Dysport® Pediatric Lower Limb Spasticity Follow-on Study

Cerebral Palsy Clinical Trial

Official title:

A Phase III, Prospective, Multicentre, Open Label, Extension Study Assessing the Long Term Safety and Efficacy of Repeated Treatment With DYSPORT® Used in the Treatment of Lower Limb Spasticity in Children With Dynamic Equinus Foot Deformity Due to Cerebral Palsy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01251380
• Other study ID #: Y-55-52120-147
• Secondary ID: 2010-019102-17
• Status: Completed
• Phase: Phase 3
• Start date: October 2011
• Est. completion date: January 2015

Study information

• Verified date: September 2022
• Source: Ipsen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this research study was to determine the long term safety and efficacy of repeated treatments with Dysport® used in the treatment of lower limb spasticity in children with dynamic equinus foot deformity due to cerebral palsy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 216
• Est. completion date: January 2015
• Est. primary completion date: January 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 17 Years

Eligibility

Inclusion Criteria:

Subjects were eligible for participation in the study if they met the following criteria:

1. Completion of the double blind study (Study 141) up to the Week 12, Week 16, Week 22 or Week 28 follow up visit.

2. Without any major protocol deviations and/or any ongoing adverse events (AEs), either of which, in the opinion of the Investigator would pose an unacceptable risk to the subject were he/she to continue receiving treatment in this open label extension study.

3. Written informed consent obtained from the child's parent(s)/guardian(s) for this study, and assent from the child when and where applicable.

Exclusion Criteria:

Subjects were excluded from entering the study for the following reasons:

1. Major limitation in the passive range of motion at the ankle, as defined by maximum ankle dorsiflexion measured by the angle of arrest (XV1) at slow speed <80° (TS angle) in the most affected leg to be injected.

2. Unwillingness or inability to comply with the protocol.

3. Current need for surgery for spasticity of the gastrocnemius-soleus complex (GSC) and/or hamstring muscles (and/or tendons) in the most affected leg to be injected.

4. Treatment with any drug that interferes either directly or indirectly with neuromuscular function (e.g. aminoglycoside antibiotics) or neuroblocking agents used during surgery (e.g. curare) within the last 30 days prior to study medication or a planned treatment with such drugs.

5. Be pregnant and/or lactating.

6. Female subjects, not willing to use contraceptive measures throughout the course of the study if post pubertal and sexually active.

7. An infection at the injection site(s).

8. Planned treatment with any new investigational drug or device during the study period.

Related Conditions & MeSH terms

• Cerebral Palsy
• Children
• Muscle Spasticity

Intervention

Biological:
• Botulinum toxin type A
Intramuscular (IM) injection on day 1 of each treatment cycle.

Locations

Country	Name	City	State
Chile	Club De Leones Cruz Del Sur Rehabilitation Corporation Punta Arenas	Punta Arenas
Chile	Dr Roberto Del Rio Hospital	Santiago
Chile	Neurorehabilitation Laboratory, Pontifical Catholic University	Santiago
France	CHU Jean Minjoz	Besancon
Mexico	Hospital San José Celaya	Celaya
Mexico	Centro de Rehabilitacion Infantil	Mexico City
Mexico	Centro de Rehabilitacion Integral de Queretaro (CRIQ)	Queretaro
Poland	Non-public Healthcare Unit at the Association for Disabled People KROK PO KROKU	Gdansk
Poland	B i L- Specjalistyczne Centrum Medyczne	Lodz
Poland	Non-public Healthcare Unit - Grunwaldzka Clinic	Poznan
Poland	Non-public Healthcare Unit Mazovian Neurorehabilitatio	Wiazowna
Turkey	Ghulane Military Medical Academy and School of Medicine	Ankara
Turkey	Ibn-i-Sina Hospital	Ankara
Turkey	Yildirim Beyazit Training and Research Hospital	Ankara
Turkey	GATA Haydarpasa Training Hospital	Istanbul
Turkey	Istanbul Fizik Tedavi Rehabilitasyon Egitim ve Arastirma Hastanesi	Istanbul
Turkey	Istanbul University Medical School	Istanbul
Turkey	Dokuz Eylül University Medical Faculty	Izmir
Turkey	Kocaeli University Medical Faculty	Izmit
United States	The Children's Hospital	Aurora	Colorado
United States	Rehabilitation Institute of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Texas Scottish Rite - Hospital for Children	Dallas	Texas
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	Shriner's Hospital for Children	Portland	Oregon
United States	Gillette Children's Speciality Healthcare	Saint Paul	Minnesota

