Effect of Single Event Multi Level Chemoneurolysis With Dysport on Energy Expenditure and Walking Efficiency
Phase: PHASE3
Conditions: Cerebral Palsy
Sponsor: Columbia University

 
 
 
 
 
 
 
 
 
 
Title: Effect of Single Event Multi Level Chemoneurolysis with AbobotulinumtoxinA 
(Dysport®) on Energy Expenditure and Walking Efficiency in Children with Cerebral 
Palsy 
Heakyung Kim, MD 
Columbia University Irving Medical Center, Department of Rehabilitation and Regenerative  
AAAR1322 
NCT03469999 
Version 10/08/2021   
 
 
 
 
 
Principal Investigator: Heakyung Kim, MD 
Columbia University Irving Medical Center 
180 Fort Washington Ave 
New York, NY 10032 
 
 
 
 
 
Sponsor: Ipsen Pharmeceuticals 
One Main St. 
Cambridge, MA 02142 
Dysport® (AbobotulinumtoxinA) 
 
 
 
 
 
 
 
 
 
 

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1. INTRODUCTION 
 
Cerebral palsy (CP) is a movement and postural disorder due to lesion to immature brain. 
Spasticity is the most common movement disorder in children with cerebral palsy (CDC) and 
causes difficulty with walking, musculoskeletal complications such as hip dislocation, scoliosis 
and joint contracture, pain and balance issues (Balaban et al., 2012). Spastic muscles are stiff and 
weak (Campbell & Ball, 1978). A combination of spasticity and weakness in children with CP 
makes them walk difficult and less efficient. Spasticity management has been very important for 
children with CP for activity of daily living including walking (Massin & Allington, n.d.) Using 
botulinum toxin A (BoNT-A) injections to control spastic lower limbs became almost first line 
treatment for children with CP to improve gait, range of motion and quality of life. (Ade-Hall & 
Moore, 2000). Several studies reported that children with CP showed higher energy expenditure 
during walking compared to typically developing peers. (Balaban 2007 & Rose et al 1990 Steele 
K et al 2017) This increase is due to combination of the mechanical inefficiencies during 
ambulation caused by spasticity (Reddihough et al., 2002), muscle co-contraction ((Balaban et 
al., 2012), limited range of motion, muscle weakness and loss of balance (Norman, 2004).  
Perhaps, improving coordination of walking by reducing in spasticity with BoNT-A may 
improve energy expenditure by improving coordination of muscle activity which is related to 
peak power output (Wakeling et al, 2010). Energy expenditure is an objective measure of 
evaluating the energy cost required for movement (Rose et al., n.d.) Generally, the oxygen 
consumption (VO2) is used to measure energy expenditure and one of the most significant 
markers of aerobic fitness and endurance (ACSM’s Advanced Exercise Physiology, 2006). The 
rate of oxygen consumption (mL/kg/min) was significantly higher in the children with diplegia 
than in those with hemiplegia or with spina bifida or the healthy children (Rose et al., n.d.). 
Oxygen cost (mL/kg/m) was significantly higher, and velocity was significantly slower in all the 
groups with disability than in the healthy children (Duffy and Graham 2014). Balaban et al 
showed that botulinum toxin A injections to spastic gastric muscles decreased VO2 and gait 
parameters at 2-month post injections. We hypothesized that BoNT-A injections to spastic lower 
limbs of ambulant spastic CP decrease energy expenditure during walking. The aim of this study 
is to investigate the effect of spasticity management using Dysport® (AbobotulinumtoxinA) on 
the walking efficiency, oxygen consumption and gross motor function and gait parameters of 
children with CP. 
 
 
 2.DESIGN 
 
This study is a single center, open label study.  
 
We seek to recruit 15 children diagnosed with Cerebral Palsy (CP) in order to determine the 
efficacy of single event multi level chemoneurolysis (SEMLC) with Dysport® on energy 
expenditure as measured by oxygen consumption (VO2) during the 6 minute walk test. 
 
Subject Visits: 
 Baseline: Consent, Modified Ashworth Scale, modified Tardieu Scale, CP Quality of 
Life Questionnaire for Children/Adolescents, 6 minute walk with VO2 and gait analysis 
 Treatment: SEMLC treatment 

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 4 week follow-up: Modified Ashworth Scale, modified Tardieu Scale, CP Quality of Life 
Questionnaire for Children/Adolescents, 6 minute walk with VO2 and gait analysis 
 12 week follow-up: Modified Ashworth Scale, modified Tardieu Scale, CP Quality of 
Life Questionnaire for Children/Adolescents, 6 minute walk with VO2 and gait analysis 
 
 2.1 Participants 
 
All subjects will be recruited from Dr. Kim’s Pediatric Physical Medicine & Rehabilitation 
clinic. Dr. Kim will approach eligible patients and their parents in order to explain the study and 
to determine interest. A researcher of the study team will email and/or telephone call eligible 
participants on behalf of Dr. Kim and with her permission to inform the parents of the eligible 
participant of the study. 
 
