BOTOX® Treatment in Pediatric Upper Limb Spasticity | NCT01603602

ID	Type	Description	Link
2012-000062-38	EudraCT Number

Label	Type	Description	Intervention Names
BOTOX® 3 U/kg	Experimental	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 3 units (U) per kilogram (kg) of body weight (3 U/kg) into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT).	Biological: botulinum toxin Type A
BOTOX® 6 U/kg	Experimental	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 6 U per kg of body weight (6 U/kg) into specified muscles of the upper limb on Day 1. Participants received weekly OT.	Biological: botulinum toxin Type A
Placebo	Placebo Comparator	Participants received intramuscular injections of normal saline (placebo) into specified muscles of the upper limb on Day 1. Participants received weekly OT.	Drug: Normal Saline (Placebo)

Name	Type	Description	Arm Group Labels	Other Names
botulinum toxin Type A	Biological	Intramuscular injections of botulinum toxin Type A into specified muscles of the upper limb on Day 1.	BOTOX® 3 U/kg BOTOX® 6 U/kg

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Average Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of the Principal Muscle Group at Weeks 4 and 6	The MAS-B was used to evaluate spasticity based on grading the resistance encountered in the principal muscle group (elbow and wrist) by means of passively moving a limb through its range of motion at a study specified velocity. The resistance encountered to passive stretch was graded using a 6-point scale where: 0=no increase in muscle tone (best) to 4=affected part(s) rigid in flexion or extension (worst). For analysis purposes, the MAS-B was recoded as follows: 0=1, 1=1, 1+=2, 2=3, 3=4, 4=5. The scores at Weeks 4 and 6 were averaged. A Mixed Model Repeated Measures (MMRM) model was used for analysis. A negative change from Baseline indicates improvement.	Baseline (Day 1) to Weeks 4 and 6
Average Clinical Global Impression (CGI) of Overall Change by Physician at Weeks 4 and 6	The CGI of overall change (improvement or worsening) was assessed by the physician considering the participant's clinical condition and severity of side effects using a 9-point scale where: -4=very marked worsening to +4=very marked improvement. The scores at Weeks 4 and 6 were averaged. A MMRM model was used for analysis.	Weeks 4 and 6

Secondary Outcomes

Measure	Description	Time Frame
Average Change From Baseline in MAS-B Score of the Finger Flexor Muscle Group at Weeks 4 and 6	The MAS-B was used to evaluate spasticity based on grading the resistance encountered in the finger flexor muscle group by means of passively moving a limb through its range of motion at a study specified velocity. The resistance encountered to passive stretch was graded using a 6-point scale where: 0=no increase in muscle tone (best) to 4=affected part(s) rigid in flexion or extension (worst). For analysis purposes, the MAS-B was recoded as follows: 0=1, 1=1, 1+=2, 2=3, 3=4, 4=5. The scores at Weeks 4 and 6 were averaged. An Analysis of Covariance (ANCOVA) model was used for analysis. A negative change from Baseline indicates improvement.

Name	Affiliation	Role
Rozalina Dimitrova	Allergan	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
AMS Neurology		Pasadena	California	91106	United States
Harrison Clinical Management

Label	URL
Additional information on study locations near you may be found at AllerganClinicalTrials.com. For any study not on AllerganClinicalTrials.com, please contact IR-CTRegistration@Allergan.com for assistance.	View source

ID	Title	Description
FG000	BOTOX® 6 U/kg	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 6 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT).
FG001	BOTOX® 3 U/kg

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jul 22, 2016	Jun 12, 2018

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Average Change From Baseline in Modified Ashworth Scale-Bohannon (MAS-B) Score of the Principal Muscle Group at Weeks 4 and 6

The MAS-B was used to evaluate spasticity based on grading the resistance encountered in the principal muscle group (elbow and wrist) by means of passively moving a limb through its range of motion at a study specified velocity. The resistance encountered to passive stretch was graded using a 6-point scale where: 0=no increase in muscle tone (best) to 4=affected part(s) rigid in flexion or extension (worst). For analysis purposes, the MAS-B was recoded as follows: 0=1, 1=1, 1+=2, 2=3, 3=4, 4=5. The scores at Weeks 4 and 6 were averaged. A Mixed Model Repeated Measures (MMRM) model was used for analysis. A negative change from Baseline indicates improvement.

