Long-term Open-label Study of Botulinumtoxin Type A to Treat Spasticity of Leg(s) or Leg(s) and Arm in Cerebral Palsy

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

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.

Study Overview

• Status: Completed
• Conditions: Lower Limb and Combined Lower Limb and Upper Limb Spasticity Due to Cerebral Palsy
• Intervention / Treatment: Drug: IncobotulinumtoxinA (16-20 Units per kg body weight)

• Study Type: Interventional
• Enrollment (Actual): 370
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1100
    • Merz Investigational Site #043036
• Czechia
  • Brno, Czechia, 65691
    • Merz Investigational Site #420029
  • Olomouc, Czechia, 77520
    • Merz Investigational Site #420028
• Estonia
  • Tallinn, Estonia, 13419
    • Merz Investigational Site #372001
  • Tartu, Estonia, 51014
    • Merz Investigational Site #372002
• Germany
  • Bochum, Germany, 44791
    • Merz Investigational Site #049328
  • Muenster, Germany, 48149
    • Merz Investigational Site #049329
  • Munich, Germany, 80337
    • Merz Investigational Site #049327
  • Vogtareuth, Germany, 83569
    • Merz Investigational Site #049326
• Israel
  • Jerusalem, Israel, 91240
    • Merz Investigational Site #972003
  • Tel Aviv, Israel, 6423906
    • Merz Investigational Site #972001
  • Tel Aviv, Israel, 6423906
    • Merz Investigational Site #972002
• Korea, Republic of
  • Goyang, Korea, Republic of, 410-773
    • Merz Investigational Site #082019
  • Incheon, Korea, Republic of, 400-711
    • Merz Investigational Site #082021
  • Seongnam-si, Korea, Republic of, 463-712
    • Merz Investigational Site #082018
  • Seoul, Korea, Republic of, 135-710
    • Merz Investigational Site #082020
• Poland
  • Bialystok, Poland, 15-274
    • Merz Investigational Site #048089
  • Gdansk, Poland, 80-389
    • Merz Investigational Site #048063
  • Kraków, Poland, 30-539
    • Merz Investigational Site #048059
  • Lublin, Poland, 20-828
    • Merz Investigational Site #048084
  • Lubon, Poland, 62-030
    • Merz Investigational Site #048072
  • Sandomierz, Poland, 27-600
    • Merz Investigational Site #048075
  • Warsaw, Poland, 02-315
    • Merz Investigational Site #048061
• Romania
  • Bucharest, Romania, 041408
    • Merz Investigational Site #040003
  • Bucharest, Romania, 041914
    • Merz Investigational Site #040001
  • Iasi, Romania, 700309
    • Merz Investigational Site #040002
• Russian Federation
  • Kazan, Russian Federation, 420097
    • Merz Investigational Site #007014
  • Khabarovsk, Russian Federation, 680038
    • Merz Investigational Site #007015
  • Novosibirsk, Russian Federation, 630091
    • Merz Investigational Site #007018
  • Saint-Petersburg, Russian Federation, 194100
    • Merz Investigational Site #007017
  • Smolensk, Russian Federation, 214029
    • Merz Investigational Site #007013
  • Stavropol, Russian Federation, 355029
    • Merz Investigational Site #007019
• Slovakia
  • Banska Bystrica, Slovakia, 97409
    • Merz Investigational Site #421003
  • Bratislava, Slovakia, 82108
    • Merz Investigational Site #421008
  • Krompachy, Slovakia, 05342
    • Merz Investigational Site #421006
  • Levoca, Slovakia, 05401
    • Merz Investigational Site #421004
• Turkey
  • Elazig, Turkey, 23119
    • Merz Investigational Site #090005
  • Izmir, Turkey, 35100
    • Merz Investigational Site #090003
  • Izmit, Turkey, 41380
    • Merz Investigational Site #090002
• Ukraine
  • Dnipropetrovsk, Ukraine, 49027
    • Merz Investigational Site #380001
  • Kharkiv, Ukraine, 61068
    • Merz Investigational Site #380005
  • Kiev, Ukraine, 04209
    • Merz Investigational Site #380002
  • Odessa, Ukraine, 65012
    • Merz Investigational Site #380003

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 16-20 Units per kg body weight incobotulinumtoxinA

Drug: IncobotulinumtoxinA (16-20 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); Total dose per injection cycle: up to 500 units; Mode of administration: intramuscular injection into spastic muscles.; Other Names: Xeomin; NT 201; Botulinum toxin type A (150 kiloDalton), free from complexing proteins

