Clinical trial NCT01905683: Long-term Open-label Study of Botulinumtoxin Type A to Treat Spasticity of Leg(s) or Leg(s) and Arm in Cerebral Palsy
Official title: Open-label, Non-controlled, Multicenter Long-term Study to Investigate the Safety and Efficacy of Xeomin® (Incobotulinumtoxin A, 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lower Limb and Combined Lower Limb and Upper Limb Spasticity Due to Cerebral Palsy
Lead sponsor: Merz Pharmaceuticals GmbH
Sponsor class: INDUSTRY
First posted: 2013-07-23
Enrollment: 370
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

Main clinical inclusion criteria for completers of study MRZ60201_3070_1:

* Subject with lower limb \[LL\] spasticity who completed lead-in study MRZ60201_3070_1 in any of the three dose groups with duration of both injection cycles between 12 and 16 weeks.
* Ashworth scale \[AS\] score ≥2 in plantar flexors (at least unilaterally). For subjects with an AS score of 1, the investigator has to decide on the clinical need for reinjection.
* Clinical need for spasticity treatment with NT 201 according to the clinical judgment of the investigator for:

Unilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) into pes equinus and need for additional 8 U/kg BW NT 201 (maximum of 200 U) for treatment of clinical pattern flexed knee or adducted thigh (ipsilateral) or bilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) into pes equinus on each side.

No treatment of other clinical patterns is allowed.

Main clinical inclusion criteria for subjects who did not participate in MRZ60201_3070_1:

* Female or male subject of 2 to 17 years age (inclusive).
* Uni- or bilateral CP with clinical need for BoNT injection to treat limb spasticity.
* AS score ≥ 2 in plantar flexors (at least unilaterally).
* Clinical need according to the clinical judgment of the investigator in one out of four treatment combinations:

  1. For LL(s) treatment only (Gross Motor Function Classification System \[GMFCS\] levels IV): Unilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) into pes equinus, and 8 U/kg BW NT 201 (maximum of 200 U) into flexed knee or adducted thigh or bilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) into each pes equinus (AS score ≥ 2 on both sides).
  2. For combined unilateral UL and unilateral LL, (GMFCS levels I-III): Unilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) into pes equinus, and 8 U/kg BW NT 201 (maximum of 200 U) into flexed knee or adducted thigh plus Unilateral treatment of UL spasticity with 4 U/kg BW NT 201 (maximum of 100 U) into flexed elbow, flexed wrist, clenched fist, thumb in palm and/or pronated forearm.
  3. For combined unilateral UL and unilateral LL (GMFCS level IV-V): Unilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum 200 U) into pes equinus, and 4 U/kg BW NT201 (maximum 100 U) into flexed knee or adducted thigh plus unilateral treatment of UL spasticity with 4 U/kg BW NT 201 (maximum of 100 U) into flexed elbow, flexed wrist, clenched fist, thumb in palm and/or pronated forearm.
  4. For combined unilateral UL and bilateral LL (GMFCS levels I-III): Bilateral treatment of LL spasticity with 8 U/kg BW NT 201 (maximum of 200 U) into each pes equinus (AS score ≥ 2 on both sides) plus unilateral treatment of UL spasticity with 4 U/kg BW NT 201 (maximum of 100 U) into flexed elbow, flexed wrist, clenched fist, thumb in palm and/or pronated forearm.

Exclusion Criteria:

Exclusion Criteria for subjects who completed MRZ60201_3070_1:

* Infection and/or inflammation in the area of the planned injection points.
* Pregnancy for female with history of menarche.
* Clinically relevant pathological findings indicating active disease of vital organs.

Exclusion Criteria for subjects who did not participate in MRZ60201_3070_1:

* Fixed contracture defined as severe restriction of the range of joint movement on passive stretch in the target clinical pattern(s) or predominant forms of muscle hypertonia other than spasticity (e.g., dystonia) in the target limb(s).
* Surgery in the pes equinus on side(s) intended to treat with BoNT injections within 12 months prior to Screening Visit (V1), within the screening period or planned for the time of participation in this study.
* Hip flexion requiring BoNT injection.
* Limitation of hip abduction to less than 40° or pre-diagnosed migrational percentage greater than 30.
* Vaccination within 2 weeks prior to Screening Visit (V1) and/or within the screening period.
* Non-resolved fractures of the treated limb.
* Ventilator dependency.
* Severe neurological diagnosis and comorbidity outside the spectrum of cerebral palsy.
* Pure dyskinetic CP or mixed CP with predominantly dyskinetic movements.
* Treatment with BoNT (other than study drug in this study) for any body region within 14 weeks prior to Screening Visit (V1), within the screening period and/or intended to be administered during the study period.
* Treatment with phenol or alcohol of any muscle within 6 months prior to Screening Visit (V1), within the screening period, and/or intended to be administered during the study period.
* Treatment with

  * drugs acting as peripheral muscle relaxants
  * intrathecal baclofen, or
  * oral anticoagulants administered within 2 weeks prior to Screening Visit (V1), within the screening period, and/or intended to be administered during the study period.