Participants from the Modified Intent-to treat (mITT) population, all randomized participants with a valid MAS-B baseline score and at least one post-baseline measurement at weeks 2, 4, or 6 for the MAS-B of the principal muscle group and the CGI by physician, with data available for analysis.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline (Day 1) to Weeks 4 and 6

ID	Title	Description
OG000	BOTOX® 6 U/kg	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 6 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT).
OG001	BOTOX® 3 U/kg	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 3 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly OT.
OG002	Placebo	Participants received intramuscular injections of normal saline (placebo) into specified muscles of the upper limb on Day 1. Participants received weekly OT.

Units	Counts
Participants	OG00074 OG00176 OG00275

Title

Denominators

Categories

Title	Measurements
	OG000-1.87± 0.102 OG001-1.92± 0.101 OG002-1.21± 0.102

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002		Mixed Model Repeated Measures (MMRM)		<0.001	MMRM model with baseline MAS-B score as covariate; factors of age, principal muscle group, treatment, visit, treatment-by-visit interaction, study center and previous botulinum toxin exposure, stratified by age and principal muscle group categories.	Least Squares (LS) Mean Difference	-0.66			2-Sided	95	-0.938	-0.379					Superiority

Primary

Average Clinical Global Impression (CGI) of Overall Change by Physician at Weeks 4 and 6

The CGI of overall change (improvement or worsening) was assessed by the physician considering the participant's clinical condition and severity of side effects using a 9-point scale where: -4=very marked worsening to +4=very marked improvement. The scores at Weeks 4 and 6 were averaged. A MMRM model was used for analysis.

Participants from the m ITT population, all randomized participants with a valid MAS-B baseline score and at least one post-baseline measurement at weeks 2, 4, or 6 for the MAS-B of the principal muscle group and the CGI by physician, with data available for analysis at the given time-point.

Posted

Least Squares Mean

Standard Error

score on a scale

Weeks 4 and 6

ID	Title	Description
OG000	BOTOX® 6 U/kg	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 6 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT).
OG001	BOTOX® 3 U/kg	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 3 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly OT.
OG002	Placebo

Secondary

Average Change From Baseline in MAS-B Score of the Finger Flexor Muscle Group at Weeks 4 and 6

The MAS-B was used to evaluate spasticity based on grading the resistance encountered in the finger flexor muscle group by means of passively moving a limb through its range of motion at a study specified velocity. The resistance encountered to passive stretch was graded using a 6-point scale where: 0=no increase in muscle tone (best) to 4=affected part(s) rigid in flexion or extension (worst). For analysis purposes, the MAS-B was recoded as follows: 0=1, 1=1, 1+=2, 2=3, 3=4, 4=5. The scores at Weeks 4 and 6 were averaged. An Analysis of Covariance (ANCOVA) model was used for analysis. A negative change from Baseline indicates improvement.

Participants from the mITT population, all randomized participants with a valid MAS-B baseline score and at least one post-baseline measurement at weeks 2, 4, or 6 for the MAS-B of the principal muscle group and the CGI by physician, with data available for analysis at the given time-point.

Posted

Least Squares Mean

Standard Error

score on a scale

Baseline (Day 1) to Weeks 4 and 6

ID	Title	Description
OG000	BOTOX® 6 U/kg	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 6 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT).
OG001	BOTOX® 3 U/kg	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 3 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly OT.

Secondary

Goal Attainment Score (GAS) as Assessed by Physician Using a 6-Point Scale

Two functional goals, one active and one passive, were selected by the participant and family in consultation with the physician investigator and/or treating physical therapist relative to the lower limb impairment due to spasticity. The physician assessed the achievement of the goals using a 6-point scale: where -3=worse than start to +2=much more than expected: improvements clearly exceed the defined therapeutic goal. An ANCOVA model was used for analysis.

Participants from the mITT population, all randomized participants with a valid MAS-B baseline score and at least one post-baseline measurement at weeks 2, 4, or 6 for the MAS-B of the principal muscle group and the CGI by physician, with data available for analysis at the given time-point.

