Clinical trial NCT02002884: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cerebral Palsy
Spasticity
Keywords: Upper limb spasticity
lower limb spasticity
combined upper and lower limb spasticity
Lead sponsor: Merz Pharmaceuticals GmbH
Sponsor class: INDUSTRY
First posted: 2013-12-06
Enrollment: 351
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: MP: Change From Baseline in Ashworth Scale (AS) in UL Primary Clinical Target Pattern at Week 4
timeFrame: Baseline and Week 4
measure: Co-primary Variable MP: Investigator's Global Impression of Change Scale (GICS) at Week 4
timeFrame: Week 4
Secondary outcomes:
measure: MP: Change From Baseline in AS Score of the Other Treated UL Main Clinical Target Pattern at Week 4
timeFrame: Baseline and Week 4
measure: MP: Change From Baseline in AS Score in UL Treated Clenched Fist With Flexed Wrist at Week 4
timeFrame: Baseline and Week 4
measure: MP: Change From Baseline in AS Score for Each Treated Clinical Pattern of the UL at Week 4
timeFrame: Baseline up to Week 4
measure: 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)'
timeFrame: Baseline, Weeks 4, 8, and 14
measure: MP: Child's/Adolescent's, and Parent's/Caregiver's GICS in UL at Week 4
timeFrame: Week 4
measure: Number of Participants With Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and Per Treatment Cycle
timeFrame: Baseline up to Week 66
measure: Number of Participants With Occurrence of TEAEs of Special Interest (TEAESIs) Overall and Per Treatment Cycle
timeFrame: Baseline up to Week 66
measure: Number of Participants With Occurrence of Serious TEAEs (TESAEs) Overall and Per Treatment Cycle
timeFrame: Baseline up to Week 66
measure: Number of Participants With Occurrence of TEAEs Related to Treatment Overall and Per Treatment Cycle
timeFrame: Baseline up to Week 66
measure: Number of Participants With Occurrence of TEAEs by Worst Intensity Overall and Per Treatment Cycle
timeFrame: Baseline up to Week 66
measure: Number of Participants With Occurrence of TEAEs by Worst Causal Relationship Overall and Per Treatment Cycle
timeFrame: Baseline up to Week 66
measure: Number of Participants With Occurrence of TEAEs by Final Outcome Overall and Per Treatment Cycle
timeFrame: Baseline up to Week 66
measure: Number of Participants With Occurrence of TEAEs Leading to Discontinuation Overall and Per Treatment Cycle
timeFrame: Baseline up to Week 66
Other outcomes:
Locations:
city: Gulf Breeze
country: United States
facility: Merz Investigational Site #001286
state: Florida
city: Loxahatchee Groves
country: United States
facility: Merz Investigational Site #001284
state: Florida
city: Savannah
country: United States
facility: Merz Investigational Site #001285
state: Georgia
city: Chicago
country: United States
facility: Merz Investigational Site #001186
state: Illinois
city: Royal Oak
country: United States
facility: Merz Investigational Site No. #001302
state: Michigan
city: Columbia
country: United States
facility: Merz Investigational Site #001283
state: Missouri
city: Godoy Cruz
country: Argentina
facility: Merz Investigational Site #054010
state: Provincia De Mendoza
city: Caba
country: Argentina
facility: Merz Investigational Site #054005
city: Aguascalientes
country: Mexico
facility: Merz Investigational Site #052023
city: Guadalajara
country: Mexico
facility: Merz Investigational Site #052003
city: Mexico City
country: Mexico
facility: Merz Investigational Site #052024
city: Mexico City
country: Mexico
facility: Merz Investigational Site #052022
city: Monterrey
country: Mexico
facility: Merz Investigational Site #052027
city: Monterrey
country: Mexico
facility: Merz Investigational Site #052028
city: Zapopan
country: Mexico
facility: Merz Investigational Site #052026
city: Bialystok
country: Poland
facility: Merz Investigational Site #048089
city: Gdansk
country: Poland
facility: Merz Investigational Site #048063
city: Krakow
country: Poland
facility: Merz Investigational Site #048059
city: Lublin
country: Poland
facility: Merz Investigational Site #048084
city: Poznan
country: Poland
facility: Merz Investigational Site #048094
city: Sandomierz
country: Poland
facility: Merz Investigational Site #048075
city: Wiazowna
country: Poland
facility: Merz Investigational Site #048060
city: Kazan
country: Russian Federation
facility: Merz Investigational Site #007014
city: Khabarovsk
country: Russian Federation
facility: Merz Investigational Site #007015
city: Novosibirsk
country: Russian Federation
facility: Merz Investigational Site #007018
city: Saint Petersburg
country: Russian Federation
facility: Merz Investigational Site #007298
city: Smolensk
country: Russian Federation
facility: Merz Investigational Site #007013
city: Stavropol
country: Russian Federation
facility: Merz Investigational Site #007019
city: Dnipropetrovsk
country: Ukraine
facility: Merz Investigational Site #380001
city: Kharkiv
country: Ukraine
facility: Merz Investigational Site #380005
city: Kyiv
country: Ukraine
facility: Merz Investigational Site #380002
city: Odessa
country: Ukraine
facility: Merz Investigational Site #380003
Study officials:
affiliation: Merz Pharmaceuticals GmbH
name: Merz Medical Expert
role: STUDY_DIRECTOR
References:
citation: Dabrowski E, Chambers HG, Gaebler-Spira D, Banach M, Kanovsky 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 Oct;123:10-20. doi: 10.1016/j.pediatrneurol.2021.05.014. Epub 2021 May 21.
citation: Berweck S, Banach M, Gaebler-Spira D, Chambers HG, Schroeder AS, Geister TL, Althaus M, Hanschmann A, Vacchelli M, Bonfert MV, Heinen F, Dabrowski E. Safety Profile and Lack of Immunogenicity of IncobotulinumtoxinA in Pediatric Spasticity and Sialorrhea: A Pooled Analysis. Toxins (Basel). 2022 Aug 25;14(9):585. doi: 10.3390/toxins14090585.