Primary outcomes:
measure: Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and Per Injection Cycle
timeFrame: From the timepoint of first injection up to end of study visit (Week 50-66)
measure: Occurrence of Treatment Emergent Adverse Events of Special Interest (TEAESI) Overall and Per Injection Cycle
timeFrame: From the timepoint of first injection until end of study visit (Week 50-66)
measure: Occurrence of Treatment-emergent Serious Adverse Events (TESAEs) Overall and Per Injection Cycle
timeFrame: From the timepoint of first injection until end of study visit (Week 50-66)
Secondary outcomes:
measure: Investigator's Global Assessment of Tolerability at Day 99 (Week 14) of Each Injection Cycle
timeFrame: Day 99 (Week 14) of 1st, 2nd, 3rd and 4th injection cycle
measure: Changes in 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 Injection Cycle Only) and Day 99 (Week 14) of the Respective Injection Cycle
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 Injection Cycle to Day 29 (Week 4), Day 57 (Week 8, 1st Injection Cycle only) and Day 99 (Week 14) of the respective Injection Cycle
measure: 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
timeFrame: Day 29 (Week 4) of 1st, 2nd, 3rd and 4th injection cycle
measure: Investigator's Global Impression of Change of Plantar Flexor Spasticity Scale (GICS-PF) of Left and Right PF at Day 29 (Week 4) of Each Injection Cycle
timeFrame: Day 29 (Week 4) of 1st, 2nd, 3rd and 4th injection cycle
measure: Changes in Modified Tardieu Scale (MTS) of Left and Right PF From Baseline to All Other Visits, From Day 1 of Each Injection Cycle (IC) to Day 29 (Week 4), Day 57 (Week 8, 1st IC Only) and Day 99 (Week 14) of the Respective Injection Cycle
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
measure: Change in Scores of Pain Intensity (From Participants) and Frequency (From Parent/Caregiver) From Baseline to All Visits, 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 Respective Injection
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
measure: Changes in Gross Motor Function Measure (GMFM)-66 Score From Baseline to All Injection Visits and End of Study
timeFrame: Baseline to Day 1 of 2nd (V5), 3rd (V7), 4th (V9) IC and End of study (Week 44-68) (V11)
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Merz Investigational Site #043036
city: Brno
country: Czechia
facility: Merz Investigational Site #420029
city: Olomouc
country: Czechia
facility: Merz Investigational Site #420028
city: Tallinn
country: Estonia
facility: Merz Investigational Site #372001
city: Tartu
country: Estonia
facility: Merz Investigational Site #372002
city: Bochum
country: Germany
facility: Merz Investigational Site #049328
city: Muenster
country: Germany
facility: Merz Investigational Site #049329
city: Munich
country: Germany
facility: Merz Investigational Site #049327
city: Vogtareuth
country: Germany
facility: Merz Investigational Site #049326
city: Jerusalem
country: Israel
facility: Merz Investigational Site #972003
city: Tel Aviv
country: Israel
facility: Merz Investigational Site #972001
city: Tel Aviv
country: Israel
facility: Merz Investigational Site #972002
city: Goyang
country: Korea, Republic of
facility: Merz Investigational Site #082019
city: Incheon
country: Korea, Republic of
facility: Merz Investigational Site #082021
city: Seongnam-si
country: Korea, Republic of
facility: Merz Investigational Site #082018
city: Seoul
country: Korea, Republic of
facility: Merz Investigational Site #082020
city: Bialystok
country: Poland
facility: Merz Investigational Site #048089
city: Gdansk
country: Poland
facility: Merz Investigational Site #048063
city: Kraków
country: Poland
facility: Merz Investigational Site #048059
city: Lublin
country: Poland
facility: Merz Investigational Site #048084
city: Lubon
country: Poland
facility: Merz Investigational Site #048072
city: Sandomierz
country: Poland
facility: Merz Investigational Site #048075
city: Warsaw
country: Poland
facility: Merz Investigational Site #048061
city: Bucharest
country: Romania
facility: Merz Investigational Site #040003
city: Bucharest
country: Romania
facility: Merz Investigational Site #040001
city: Iasi
country: Romania
facility: Merz Investigational Site #040002
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 #007017
city: Smolensk
country: Russian Federation
facility: Merz Investigational Site #007013
city: Stavropol
country: Russian Federation
facility: Merz Investigational Site #007019
city: Banska Bystrica
country: Slovakia
facility: Merz Investigational Site #421003
city: Bratislava
country: Slovakia
facility: Merz Investigational Site #421008
city: Krompachy
country: Slovakia
facility: Merz Investigational Site #421006
city: Levoca
country: Slovakia
facility: Merz Investigational Site #421004
city: Elazig
country: Turkey
facility: Merz Investigational Site #090005
city: Izmir
country: Turkey
facility: Merz Investigational Site #090003
city: Izmit
country: Turkey
facility: Merz Investigational Site #090002
city: Dnipropetrovsk
country: Ukraine
facility: Merz Investigational Site #380001
city: Kharkiv
country: Ukraine
facility: Merz Investigational Site #380005
city: Kiev
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: 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.