Dose-response Study of Efficacy and Safety of Botulinum Toxin Type A to Treat Spasticity of the Arm(s) or of Arm(s) and Leg(s) in Cerebral Palsy

Cerebral Palsy Clinical Trial

— XARA  

Official title:

Prospective, Multicenter, Randomized, Double-blind, Parallel-group, Dose-response Study of Three Doses Xeomin® (incobotulinumtoxinA, NT 201) for the Treatment of Upper Limb Spasticity Alone or Combined Upper and Lower Limb Spasticity in Children and Adolescents (Age 2 - 17 Years) With Cerebral Palsy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02002884
• Other study ID #: MRZ60201_3072_1
• Secondary ID: 2012-005496-14
• Status: Completed
• Phase: Phase 3
• Start date: March 28, 2014
• Est. completion date: August 28, 2018

Study information

• Verified date: July 2020
• Source: Merz Pharmaceuticals GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine whether injections of Botulinum toxin type A into muscles of one or both arms alone or in combination with injections into one or both legs are effective and safe in treating children/adolescents (age 2-17 years) with increased muscle tension/uncontrollable muscle stiffness (spasticity) due to cerebral palsy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 351
• Est. completion date: August 28, 2018
• Est. primary completion date: July 4, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 17 Years

Eligibility

Inclusion Criteria:

• Female or male subject of 2 to 17 years of age (inclusive).

• Uni- or bilateral Cerebral Palsy (CP) with clinical need for injections with NT 201 for the treatment of upper limb (UL) spasticity at least unilaterally.

• Ashworth Scale (AS) score in the main clinical target patterns in this study:

1. Flexed elbow: AS=2 in elbow flexors (at least unilaterally). and/or

2. Flexed Wrist: AS=2 in wrist flexors (at least unilaterally).

• Clinical need according to the judgment of the investigator in one out of five treatment combinations (A-E, as shown below). AS score must be =2 for each target pattern chosen for injection at the Baseline Injection Visit V2.

A. UL(s) treatment only (GMFCS I-V):

A1) Unilateral treatment of UL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) for:

1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW).

and

2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW (maximum of 200 U) for treatment of a single UL is reached.

or

A2) Bilateral treatment of UL spasticity with equal doses of 8 U/kg BW NT 201 (maximum of 200 U) to each UL. Dose per UL must be distributed between:

1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW).

and

2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW (maximum of 200 U) for treatment of a single UL is reached.

B. Unilateral UL and unilateral lower limb (LL) treatment (GMFCS I-V):

B1) Unilateral treatment of UL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) for:

1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW).

and

2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW (maximum of 200 U) for treatment of a single UL is reached.

plus

B2) Ipsilateral unilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U). Dose to LL must be distributed to at least one of clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great toe as clinically needed.

C. Unilateral UL and bilateral LL treatment (GMFCS I-III)

C1) Unilateral treatment of UL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) for:

1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW).

and

2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW (maximum of 200 U) for treatment of a single UL is reached.

plus

C2) Bilateral treatment of LL spasticity with 12 U/kg BW (maximum of 300 U). Dose must be distributed into at least one of clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great toe, on each side. Dose distribution may vary between sides as clinically needed.

D. Unilateral UL and bilateral LL treatment (GMFCS IV and V)

D1) Unilateral treatment of UL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) for:

1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW).

and

2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW (maximum of 200 U) for treatment of a single UL is reached.

plus

D2) Bilateral treatment of LL spasticity with 8 U/kg BW (maximum of 200 U). Dose must be distributed into at least one of clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great toe, on each side. Dose distribution may vary between sides as clinically needed.

E. Bilateral UL treatment and bilateral LL treatment (GMFCS I-III)

E1) Bilateral treatment of UL spasticity with equal doses of 8 U/kg BW NT 201 (maximum of 200 U) to each UL. Dose per UL must be distributed between

1. At least one of the main clinical target patterns flexed elbow (4 U/kg BW) and/or flexed wrist (2 U/kg BW) and

2. Additional clinical patterns in the same limb (i.e., clenched fist, thumb in palm, and/or pronated forearm) with the remaining units until maximum dose of 8 U/kg BW (maximum of 200 U) for treatment of a single UL is reached.

plus

E2) Bilateral treatment of LL spasticity with 4 U/kg BW (maximum of 100 U). Dose must be distributed into at least one of clinical target patterns pes equinus, flexed knee, adducted thigh, and extended great toe, on each side. Dose distribution may vary between sides as clinically needed.