Inclusion Criteria: 
 Age: 5-17 years. Must be <18 prior to injection. 
 >10 kilograms at screening and injection visits 
 Diagnosis of spastic diplegia OR mild- to moderate spastic quadriplegia Cerebral Palsy 
 Gross Motor Function Classification System level: I, II, III 
 Ability to ambulate independently without aid, equinus gait 
 Absent of joint or bone deformities 
 Eligible to receive SEMLC 
 Cooperative and tolerant to testing procedures during clinic screening 
 Presence of spasticity in one or both legs 
 Be on a stable dose and regimen if on any prescribed medication/s 
 Parent must have signed written informed consent and the Patient Authorization for Use 
and Release of Health and Research Study Information 
 
Exclusion Criteria: 
 Ankle contractures no more than -10 degrees with the knee extended 
 Hemiplegia 
 Wheelchair dependent 
 Received Botulinum toxin within previous 4 months 
 Uncontrolled epilepsy or certain types of seizures 
 Fracture in the study limb within previous 12 months 
 Infection or skin disorder at planned injection site 
 Shortness of breath or other respiratory issues 
 Uncontrolled clinically significant medical condition 
 Received phenol or alcohol block in the study limb within previous 6 months 
 Surgery in the study limb within previous 12 months 
 Serial casting within previous 12 months 
 New physiotherapy and/or orthotic regimen <1 month before study start. (physiotherapy 
and/or orthotic regimen will be permitted if it began >1 month before study start and 
maintained throughout study) 
 
 

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2.2 Outcome Measures 
 
Primary Question: Does single event multi level chemoneurolysis (SEMLC) have an effect 
on energy expenditure and walking efficiency as measured by oxygen consumption (VO2) 
and gait parameters during the 6 minute walk test in 15 children diagnosed with cerebral 
palsy (CP)? 
Hypothesis: If 15 children receive SEMLC, then energy expenditure (VO2) will decrease due to 
increased walking efficiency and gait parameters during the 6 minute walk test. 
 
Secondary Question: Does SEMLC have an effect on 6 minute walking distance in 15 children 
diagnosed with CP? 
Hypothesis: SEMLC will increase the distance walked during the 6 minute walk test. 
 
Secondary Question: Does SEMLC have an effect on the Gross Motor Functional Classification 
System (GMFCS) classification in 15 children diagnosed with CP? 
Hypothesis: SEMLC will decrease a child's GMFCS classification due to increased physical 
function. 
 
Secondary Question: Does SEMLC have an effect on ankle muscle spasticity as measured by 
the Modified Ashworth Scale (MAS) and the modified Tardieu Scale? 
Hypothesis: SEMLC will decrease ankle muscle spasticity and in turn improve MAS and 
modified Tardieu Scale scores. 
 
Secondary Question: Does SEMLC have an effect on dynamic balance during walking in 15 
children diagnosed with CP? 
Hypothesis: SEMLC will increase dynamic balance during walking. 
 
2.3 Procedures 
 
Baseline (within 1 week prior to Dysport® treatment): 
 
Before initiating any study procedures the informed consent will be discussed and signed with 
the parent(s) of the participants and the researcher will answer any questions. If capable of 
providing assent (>7 years old), the participant will sign the assent form. Once the consent and 
assent forms are discussed and signed the following assessments will be performed: 
demographics, height, weight, calculated body mass index (BMI), Modified Ashworth Scale 
(MAS), modified Tardieu Scale, range of motion of major joints (i.e., hip, knee, ankle), the 
Cerebral Palsy Quality of Life Questionnaire (CP QOL) for Children (9-12 years) or Adolescents 
(13-18 years), and the CP QOL for caregivers, 6 minute walk test (with mobile oxygen 
consumption), and gait analysis. 
 
Degree of spasticity/tone in the lower limbs will be measured by the Modified Ashworth scale 
while the participant is relaxed and in the supine position (1). If testing a muscle that primarily 
flexes the hip, knee, or ankle joint the investigator will place the joint in a maximally flexed 
position and move the joint to a position of maximal extension over one second. If testing a 
muscle that primarily extends the hip, knee, or ankle joint the investigator will place the 

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joint in a maximally extended position and move the joint to a position of maximal flexion over 
one second. 
 
The Modified Tardieu Scale will be used to assess spasticity by measuring different angles of 
muscle reaction in response to a passive force (2). Two angles will be measured from each major 
joint (i.e., hip, knee, ankle): R1, the angle in which clonus was felt during a quick passive stretch 
of the muscle; R2, the angle of full passive range of motion. The difference between the two 
angles (R2 – R1) will be recorded for each muscle group. The participant will be lying supine for 
all angle measurements. 
 
Range of motion of the lower limbs (hip, knee, ankle) will be measured by passively moving the 
patient’s joint to a point of resistance where then the joint angle will be measured by a 
goniometer. Hip flexion will be measured with the patient lying supine. Knee flexion and 
extension will be measured with the patient lying supine. Ankle dorsiflexion will be measured 
with the knee extended in the supine position. The Thomas Test will also be used to assess hip 
flexion with the patient lying in supine (3). 
 