Posted

Least Squares Mean

Standard Error

score on a scale

Week 8 and 12

ID	Title	Description
OG000	BOTOX® 6 U/kg	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 6 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT).
OG001	BOTOX® 3 U/kg	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 3 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly OT.
OG002

Secondary

Change From Baseline in Severity of Spasticity of the Principal Muscle Group (R2-R1) Calculated Using the Modified Tardieu Scale (MTS)

The MTS measured the difference between slow and fast range of motion (R2-R1) and respective change from baseline to each posttreatment office visit. The MTS of the ankle was used to determine the passive range of movement at different movement velocities, V1 (as slow as possible) and V3 (as fast as possible) with the relative difference between a slow and a fast velocity passive stretch determining the dynamic component of the muscle contracture for the joint. At each visit, the investigator measured 2 joint angles by goniometer: the R1 angle which is the angle of catch after a fast velocity (V3) stretch and the R2 angle defined as the passive joint range of movement following a slow velocity (V1) stretch. The R2 - R1 value indicated the level of the dynamic component of spasticity in the joint. The difference between slow (R2) and fast (R1) range of motion and respective change from baseline to each posttreatment office visit on the MTS was derived.

Participants from the mITT population, all randomized participants with a valid MAS-B baseline score and at least one post-baseline measurement at weeks 2, 4, or 6 for the MAS-B of the principal muscle group and the CGI by physician, with data available for analysis at the given time-point.

Posted

Least Squares Mean

Standard Error

degrees

Baseline (Day 1) to Week 6

ID	Title	Description
OG000	BOTOX® 6 U/kg	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 6 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT).

Group IDs	Group Description	Statistical Method	P-Value	P-Value Comment	Parameter Type	Parameter Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	Non-Inferiority Type
OG000 OG002	Change from Baseline to Week 2, Elbow	ANCOVA	0.117	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	12.10	2-Sided	95	-3.089	27.293	Superiority
OG001 OG002	Change from Baseline to Week 2, Elbow	ANCOVA	0.273	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	8.41	2-Sided	95	-6.717	23.527	Superiority
OG000 OG002	Change from Baseline to Week 4, Elbow	ANCOVA	0.015	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	14.71	2-Sided	95	2.958	26.458	Superiority
OG001 OG002	Change from Baseline to Week 4, Elbow	ANCOVA	0.046	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	11.85	2-Sided	95	0.203	23.504	Superiority
OG000 OG002	Change from Baseline to Week 6, Elbow	ANCOVA	<0.001	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	20.97	2-Sided	95	8.801	33.137	Superiority
OG001 OG002	Change from Baseline to Week 6, Elbow	ANCOVA	0.064	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	11.35	2-Sided	95	-0.662	23.362	Superiority
OG000 OG002	Change from Baseline to Week 8, Elbow	ANCOVA	0.013	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	15.25	2-Sided	95	3.317	27.178	Superiority
OG001 OG002	Change from Baseline to Week 8, Elbow	ANCOVA	0.225	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	7.22	2-Sided	95	-4.488	18.934	Superiority
OG000 OG002	Change from Baseline to Week 12, Elbow	ANCOVA	0.409	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	4.50	2-Sided	95	-6.239	15.236	Superiority
OG001 OG002	Change from Baseline to Week 12, Elbow	ANCOVA	0.470	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	3.86	2-Sided	95	-6.690	14.419	Superiority
OG000 OG002	Change from Baseline to Week 2, Wrist	ANCOVA	0.263	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	-6.13	2-Sided	95	-16.962	4.706	Superiority
OG001 OG002	Change from Baseline to Week 2, Wrist	ANCOVA	0.012	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	-14.60	2-Sided	95	-25.846	-3.360	Superiority
OG000 OG002	Change from Baseline to Week 4, Wrist	ANCOVA	0.098	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	-10.64	2-Sided	95	-23.277	1.996	Superiority
OG001 OG002	Change from Baseline to Week 4, Wrist	ANCOVA	0.051	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	-13.10	2-Sided	95	-26.260	0.068	Superiority
OG000 OG002	Change from Baseline to Week 6, Wrist	ANCOVA	0.010	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	-17.11	2-Sided	95	-30.031	-4.189	Superiority
OG001 OG002	Change from Baseline to Week 6, Wrist	ANCOVA	0.098	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	-11.25	2-Sided	95	-24.622	2.131	Superiority
OG000 OG002	Change from Baseline to Week 8, Wrist	ANCOVA	0.005	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	-17.71	2-Sided	95	-29.888	-5.537	Superiority
OG001 OG002	Change from Baseline to Week 8, Wrist	ANCOVA	0.015	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	-15.74	2-Sided	95	-28.293	-3.194	Superiority
OG000 OG002	Change from Baseline to Week 12, Wrist	ANCOVA	0.020	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	-15.25	2-Sided	95	-28.010	-2.492	Superiority
OG001 OG002	Change from Baseline to Week 12, Wrist	ANCOVA	0.046	ANCOVA model including baseline MTS as a covariate and factors of age group, treatment group, study center and botulinum toxin exposure where age group is represented by stratification categories.	LS Mean Difference	-13.52	2-Sided	95	-26.797	-0.243	Superiority

