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

• ClinicalTrials.gov Identifier: NCT02106351
• Recruitment Status: Completed
• First Posted: April 8, 2014
• Results First Posted: December 24, 2019
• Last Update Posted: September 28, 2022
• Sponsor: Ipsen
• Information provided by (Responsible Party): Ipsen

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Upper Limb Spasticity (Altered Skeletal Muscle Performance) in Children	Biological: Botulinum toxin type A	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 212 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: April 2014
• Actual Primary Completion Date: September 21, 2017
• Actual Study Completion Date: September 4, 2018

Arms and Interventions

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 Name: 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 Name: 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 Name: AbobotulinumtoxinA (Dysport®)

Outcome Measures

Primary Outcome Measures :

1. Mean Change From Baseline to TC 1, Week 6 in MAS Score in the TC 1 PTMG [ Time Frame: Baseline (TC 1, Day 1) and TC 1, Week 6. ]
   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.

Secondary Outcome Measures :

1. Mean Physician's Global Assessment (PGA) Score at TC 1, Week 6 [ Time Frame: 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.
2. Mean Goal Attainment Scale (GAS) Total Score at TC 1, Week 6 [ Time Frame: 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.

Other Outcome Measures:

1. Mean Change From Baseline to TC 1 Week 16 in MAS Score in the TC 1 PTMG [ Time Frame: Baseline (TC 1, Day 1) and TC 1, Week 16. ]
   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.
2. Mean Change From Baseline to TC 1 Weeks 6 and 16 in MAS Score in the Elbow Flexors of the Study Limb [ Time Frame: Baseline (TC 1, Day 1) and TC 1, Weeks 6 and 16. ]
   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.
3. Mean Change From Baseline to TC 1 Weeks 6 and 16 in MAS Score in the Wrist Flexors of the Study Limb [ Time Frame: Baseline (TC 1, Day 1) and TC 1, Weeks 6 and 16. ]
   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.
4. Mean Change From Baseline to TC 1 Weeks 6 and 16 in MAS Score in the Finger Flexors of the Study Limb [ Time Frame: Baseline (TC 1, Day 1) and TC 1, Weeks 6 and 16. ]
   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.
5. Mean PGA Score at TC 1 Week 16 [ Time Frame: Baseline (TC 1, Day 1) and 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.
6. Mean GAS Total Score at TC 1, Week 16 [ Time Frame: Baseline (TC 1, Day 1) and 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.
7. Mean Change From Baseline to TC 1, Week 16 in the Paediatric Quality of Life (PedsQL) Scores [ Time Frame: Baseline (TC 1, Day 1) and TC 1, Week 16. ]
   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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Colorado

Aurora, Colorado, United States

United States, District of Columbia

Washington, District of Columbia, United States

United States, Louisiana

New Orleans, Louisiana, United States

United States, Michigan

Royal Oak, Michigan, United States

United States, Minnesota

Saint Paul, Minnesota, United States

United States, Nebraska

Omaha, Nebraska, United States

United States, New Mexico

Albuquerque, New Mexico, United States

United States, New York

New York, New York, United States

United States, Ohio

Columbus, Ohio, United States

United States, Oregon

Portland, Oregon, United States

United States, Texas

Austin, Texas, United States

Dallas, Texas, United States

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

La Paz, Baja California Sur, Mexico

Celaya, Mexico

Monterrey, Mexico

Poland

Gdansk, Poland

Poznan, Poland

Wiazowna, Poland

Spain

Barcelona, Spain

Terrassa, Spain

Turkey

Istanbul, Turkey

Izmir, Turkey

Kocaeli, Turkey

Sponsors and Collaborators

Ipsen

Investigators

• Study Director: Ipsen Medical Director; Ipsen

  Study Documents (Full-Text)

Documents provided by Ipsen:

Study Protocol  [PDF] July 24, 2017

Statistical Analysis Plan  [PDF] October 19, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Ipsen
• ClinicalTrials.gov Identifier: NCT02106351
• Other Study ID Numbers: Y-52-52120-153; 2010-021817-22 ( EudraCT Number )
• First Posted: April 8, 2014
• Results First Posted: December 24, 2019
• Last Update Posted: September 28, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

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.

• 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.
• Access Criteria: Further details on Ipsen's sharing criteria, eligible studies and process for sharing are available here (https://vivli.org/members/ourmembers/).
• URL: https://vivli.org/members/ourmembers

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Muscle Spasticity; Muscular Diseases; Musculoskeletal Diseases; Muscle Hypertonia; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA; Acetylcholine Release Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Neurotransmitter Agents; Physiological Effects of Drugs; Neuromuscular Agents; Peripheral Nervous System Agents