Efficacy And Safety Of Dysport In The Treatment Of Upper Limb Spasticity In Children (PUL)

A Phase III, Multicentre, Double Blind, Prospective, Randomised, Controlled, Multiple Treatment Study Assessing Efficacy And Safety Of DYSPORT® Used In The Treatment Of Upper Limb Spasticity In Children

The purpose of this study is to assess the efficacy and safety of multiple doses of Dysport used in the treatment of upper limb spasticity (altered skeletal muscle performance) in children with cerebral palsy (CP).

Study Overview

• Status: Completed
• Conditions: Upper Limb Spasticity (Altered Skeletal Muscle Performance) in Children
• Intervention / Treatment: Biological: Botulinum toxin type A

• Study Type: Interventional
• Enrollment (Actual): 212
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
• Czechia
  • Brno, Czechia
  • Prague, Czechia
• Israel
  • Be'er Sheva, Israel
  • Jerusalem, Israel
  • Petaẖ Tiqwa, Israel
  • Tel Aviv, Israel
  • Tel Hashomer, Israel
• Mexico
  • Celaya, Mexico
  • Monterrey, Mexico
  • Baja California Sur
    • La Paz, Baja California Sur, Mexico
• Poland
  • Gdansk, Poland
  • Poznan, Poland
  • Wiazowna, Poland
• Spain
  • Barcelona, Spain
  • Terrassa, Spain
• Turkey
  • Istanbul, Turkey
  • Izmir, Turkey
  • Kocaeli, Turkey
• United States
  • Colorado
    • Aurora, Colorado, United States
  • District of Columbia
    • Washington, District of Columbia, United States
  • Louisiana
    • New Orleans, Louisiana, United States
  • Michigan
    • Royal Oak, Michigan, United States
  • Minnesota
    • Saint Paul, Minnesota, United States
  • Nebraska
    • Omaha, Nebraska, United States
  • New Mexico
    • Albuquerque, New Mexico, United States
  • New York
    • New York, New York, United States
  • Ohio
    • Columbus, Ohio, United States
  • Oregon
    • Portland, Oregon, United States
  • Texas
    • Austin, Texas, United States
    • Dallas, Texas, United States

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:

• Upper limb spasticity due to cerebral palsy
• Body weight 10 kg or over
• MAS score of 2 or more in affected elbow or wrist flexors

Exclusion Criteria:

• Fixed myocontracture
• Previous phenol or alcohol injection within 1 year
• Severe athetoid or dystonic movements
• Previous or planned surgery for spasticity in elbow or wrist flexors
• Neuromuscular disorders
• Previous Rhizotomy within 6 months
• Intrathecal baclofen within 30 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A; Group A - Treatments 1, 2, 3 and 4: Dysport 16 Units (U)/kg in one upper extremity (the study limb).	Biological: Botulinum toxin type A; Subjects randomised to receive Dysport 2 U/kg, 8 U/kg or 16 U/kg administered intramuscularly in the study limb.; Other Names: AbobotulinumtoxinA (Dysport®)
Experimental: Group B; Group B - Treatments 1, 2, 3 and 4: Dysport 8 U/kg in one upper extremity (the study limb).	Biological: Botulinum toxin type A; Subjects randomised to receive Dysport 2 U/kg, 8 U/kg or 16 U/kg administered intramuscularly in the study limb.; Other Names: AbobotulinumtoxinA (Dysport®)
Experimental: Group C; Group C - Treatment 1: Dysport 2 U/kg in one upper extremity (the study limb). Group C - Treatments 2, 3 and 4: Dysport 8 or 16 U/kg in one upper extremity (the study limb).	Biological: Botulinum toxin type A; Subjects randomised to receive Dysport 2 U/kg, 8 U/kg or 16 U/kg administered intramuscularly in the study limb.; Other Names: AbobotulinumtoxinA (Dysport®)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline to TC 1, Week 6 in MAS Score in the TC 1 PTMG	The MAS was used to assess muscle tone in the upper limb PTMG and consists of 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the ROM) when the affected part is moved in flexion or extension, 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion or extension). The original score '+1' was given a derived numeric score of '2' and the higher numeric scores were incremented by 1 so that the MAS score range was from 0 to 5 with higher scores indicating greater muscle tone. A negative change from baseline indicates a decrease in muscle tone.	Baseline (TC 1, Day 1) and TC 1, Week 6.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Physician's Global Assessment (PGA) Score at TC 1, Week 6	The PGA of treatment response was assessed by asking the investigator the following question: 'How would you rate the response to treatment in the subject's upper limb since the start of the study?'. Answers were on a 9-point rating scale (-4: markedly worse, -3: much worse, -2: worse, -1: slightly worse, 0: no change, +1: slightly improved, +2: improved, +3: much improved and +4: markedly improved). The mean scores for each treatment group at TC 1, Week 6 are presented.	TC 1, Week 6.
Mean Goal Attainment Scale (GAS) Total Score at TC 1, Week 6	The GAS is a functional 5-point scale used to measure progress towards individual therapy goals. At start of each TC, 1 to 3 individual goals were defined for each subject by investigator and child's parents/guardians/caregivers prior to treatment. Outcome to reach each goal was rated on a 5-point scale ranging from -2 to +2 (-2: much less than expected outcome, -1: somewhat less than expected outcome, 0: expected outcome, +1: somewhat more than expected outcome, +2: much more than expected outcome). Higher score indicates a better outcome. A GAS T-score was calculated as: 50+(10∑_(i=1)^n wi xi)/√(0.7∑_(i=1)^n wi^2 +0.3(∑_(i=1)^n wi)^2) where, xi = rating of ith goal post-baseline; wi = weight of ith goal, calculated as importance * difficulty as defined at baseline; n = number of goals assessed at baseline and post-baseline. A GAS T-score of 50 indicates goals achieved as expected. Scores below 50 reflect under attainment of goals and scores above 50 reflect over attainment of goals.	TC 1, Week 6.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline to TC 1 Week 16 in MAS Score in the TC 1 PTMG	The MAS was used to assess muscle tone in the upper limb PTMG and consists of 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the ROM) when the affected part is moved in flexion or extension, 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion or extension). The original score '+1' was given a derived numeric score of '2' and the higher numeric scores were incremented by 1 so that the MAS score range was from 0 to 5 with higher scores indicating greater muscle tone. A negative change from baseline indicates a decrease in muscle tone.	Baseline (TC 1, Day 1) and TC 1, Week 16.
Mean Change From Baseline to TC 1 Weeks 6 and 16 in MAS Score in the Elbow Flexors of the Study Limb	The MAS was used to assess muscle tone in the upper limb PTMG and consists of 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the ROM) when the affected part is moved in flexion or extension, 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion or extension). The original score '+1' was given a derived numeric score of '2' and the higher numeric scores were incremented by 1 so that the MAS score range was from 0 to 5 with higher scores indicating greater muscle tone. A negative change from baseline indicates a decrease in muscle tone. Data is presented for subjects injected in the elbow flexors.	Baseline (TC 1, Day 1) and TC 1, Weeks 6 and 16.
Mean Change From Baseline to TC 1 Weeks 6 and 16 in MAS Score in the Wrist Flexors of the Study Limb	The MAS was used to assess muscle tone in the upper limb PTMG and consists of 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the ROM) when the affected part is moved in flexion or extension, 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion or extension). The original score '+1' was given a derived numeric score of '2' and the higher numeric scores were incremented by 1 so that the MAS score range was from 0 to 5 with higher scores indicating greater muscle tone. A negative change from baseline indicates a decrease in muscle tone. Data is presented for subjects injected in the wrist flexors.	Baseline (TC 1, Day 1) and TC 1, Weeks 6 and 16.
Mean Change From Baseline to TC 1 Weeks 6 and 16 in MAS Score in the Finger Flexors of the Study Limb	The MAS was used to assess muscle tone in the upper limb PTMG and consists of 6 grades: 0 (no increase in muscle tone), 1 (slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the ROM) when the affected part is moved in flexion or extension, 1+ (slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM), 2 (more marked increase in muscle tone), 3 (considerable increase in muscle tone) or 4 (affected part(s) rigid in flexion or extension). The original score '+1' was given a derived numeric score of '2' and the higher numeric scores were incremented by 1 so that the MAS score range was from 0 to 5 with higher scores indicating greater muscle tone. A negative change from baseline indicates a decrease in muscle tone. Data is presented for subjects injected in the finger flexors.	Baseline (TC 1, Day 1) and TC 1, Weeks 6 and 16.
Mean PGA Score at TC 1 Week 16	The PGA of treatment response was assessed by asking the investigator the following question: 'How would you rate the response to treatment in the subject's upper limb since the start of the study?'. Answers were on a 9-point rating scale (-4: markedly worse, -3: much worse, -2: worse, -1: slightly worse, 0: no change, +1: slightly improved, +2: improved, +3: much improved and +4: markedly improved). The mean scores for each treatment group at TC 1 Week 16 are presented.	Baseline (TC 1, Day 1) and TC 1, Week 16.
Mean GAS Total Score at TC 1, Week 16	The GAS is a functional 5-point scale used to measure progress towards individual therapy goals. At start of each TC, 1 to 3 individual goals were defined for each subject by investigator and child's parents/guardians/caregivers prior to treatment. Outcome to reach each goal was rated on a 5-point scale ranging from -2 to +2 (-2: much less than expected outcome, -1: somewhat less than expected outcome, 0: expected outcome, +1: somewhat more than expected outcome, +2: much more than expected outcome). Higher score indicates a better outcome. A GAS T-score was calculated as: 50+(10∑_(i=1)^n wi xi)/√(0.7∑_(i=1)^n wi^2 +0.3(∑_(i=1)^n wi)^2) where, xi = rating of ith goal post-baseline; wi = weight of ith goal, calculated as importance * difficulty as defined at baseline; n = number of goals assessed at baseline and post-baseline. A GAS T-score of 50 indicates goals achieved as expected. Scores below 50 reflect under attainment of goals and scores above 50 reflect over attainment of goals.	Baseline (TC 1, Day 1) and TC 1, Week 16.
Mean Change From Baseline to TC 1, Week 16 in the Paediatric Quality of Life (PedsQL) Scores	Parents/guardians completed questionnaires on their child's quality of life. The PedsQL parent inventory measured healthcare concepts for children/adolescents aged 2-18 years. The Generic Core Scales include physical, emotional, social and school aspects. The CP module was also completed. Scores were transformed on a scale from 0 to 100 with higher scores indicating a better quality of life. Mean changes from baseline to TC 1, Week 16 are presented for the General Core Scale and for the CP module. A positive change from baseline indicates an improvement in quality of life.	Baseline (TC 1, Day 1) and TC 1, Week 16.

