg) body weight onabotulinumtoxin A (Botox) | ||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||
Investigational medicinal product name |
Onabotulinumtoxin A
|
||||||||||||||||||
Investigational medicinal product code |
|||||||||||||||||||
Other name |
Botox; Complex of botulinum toxin type A and hemagglutinin
|
||||||||||||||||||
Pharmaceutical forms |
Powder for solution for injection
|
||||||||||||||||||
Routes of administration |
Intramuscular use
|
||||||||||||||||||
Dosage and administration details |
Subjects received 4 U/kg body weight onabotulinumtoxin A (Botox) treatment via intramuscular injection into gastrocnemius muscles for one leg and 6 U/kg bodyweight Onabotulinumtoxin A (Botox) for both legs on Day 0.
|
||||||||||||||||||
|
|||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
|
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
IncobotulinumtoxinA (Xeomin)
|
||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received 4 (8) units per kilogram (U/kg) body weight incobotulinumtoxinA (Xeomin) | ||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Onabotulinumtoxin A (Botox)
|
||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received 4 (6) units per kilogram (U/kg) body weight onabotulinumtoxin A (Botox) | ||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
|
End points reporting groups
|
|||
Reporting group title |
IncobotulinumtoxinA (Xeomin)
|
||
Reporting group description |
Subjects received 4 (8) units per kilogram (U/kg) body weight incobotulinumtoxinA (Xeomin) | ||
Reporting group title |
Onabotulinumtoxin A (Botox)
|
||
Reporting group description |
Subjects received 4 (6) units per kilogram (U/kg) body weight onabotulinumtoxin A (Botox) | ||
Subject analysis set title |
Full Analysis Set (FAS)
|
||
Subject analysis set type |
Full analysis | ||
Subject analysis set description |
FAS was a subgroup of subjects in the safety evaluation set (SES) group for whom an assessment of primary efficacy criteria was possible (that is all subjects who had initial indicators and at least one of the subsequent indicators for efficacy assessment).
|
||
Subject analysis set title |
Safety Evaluation Set (SES)
|
||
Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
SES was defined as a group of the subjects who have signed an informed consent and who had been administered the study products (Xeomin and Botox).
|
||
|
|||||||||||||
End point title |
Change From Baseline (Day 0) in the Degree of Spasticity in Gastrocnemius According to Modified Ashworth Scale (MAS) at Visit 2 (Day 30) | ||||||||||||
End point description |
The MAS 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 6-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension) and includes intermediate scores of 1, 1+, 2, and 3.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Baseline to Visit 2 (Day 30)
|
||||||||||||
|
|||||||||||||
| Notes [1] - FAS [2] - FAS |
|||||||||||||
Statistical analysis title |
Statistical analysis | ||||||||||||
Statistical analysis description |
Comparison of mean changes from baseline.