Exclusion Criteria:

Pre-treated (non-naïve) subjects must not have received BoNT treatment within the last 14 weeks prior to Screening Visit (V1) in any indication.

Related Conditions & MeSH terms

• Cerebral Palsy
• Muscle Spasticity
• Spasticity

Intervention

Drug:
• IncobotulinumtoxinA (8 Units per kg body weight)
Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Mode of administration: intramuscular injection into spastic muscles.
• IncobotulinumtoxinA (6 Units per kg body weight)
Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Mode of administration: intramuscular injection into spastic muscles.
• IncobotulinumtoxinA (2 Units per kg body weight)
Active ingredient: Clostridium Botulinum neurotoxin Type A free from complexing proteins. Solution for injection prepared by reconstitution of powder with 0.9% Sodium Chloride (NaCl); Mode of administration: intramuscular injection into spastic muscles.

Locations

Country	Name	City	State
Argentina	Merz Investigational Site #054005	Caba
Argentina	Merz Investigational Site #054010	Godoy Cruz	Provincia De Mendoza
Mexico	Merz Investigational Site #052023	Aguascalientes
Mexico	Merz Investigational Site #052003	Guadalajara
Mexico	Merz Investigational Site #052022	Mexico City
Mexico	Merz Investigational Site #052024	Mexico City
Mexico	Merz Investigational Site #052027	Monterrey
Mexico	Merz Investigational Site #052028	Monterrey
Mexico	Merz Investigational Site #052026	Zapopan
Poland	Merz Investigational Site #048089	Bialystok
Poland	Merz Investigational Site #048063	Gdansk
Poland	Merz Investigational Site #048059	Krakow
Poland	Merz Investigational Site #048084	Lublin
Poland	Merz Investigational Site #048094	Poznan
Poland	Merz Investigational Site #048075	Sandomierz
Poland	Merz Investigational Site #048060	Wiazowna
Russian Federation	Merz Investigational Site #007014	Kazan
Russian Federation	Merz Investigational Site #007015	Khabarovsk
Russian Federation	Merz Investigational Site #007018	Novosibirsk
Russian Federation	Merz Investigational Site #007298	Saint Petersburg
Russian Federation	Merz Investigational Site #007013	Smolensk
Russian Federation	Merz Investigational Site #007019	Stavropol
Ukraine	Merz Investigational Site #380001	Dnipropetrovsk
Ukraine	Merz Investigational Site #380005	Kharkiv
Ukraine	Merz Investigational Site #380002	Kyiv
Ukraine	Merz Investigational Site #380003	Odessa
United States	Merz Investigational Site #001186	Chicago	Illinois
United States	Merz Investigational Site #001283	Columbia	Missouri
United States	Merz Investigational Site #001286	Gulf Breeze	Florida
United States	Merz Investigational Site #001284	Loxahatchee Groves	Florida
United States	Merz Investigational Site No. #001302	Royal Oak	Michigan
United States	Merz Investigational Site #001285	Savannah	Georgia

Sponsors (1)

Lead Sponsor	Collaborator
Merz Pharmaceuticals GmbH

Countries where clinical trial is conducted

United States,  Argentina,  Mexico,  Poland,  Russian Federation,  Ukraine, 

References & Publications (1)