Sponsors (1)

Lead Sponsor	Collaborator
Ipsen

Countries where clinical trial is conducted

United States,  Chile,  France,  Mexico,  Poland,  Turkey, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Subjects With Treatment Emergent Adverse Events (TEAEs) Reported in the Double Blind (DB) + Open Label (OL) Period.	Adverse events (AEs) were monitored from the time of informed consent to the end of the study. All AEs were elicited by direct, non-leading questioning or by spontaneous reports.	From baseline (Day 1) until end of study (Week 40) of Cycle 1 and up to Week 28 of Cycles 2 to 4.
Secondary	Mean Change From Baseline (in the DB Study) in the MAS Score in the GSC Assessed at the Ankle Joint of the (Most) Affected Lower Limb	Baseline for the 'change from DB baseline' was defined as the baseline of Study 141 for all treatment cycles. The Modified Ashworth Scale (MAS) is a 6-point scale which measures the intensity of muscle tone by measuring the resistance of the muscle to passive lengthening or stretching. The investigator graded muscle tone in the GSC from 0 (no increase in tone) to 4 (affected parts rigid in flexion or extension).	DB baseline; Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4
Secondary	Mean Change From Baseline (Prior to the First Injection Cycle in the Hamstrings) in the MAS Score in the Knee Flexors Assessed at the Knee Joint of the (Most) Affected Lower Limb	Baseline was defined as the value obtained prior to the first injection in the hamstrings. The MAS is a 6-point scale which measures the intensity of muscle tone by measuring the resistance of the muscle to passive lengthening or stretching. The investigator graded muscle tone in the GSC from 0 (no increase in tone) to 4 (affected parts rigid in flexion or extension).	Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Baseline and Week 4 of Treatment Cycle 4.
Secondary	Mean Change From Baseline (Prior to the First Injection Cycle in Upper Limb Muscle Groups) in the Mean MAS Score for All Injected Upper Limb Muscle Groups From Treatment Cycle 2 Onwards	Baseline was defined as the value obtained prior to the first injection in the upper limb(s). The MAS is a 6-point scale which measures the intensity of muscle tone by measuring the resistance of the muscle to passive lengthening or stretching. The investigator graded muscle tone in the GSC from 0 (no increase in tone) to 4 (affected parts rigid in flexion or extension). No subjects were treated in the upper limb in Treatment Cycle 4.	Baseline and Weeks 4 and 12 of Treatment Cycles 2 and 3.
Secondary	Mean Physician's Global Assessment (PGA) Score	Global assessment of treatment response based on changes since the first injection in the DB study. PGA Scale of the Treatment Response: Global assessment of treatment response was assessed by asking the Investigator the following question: "how would you rate the response to treatment in the subject's lower limb(s) since the first injection in the DB study?" Answers were made 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, +4: markedly improved).	Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4.
Secondary	Mean Goal Attainment Scale (GAS) Score	Individual goals were defined prior to treatment in each treatment period. The GAS is a functional scale used to measure progress towards individual therapy goals. Individual goals were defined for each subject by the physician, and the child's parents (caregiver) where applicable, prior to treatment. After treatment in each treatment cycle, the GAS for each goal was rated using a defined scale (-2: Much less than expected outcome, -1: Somewhat less than expected outcome, 0: Expected outcome, 1: Somewhat more than expected outcome, and 2: Much more than expected outcome).	Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4
Secondary	Mean Change From DB Baseline in Angle of Arrest (XV1) Derived From the Tardieu Scale (TS), in the GSC Assessed at the Ankle Joint of the (Most) Affected Lower Limb	The TS was used to measure spasticity in the GSC at the ankle joint of the (most) affected lower limb.; The Investigator assessed muscle reactions of the tested muscle to passive stretch at two velocities: SLOW = V1: as slow as possible (slower than the rate of natural drop of the limb segment under gravity); FAST = V2 (speed of the limb segment falling under gravity) or V3 (as fast as possible - faster than the rate of natural drop of the limb segment under gravity).; The mean change from DB baseline in XV1 at slow speed was derived.	DB baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4