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of Treatment Emergent Adverse Events (TEAEs) Overall and Per Injection Cycle	TEAEs are events observed from the time point of first injection until end of study visit (Week 50-66). Values reported here refer to the number of participants affected.	From the timepoint of first injection up to end of study visit (Week 50-66)
Occurrence of Treatment Emergent Adverse Events of Special Interest (TEAESI) Overall and Per Injection Cycle	TEAEs occurring after treatment that were thought to possibly indicate toxin spread throughout the trial conduct are defined as TEAESI. Values reported here refer to the number of participants affected.	From the timepoint of first injection until end of study visit (Week 50-66)
Occurrence of Treatment-emergent Serious Adverse Events (TESAEs) Overall and Per Injection Cycle	TESAEs are events observed from the time point of first injection until end of study visit (Week 50-66). Values reported here refer to the number of participants affected.	From the timepoint of first injection until end of study visit (Week 50-66)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Investigator's Global Assessment of Tolerability at Day 99 (Week 14) of Each Injection Cycle	The investigator's global assessment of tolerability was assessed on a 4-point ordinal scale where 1 = very good, 2 = good, 3 = moderate, and 4 = poor. Results for Day 99 (Week 14) of 4th injection cycles were collected at the end of study visit.	Day 99 (Week 14) of 1st, 2nd, 3rd and 4th injection cycle
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	The Ashworth Scale (AS) 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 5-point scale that ranges from 0 (= no increase in tone) to 4 (=limb rigid in flexion or extension). For participants with bilateral pes equinus, the body side for efficacy analysis that is, "primary body side" was decided by investigator at screening and was kept throughout the entire study. V3 = Week 4 of 1st Injection Cycle; V4 = Week 8 of 1st Injection Cycle; V5 = Day 1 of 2nd Injection Cycle; V6= Week 4 of 2nd Injection Cycle; V7 = Day 1 of 3rd Injection Cycle; V8 = Week 4 of 3rd Injection Cycle; V9 = Day 1 of 4th Injection Cycle; V10 = Week 4 of 4th Injection Cycle; V11= Week 14th of 4th Injection Cycle = end of study visit.	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
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	The GICS are global outcomes to assess the impression of change due to treatment. GICS were assessed by the investigator, by the participant (if feasible) and by parents'/caregiver (if applicable). GICS is 7-Point Likert Scale ranging from +3 (very much improved function) to -3 (very much worse function).	Day 29 (Week 4) of 1st, 2nd, 3rd and 4th injection cycle
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	The GICS are global outcomes to assess the impression of change due to treatment. GICS were assessed by the investigator, by the participant (if feasible) and by parents'/caregiver (if applicable). GICS is a 7-Point Likert Scale ranging from +3 (very much improved function) to -3 (very much worse function). For participants with bilateral pes equinus, the body side for efficacy analysis that is "primary body side" was decided by investigator at screening and was kept throughout the entire study.	Day 29 (Week 4) of 1st, 2nd, 3rd and 4th injection cycle
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	The MTS assesses spastic muscle tone by subtraction of two angles measured at different conditions of passive muscle stretch. R2 is the angle of passive range of motion with a passive movement at slow speed. R1 is the angle where a "catch-and-release" or clonus can be triggered at the fastest possible speed. Score values represent the measured (R2-R1) difference, that is, the dynamic tone component of the examined muscle(s). Decreases of (R2-R1) represent reductions in the dynamic component of spasticity, that is, improvement of dynamic muscle spasticity. V3 = Week 4 of 1st IC; V4 = Week 8 of 1st IC; V5 = Day 1 of 2nd IC; V6 = Week 4 of 2nd IC; V7 = Day 1 of 3rd IC; V8 = Week 4 of 3rd IC; V9 = Day 1 of 4th IC; V10 = Week 4 of 4th IC; V11 = Week 14 of 4th IC = end of study visit.	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
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	The questionnaire on pain caused by Spasticity (QPS) is a participant-reported outcome for children and adolescents (2-17 years) with cerebral palsy on spasticity-related pain. 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). V3 = Week 4 of 1st IC; V4 = Week 8 of 1st IC; V5= Day 1 of 2nd IC; V6 = Week 4 of 2nd IC; V7 = Day 1 of 3rd IC; V8 = Week 4 of 3rd IC; V9 = Day 1 of 4th IC; V10 = Week 4 of 4th IC; V11 = Week 14 of 4th IC = end of study visit.	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
Changes in Gross Motor Function Measure (GMFM)-66 Score From Baseline to All Injection Visits and End of Study	The GMFM-66 is a standardized observational 66-item instrument designed and validated to measure change in gross motor function over time in participants with cerebral palsy. Score values represent the total GMFM-66 score. Total GMFM scores range from 0 (worst) to 100 (best).	Baseline to Day 1 of 2nd (V5), 3rd (V7), 4th (V9) IC and End of study (Week 44-68) (V11)

Collaborators and Investigators

• Sponsor: Merz Pharmaceuticals GmbH

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: August 1, 2013
• Primary Completion (Actual): January 1, 2017
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: July 18, 2013
• First Submitted That Met QC Criteria: July 18, 2013
• First Posted (Estimate): July 23, 2013

Study Record Updates

• Last Update Posted (Actual): October 27, 2017
• Last Update Submitted That Met QC Criteria: September 28, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Brain Damage, Chronic; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Muscle Hypertonia; Cerebral Palsy; Muscle Spasticity; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Cholinergic Agents; Membrane Transport Modulators; Acetylcholine Release Inhibitors; Neuromuscular Agents; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA; incobotulinumtoxinA
• Other Study ID Numbers: MRZ60201_3071_1; 2012-005055-17 (EudraCT Number)