The CP QOL for children, adolescents, and caregivers will be used to assess quality of life and 
wellbeing across multiple domains of life (4). For children 4-12 years, we will give the primary 
caregiver version to their parent or guardian. For children 9-12 years, we will give the child self-
report version. For adolescents 13-18 years, we will give the teen self-report version as well as 
the primary caregiver version to their parents or guardian. The sum for each domain will be 
calculated as well as the total sum. 
 
Gait analysis and the 6 Minute Walk Test (6MWT) with oxygen consumption measurement 
(energy expenditure) will be performed in the Department of Rehab by an exercise physiologist. 
Children will be given at least a ten minute rest between measures. 
 
Gait analysis will be measured with the GAITRite® mat, a commercially available instrumented 
mat for collection of gait data. The GAITRite system is an electronic walkway that connects to a 
computer, and automates the measurement of temporal (timing) and spatial (distance) gait 
parameters, such as cadence, step length and velocity. The standard GAITRite walkway is (5m 
long) and contains 13824 sensors encapsulated in a roll up mat to produce an active area 0.6 m 
wide and 4.25 m long. The walkway is portable, can be laid over any flat surface and requires no 
placement of any devices on the patient. GAITRite uses no radiation, electricity or ultrasound to 
measure these parameters and is therefore a safe method for evaluating walking function, even 
during pregnancy. The system has been validated for use in healthy children and children with 
movement disorders (such as cerebral palsy, and spinal muscular atrophy) (5, 6). The laboratory 
consists of a 10-meter walkway. The GAITRite mat is placed in the middle of the 10 meter 
walkway to collect data on steady state gait without the influence of gait initiation and 
termination. Subjects will be asked to wear the same shoes and orthoses throughout the study. A 
gait aid can be used during the test if the child cannot walk without it. Subjects will be asked to 
begin walking at a starting position located 1.5 meters from the mat and walk at their preferred 
typical speed until a termination position marked on the floor (1.5m from the end of the mat). 
Each subject will perform five trials of walking at their preferred speed. We will compute gait 

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velocity, step length, cadence, percent time spent in double support, foot angle, and base of 
support. 
 
After at least a ten minute rest, oxygen consumption via the breath-by-breath method using a 
portable spirometric device (Cosmed K5; COSMED USA Inc, Concord, CA) will be determined 
while the participant performs the 6MWT (7). After instruction the participant will don the face 
mask and a 12 lead ECG will be applied. In order for the child to become comfortable with the 
face mask, a three minute rest period will be given while resting heart rate (HR) and 
oxygen consumption (VO2) is measured. After the three minute rest, the participant will begin 
the 6MWT while the K5 mobile device collects gas exchange variables [VO2, VCO2, respiratory 
exchange ratio (RER)] and HR will be monitored via the 12-lead ECG as well as cardiac rhythm. 
Participants will be instructed to walk at their normal walking pace as far as they can for six 
minutes. They will be allowed to walk with any orthoses and/or assistive devices however the 
same orthoses and/or devices will be used throughout the study. The participant can stop at any 
time if they feel dizzy or fatigued to the point of increased risk of falling. The total distance 
walked (meters) will be recorded at six minutes. 
 
(Dysport® Injection/Treatment) 
The procedures for Single Event Multi Level Chemoneurolysis (SEMLC) with Dysport® will 
mimic those currently used by Dr. Kim in the pediatric rehab clinic (8). The study drug, Dysport, 
will be provided by the funding source IPSEN and will be the sole abobotulinumtoxinA used in 
the SEMLC injection. Dysport® is currently FDA-approved for pediatric patients 2 years and 
older to treat lower limb spasticity (gastrocnemius and soleus). Selected dose of medication will 
be determined by affected muscle(s), severity of spasticity, and the patient’s body weight. We 
will follow the recommended total Dysport dose of 10-15 units/kg per limb, not to exceed 15 
units/kg for unilateral lower limb, 30 units/kg for bilateral lower limb, or a total of 1000 units, 
whichever is lower in a given session. The research pharmacy will be responsible for housing 
and preparing all Dysport® vials according to manufacturer (prescribing information sheet 
attached). The research pharmacy will also be responsible for study drug disposal at end of 
study. Electrical stimulation and/or ultrasound will be used for guidance of injection point. 
General anesthesia will be used to prevent pain and anxiety in adolescents if extensive multi-
level injections are planned. All injection procedures will take place in the pediatric Endoscopy 
Suite (CHONY), and will be led by Dr. Kim (PI). 
 
(4 Weeks Post Treatment) 
All procedures during the 4 weeks post treatment will mimic those conducted during the baseline 
visit (i.e., Modified Ashworth Scale, Modified Tardieu Scale, range of motion, CP QOL, gait 
analysis, 6MWT with oxygen consumption). 
 
(12 Weeks Post Treatment) 
All procedures during the 12 weeks post treatment day 1 will mimic those conducted during the 
baseline day 1 visit (i.e., Modified Ashworth Scale, Modified Tardieu Scale, range of motion, CP 
QOL, gait analysis, 6MWT with oxygen consumption). 
 
(1) Smith, M. B. (2000). Interrater Reliability of a Modified Ashworth Scale of Muscle 
Spasticity, 1986–1987. 

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