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Stomatitis	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected77 at risk EG0010 affected78 at risk EG0020 affected79 at risk
Vomiting	Gastrointestinal disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected77 at risk EG0010 affected78 at risk EG0020 affected79 at risk
Pyrexia	General disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected77 at risk EG0010 affected78 at risk EG0020 affected79 at risk
Infectious mononucleosis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0001 affected77 at risk EG0010 affected78 at risk EG0020 affected79 at risk
Meningitis	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0000 affected77 at risk EG0011 affected78 at risk EG0020 affected79 at risk
Osteochondrosis	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0000 affected77 at risk EG0010 affected78 at risk EG0021 affected79 at risk
Seizure	Nervous system disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected77 at risk EG0010 affected78 at risk EG0020 affected79 at risk

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Upper respiratory tract infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0007 affected77 at risk EG0014 affected78 at risk EG0022 affected79 at risk
Viral upper respiratory tract infection	Infections and infestations	MedDRA 20.0	Systematic Assessment	EG0006 affected77 at risk EG0014 affected78 at risk EG0025 affected79 at risk
Pyrexia	General disorders	MedDRA 20.0	Systematic Assessment	EG0002 affected77 at risk EG0013 affected78 at risk EG0025 affected79 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA 20.0	Systematic Assessment	EG0002 affected77 at risk EG0011 affected78 at risk EG0024 affected79 at risk
Headache	Nervous system disorders	MedDRA 20.0	Systematic Assessment	EG0001 affected77 at risk EG0012 affected78 at risk EG0024 affected79 at risk

ID	Term
D009128	Muscle Spasticity
D002547	Cerebral Palsy
D020521	Stroke

ID	Term
D009135	Muscular Diseases
D009140	Musculoskeletal Diseases
D009122	Muscle Hypertonia
D020879	Neuromuscular Manifestations
D009461	Neurologic Manifestations
D009422	Nervous System Diseases
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms
D001925	Brain Damage, Chronic
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D002561	Cerebrovascular Disorders
D014652	Vascular Diseases
D002318	Cardiovascular Diseases

ID	Term
D019274	Botulinum Toxins, Type A
D000077330	Saline Solution

ID	Title	Description
BG000	BOTOX® 6 U/kg	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 6 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT).
BG001	BOTOX® 3 U/kg	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 3 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly OT.
BG002	Placebo	Participants received intramuscular injections of normal saline (placebo) into specified muscles of the upper limb on Day 1. Participants received weekly OT.
BG003	Total	Total of all reporting groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	BOTOX® 6 U/kg	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 6 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly occupational therapy (OT).	77	3	77	15	77
EG001	BOTOX® 3 U/kg	Participants received intramuscular injections of BOTOX® (botulinum toxin Type A) 3 U/kg into specified muscles of the upper limb on Day 1. Participants received weekly OT.	78	1	78	12	78
EG002	Placebo	Participants received intramuscular injections of normal saline (placebo) into specified muscles of the upper limb on Day 1. Participants received weekly OT.	79	1	79	17	79

ID	Term
D001905	Botulinum Toxins
D008666	Metalloendopeptidases
D010450	Endopeptidases
D010447	Peptide Hydrolases
D006867	Hydrolases
D004798	Enzymes
D045762	Enzymes and Coenzymes
D045726	Metalloproteases
D001426	Bacterial Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D001427	Bacterial Toxins
D014118	Toxins, Biological
D001685	Biological Factors
D000077324	Crystalloid Solutions
D007552	Isotonic Solutions
D012996	Solutions
D004364	Pharmaceutical Preparations