Dabrowski E, Chambers HG, Gaebler-Spira D, Banach M, Kanovský P, Dersch H, Althaus M, Geister TL, Heinen F. IncobotulinumtoxinA Efficacy/Safety in Upper-Limb Spasticity in Pediatric Cerebral Palsy: Randomized Controlled Trial. Pediatr Neurol. 2021 May 21; — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4	The AS categorizes severity of spasticity by judging resistance to passive movement. Spasticity was assessed by using the 5-point AS with:0 (no increase in tone); 1 (slight increase in tone giving a "catch" when the limb was moved in flexion or extension); 2 (more marked increase in tone, but limb easily flexed); 3 (considerable increase in tone -passive movements difficult); 4 (limb rigid in flexion or extension). Values represent least square (LS) mean differences between baseline and Week 4 resulting from Mixed Model Repeated Measurement (MMRM) models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison.	Baseline and Week 4
Primary	Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4	The GICS was used to measure independently the investigator's impression of change due to treatment. The response option was a common 7-point Likert scale, that ranges from +3 (very much improved); +2 (much improved); +1 (minimally improved); 0 (no change); -1 (minimally worse); -2 (much worse); -3 (very much worse). Values represent LS mean differences between baseline and Week 4 resulting from ANCOVA models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison.	Week 4
Secondary	MP: Change From Baseline in AS Score of the Other Treated UL Main Clinical Target Pattern at Week 4	The AS categorizes the severity of spasticity by judging resistance to passive movement. Spasticity was assessed by 5-point scale at visits, where: 0 (no increase in tone); 1(slight increase in tone giving a "catch" when the limb was moved in flexion or extension); 2(more marked increase in tone, but limb easily flexed); 3(considerable increase in tone - passive movements difficult); 4(limb rigid in flexion or extension). Values represent LS mean differences between baseline and Week 4 resulting from MMRM models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison.	Baseline and Week 4
Secondary	MP: Change From Baseline in AS Score in UL Treated Clenched Fist With Flexed Wrist at Week 4	The AS categorizes the severity of spasticity by judging resistance to passive movement. Spasticity was assessed by 5-point scale at visits, where: 0 (no increase in tone); 1(slight increase in tone giving a "catch" when the limb was moved in flexion or extension); 2(more marked increase in tone, but limb easily flexed); 3(considerable increase in tone - passive movements difficult); 4(limb rigid in flexion or extension). Values represent LS mean differences between baseline and Week 4 resulting from MMRM models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison.	Baseline and Week 4
Secondary	MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4	The AS categorizes the severity of spasticity by judging resistance to passive movement. Spasticity was assessed by 5-point scale at visits, where: 0 (no increase in tone); 1(slight increase in tone giving a "catch" when the limb was moved in flexion or extension); 2(more marked increase in tone, but limb easily flexed); 3(considerable increase in tone - passive movements difficult); 4(limb rigid in flexion or extension). Values represent LS mean differences between baseline and Week 4 resulting from MMRM models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison.	Baseline up to Week 4
Secondary	MP: Change From Baseline in Scores of Pain Intensity (From Participants) and Pain Frequency (From Parent/Caregiver) Assessed With 'Questionnaire on Pain Caused by Spasticity (QPS)'	Pain intensity (from participants) and pain frequency (from parent/caregiver) to be assessed with 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). Values represent LS mean differences between baseline and Week 4 resulting from MMRM models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison. P/C = Parent/Caregiver.	Baseline, Weeks 4, 8, and 14
Secondary	MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4	The GICS was used to measure independently the child's/adolescent's, and parent's or caregiver's impression of change due to treatment. The response option was a common 7-point Likert scale, that ranges from: +3(very much improved); +2(much improved); +1(minimally improved); 0(no change); -1(minimally worse); -2(much worse); -3(very much worse). Values represent LS mean differences between baseline and Week 4 resulting from ANCOVA models comparing high versus low and in a second step mid versus low dose groups, respectively. Values for the low group may differ slightly depending on the comparison and are therefore provided separately for each comparison.	Week 4
Secondary	Number of Participants With Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and Per Treatment Cycle		Baseline up to Week 66
Secondary	Number of Participants With Occurrence of TEAEs of Special Interest (TEAESIs) Overall and Per Treatment Cycle		Baseline up to Week 66
Secondary	Number of Participants With Occurrence of Serious TEAEs (TESAEs) Overall and Per Treatment Cycle		Baseline up to Week 66
Secondary	Number of Participants With Occurrence of TEAEs Related to Treatment Overall and Per Treatment Cycle		Baseline up to Week 66
Secondary	Number of Participants With Occurrence of TEAEs by Worst Intensity Overall and Per Treatment Cycle		Baseline up to Week 66
Secondary	Number of Participants With Occurrence of TEAEs by Worst Causal Relationship Overall and Per Treatment Cycle		Baseline up to Week 66
Secondary	Number of Participants With Occurrence of TEAEs by Final Outcome Overall and Per Treatment Cycle		Baseline up to Week 66
Secondary	Number of Participants With Occurrence of TEAEs Leading to Discontinuation Overall and Per Treatment Cycle		Baseline up to Week 66