Collaborators and Investigators

• Sponsor: Ipsen

Publications and helpful links

General Publications

• Delgado MR, Tilton A, Carranza-Del Rio J, Dursun N, Bonikowski M, Aydin R, Maciag-Tymecka I, Oleszek J, Dabrowski E, Grandoulier AS, Picaut P; Dysport in PUL study group. Efficacy and safety of abobotulinumtoxinA for upper limb spasticity in children with cerebral palsy: a randomized repeat-treatment study. Dev Med Child Neurol. 2021 May;63(5):592-600. doi: 10.1111/dmcn.14733. Epub 2020 Nov 18.
• Shierk A, Jimenez-Moreno AC, Roberts H, Ackerman-Laufer S, Backer G, Bard-Pondarre R, Cekmece C, Pyrzanowska W, Vilain C, Delgado MR. Development of a Pediatric Goal-Centered Upper Limb Spasticity Home Exercise Therapy Program for Use in a Phase-III Trial of Abobotulinumtoxina (Dysport(R)). Phys Occup Ther Pediatr. 2019;39(2):124-135. doi: 10.1080/01942638.2018.1486346. Epub 2018 Sep 11.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2014
• Primary Completion (Actual): September 21, 2017
• Study Completion (Actual): September 4, 2018

Study Registration Dates

• First Submitted: April 3, 2014
• First Submitted That Met QC Criteria: April 7, 2014
• First Posted (Estimate): April 8, 2014

Study Record Updates

• Last Update Posted (Actual): September 28, 2022
• Last Update Submitted That Met QC Criteria: September 15, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Muscle Hypertonia; 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
• Other Study ID Numbers: Y-52-52120-153; 2010-021817-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, annotated case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized, and study documents will be redacted to protect the privacy of study participants.

Any requests should be submitted to www.vivli.org for assessment by an independent scientific review board.

• IPD Sharing Time Frame: Where applicable, data from eligible studies are available 6 months after the studied medicine and indication have been approved in the US and EU or after the primary manuscript describing the results has been accepted for publication, whichever is later.
• IPD Sharing Access Criteria: Further details on Ipsen's sharing criteria, eligible studies and process for sharing are available here (https://vivli.org/members/ourmembers/).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No