The actual pre-specified primary efficacy analysis was a comparison of pre- and post treatment values within each reporting group:
IncobotulinumtoxinA: one-sample Wilcoxon test, p = 0.000004
OnabotulinumtoxinA: one-sample Wilcoxon test, p = 0.000002
|
||||||||||||
Comparison groups |
Onabotulinumtoxin A (Botox) v IncobotulinumtoxinA (Xeomin)
|
||||||||||||
Number of subjects included in analysis |
62
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
= 0.443 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
|||||||||||||
|
|||||||||||||||||||
End point title |
Change From Baseline (Day 0) in the Degree of Spasticity in Gastrocnemius According to MAS at Visit 3 (Day 60) and Visit 4 (Day 90) | ||||||||||||||||||
End point description |
The MAS 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 6-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension) and includes intermediate scores of 1, 1+, 2, and 3.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline to Visit 3 (Day 60) and Visit 4 (Day 90)
|
||||||||||||||||||
|
|||||||||||||||||||
| Notes [3] - FAS [4] - FAS |
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change From Baseline in Subjects Percentage in Groups by the Degree of Gastrocnemius Spasticity According to MAS at Visit 2 (Day 30), Visit 3 (Day 60) and Visit 4 (Day 90) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The MAS is a well known and commonly used scale in clinical trials with spasticity. In spasticmuscles the resistance to passive movement is assessed. It is a 6-point scale that ranges from 0 (=no increase in tone) to 4 (=limb rigid in flexion or extension) and includes intermediate scores of 1, 1+, 2, and 3.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Visit 2 (Day 30), Visit 3 (Day 60) and Visit 4 (Day 90)
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [5] - FAS [6] - FAS |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
End point title |
Percentage of Decrease in M-response Magnitude and Area Recorded From the Lateral and Medial Gastrocnemius Heads at Visit 2 (Day 30) and Visit 4 (Day 90) From Baseline Values | ||||||||||||||||||||||||||||||||||||
End point description |
EMG is performed using an electromyograph designed to perform electrical stimulation of peripheral nerves with single rectangular pulses and to record muscle responses. The amplitude of a compound muscle action potential (M-wave) is recorded in millivolts (mV) and the duration is recorded in milliseconds (ms). The measurements include the M-wave amplitude and the negative peak area under the curve of the M-wave. Values given are percentage decreases from baseline for the following muscles: LGH = Lateral gastrocnemius heads and MGH = Medial gastrocnemius heads.
|
||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Visit 2 (Day 30) and Visit 4 (Day 90)
|
||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
| Notes [7] - FAS [8] - FAS |
|||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||
End point title |
Change From Baseline in the Ratio of M-response Magnitude Recorded From the Lateral and Medial Gastrocnemius Heads and From Tibialis Anterior at Visit 2 (Day 30) and Visit 4 (Day 90) | ||||||||||||||||||||||||
End point description |
EMG is performed using an electromyograph designed to perform electrical stimulation of peripheral nerves with single rectangular pulses and to record muscle responses. The M-wave is recorded in mV, the duration in ms. A ratio of the M-wave amplitude between injected muscles (LGH, MGH) and a non-injected muscle tibialis anterior.
(TA) is calculated. Values given are changes in M-wave amplitude ratios from baseline. LGH = Lateral gastrocnemius heads; MGH = Medial gastrocnemius heads.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline to Visit 2 (Day 30) and Visit 4 (Day 90)
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
| Notes [9] - FAS [10] - FAS |
|||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change From Baseline in Angles and Angle Ratio of Ankle Joints at Passive and Voluntary Extension at Visit 2 (Day 30), Visit 3 (Day 60), and Visit 4 (Day 90) | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Using a goniometer the movement amplitude (angle) of the ankle extension was measured for the following conditions:
1) Knee flexion and extension – muscles relaxed (passive function) (subject supine);
2) Knee extension – voluntary muscle contraction (active function) (subject supine).
The ratio of the angles in passive ankle extension (knee flexion and extension) and the ratio of the angles in passive and active ankle extension (knee extension) was also calculated.
Values given are decreases from baseline in angles and ratios.
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Visit 2 (Day 30), Visit 3 (Day 60), and Visit 4 (Day 90)
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [11] - FAS [12] - FAS |
|||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||
End point title |
Change From Baseline in Motor Activity According to Gross Motor Function Classification Systems (GMFCS) Criteria | |||||||||||||||||||||
End point description |
The GMFCS is a system to classify gross motor function in children of different age groups with cerebral palsy. Five levels are defined, with Level 1 describing the best and Level 5 the worst functional level. Values given are score changes from baseline.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline to Visit 2 (Day 30), Visit 3 (Day 60), and Visit 4 (Day 90)
|
|||||||||||||||||||||
|
||||||||||||||||||||||
| Notes [13] - FAS [14] - FAS |
||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
From time point of first injection (Day 0) up to Day 90
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
IncobotulinumtoxinA (Xeomin)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received 4 (8) U/kg body weight incobotulinumtoxinA (Xeomin) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
OnabotulinumtoxinA (Botox)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received 4 (6) U/kg body weight onabotulinumtoxin A (Botox) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
|||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