Secondary	Mean Change From DB Baseline in Angle of Catch (XV3) Derived From the TS, in the GSC Assessed at the Ankle Joint of the (Most) Affected Lower Limb	The TS was used to measure spasticity in the GSC at the ankle joint of the (most) affected lower limb.; The Investigator assessed muscle reactions of the tested muscle to passive stretch at two velocities: SLOW = V1: as slow as possible (slower than the rate of natural drop of the limb segment under gravity); FAST = V2 (speed of the limb segment falling under gravity) or V3 (as fast as possible - faster than the rate of natural drop of the limb segment under gravity).; The mean change from DB baseline in XV3 at fast speed was derived.	DB baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4
Secondary	Mean Change From DB Baseline in Spasticity Angle (X) Derived From the TS, in the GSC Assessed at the Ankle Joint of the (Most) Affected Lower Limb	The TS was used to measure spasticity in the GSC at the ankle joint of the (most) affected lower limb.; The Investigator assessed muscle reactions of the tested muscle to passive stretch at two velocities: SLOW = V1: as slow as possible (slower than the rate of natural drop of the limb segment under gravity); FAST = V2 (speed of the limb segment falling under gravity) or V3 (as fast as possible - faster than the rate of natural drop of the limb segment under gravity).; X (threshold) was derived as XV1 at slow speed minus XV3 at fast speed and the mean change from DB baseline was calculated.	DB Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4
Secondary	Mean Change From DB Baseline in Spasticity Grade (Y) Derived From the TS, in the GSC Assessed at the Ankle Joint of the (Most) Affected Lower Limb	The mean change from baseline (in the DB study) in Y was derived from the TS.; Y was graded according to the following scale: Grade 0 - no resistance throughout passive movement (best outcome); Grade 1 - slight resistance throughout passive movement; Grade 2 - clear catch at precise angle, interrupting passive movement, followed by release; Grade 3 - fatigable clonus (less than 10 sec when maintaining pressure) occurring at a precise angle, followed by release; Grade 4 - unfatigable clonus (more than 10 seconds when maintaining pressure) occurring at a precise angle; Grade 5 - joint immovable (worst outcome).; Catch without release was graded 0 if XV1=XV3, 'unratable' spasticity otherwise; catch with 'minimal' release was graded 2 if XV3 was consistent and consistently less than XV1.; Angle 0 = position of minimal stretch of the tested muscle. For Grades 0 and 1, spasticity angle X = 0 by definition.	DB Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4
Secondary	Mean Change From Baseline (Prior to the First Injection Cycle in the Hamstrings) in XV1 Derived From the TS, in the Knee Flexors Assessed at the Knee Joint of the (Most) Affected Lower Limb	The TS was used to measure spasticity in the knee flexors at the knee joint of the (most) affected lower limb.; The Investigator assessed muscle reactions of the tested muscle to passive stretch at two velocities: SLOW = V1: as slow as possible (slower than the rate of natural drop of the limb segment under gravity); FAST = V2 (speed of the limb segment falling under gravity) or V3 (as fast as possible - faster than the rate of natural drop of the limb segment under gravity).; The mean change from baseline (prior to the first injection cycle in the hamstrings) in XV1 at slow speed was derived.	Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Baseline and Week 4 of Treatment Cycle 4
Secondary	Mean Change From Baseline (Prior to the First Injection Cycle in the Hamstrings) in XV3 Derived From the TS, in the Knee Flexors Assessed at the Knee Joint of the (Most) Affected Lower Limb	The TS was used to measure spasticity in the knee flexors at the knee joint of the (most) affected lower limb.; The Investigator assessed muscle reactions of the tested muscle to passive stretch at two velocities: SLOW = V1: as slow as possible (slower than the rate of natural drop of the limb segment under gravity); FAST = V2 (speed of the limb segment falling under gravity) or V3 (as fast as possible - faster than the rate of natural drop of the limb segment under gravity).; The mean change from baseline (prior to the first injection cycle in the hamstrings) in XV3 at fast speed was derived.	Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Baseline and Week 4 of Treatment Cycle 4
Secondary	Mean Change From Baseline (Prior to the First Injection Cycle in the Hamstrings) in X Derived From the TS, in the Knee Flexors Assessed at the Knee Joint of the (Most) Affected Lower Limb	The TS was used to measure spasticity in the knee flexors at the knee joint of the (most) affected lower limb.; The Investigator assessed muscle reactions of the tested muscle to passive stretch at two velocities: SLOW = V1: as slow as possible (slower than the rate of natural drop of the limb segment under gravity); FAST = V2 (speed of the limb segment falling under gravity) or V3 (as fast as possible - faster than the rate of natural drop of the limb segment under gravity).; X (threshold) was derived as XV1 at slow speed minus XV3 at fast speed and the mean change from baseline (prior to the first injection cycle in the hamstrings) was calculated.	Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Baseline and Week 4 of Treatment Cycle 4
Secondary	Mean Change From Baseline (Prior to the First Injection Cycle in the Hamstrings) in Y Derived From the TS, in the Knee Flexors Assessed at the Knee Joint of the (Most) Affected Lower Limb	The mean change from baseline (prior to the first injection cycle in the hamstrings) in Y was derived from the TS.; Y was graded according to the following scale: Grade 0 - no resistance throughout passive movement (best outcome); Grade 1 - slight resistance throughout passive movement; Grade 2 - clear catch at precise angle, interrupting passive movement, followed by release; Grade 3 - fatigable clonus (less than 10 sec when maintaining pressure) occurring at a precise angle, followed by release; Grade 4 - unfatigable clonus (more than 10 seconds when maintaining pressure) occurring at a precise angle; Grade 5 - joint immovable (worst outcome).; Catch without release was graded 0 if XV1=XV3, 'unratable' spasticity otherwise; catch with 'minimal' release was graded 2 if XV3 was consistent and consistently less than XV1.; Angle 0 = position of minimal stretch of the tested muscle. For Grades 0 and 1, spasticity angle X = 0 by definition.	Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Baseline and Week 4 of Treatment Cycle 4
Secondary	Mean Change From DB Baseline in the Observational Gait Scale (OGS) Total Score of the (Most) Affected Leg	The OGS is a measurement tool used to objectively quantify positive and negative features (impairments) of the upper motor neurone syndrome. The OGS is useful when children are too young or insufficiently cooperative for instrumented gait analysis. It is based on the Physicians Rating Scale but has some modifications to improve its sensitivity to detect changes following administration of Botulinum Toxin Type A (BTX-A).; The OGS total score was calculated as the sum of the individual question scores for Questions 1 to 7, with the highest possible score being 20. The parameters collected were: knee position in midstance, initial foot contact, foot contact at midstance, timing of heel raise, hindfoot at midstance, base of support and gait assistive devices. Higher scores indicate better gait.; The mean change from baseline (in the DB study) in the OGS total score of the (most) affected leg was derived.	DB Baseline and Weeks 4 and 12 of Treatment Cycles 1 to 3; Week 4 of Treatment Cycle 4
Secondary	Mean Change From DB Baseline in the PedsQL Score (CP Module Scores) at Each Study Visit Except Week 4	The PedsQL has a disease specific CP module that is relevant to the study population and complements the core modules.; The 35-item questionnaire encompassed 7 scales including (1) daily activities (2) school activities (3) movement and balance (4) pain and hurt (5) fatigue (6) eating activities and (7) speech and communication. A 5-point scale was utilised for parent proxy-report: 0 = never a problem; 1 = almost never a problem; 2 = sometimes a problem; 3 = often a problem; 4 = almost always a problem.; Each CP score was calculated as follows: (1) Individual item scores were reversed and transformed from a 0-4 scale to a 0-100 scale by assigning 0=100, 1=75, 2=50, 3=25 and 4=0; (2) Each scale score was calculated as the sum of the transformed individual item scores, divided by the number of non-missing items. Higher scores indicated better quality of life (fewer symptoms or problems).; A scale score was only calculated if at least 50% of the associated items were non-missing.	Baseline and Week 12
Secondary	Mean Change From DB Baseline in the PedsQL Score (Generic Core Scores) at Each Study Visit Except Week 4	The PedsQL is a validated quality of life questionnaire, designed for children from 2 to 18 years of age. The Generic Core Scale covers four multidimensional scales including physical, emotional, social and school aspects, with three summary scales of total scale score, physical health summary score and psychosocial health summary score.; Each generic core scale was calculated as follows: (1) Individual item scores were reversed and transformed from a 0-4 scale to a 0-100 scale by assigning 0=100, 1=75, 2=50, 3=25 and 4=0; (2) Each scale score was calculated as the sum of the transformed individual item scores, divided by the number of non-missing items. Higher scores indicated better quality of life (fewer symptoms or problems).; A scale score was only calculated if at least 50% of the associated items were non-missing.	Baseline and Week 12