Treatment Algorithms Based on Muscle and Tendon Morphology - Progressive Supervised Home-based Strength Training in Children With Spastic Cerebral Palsy
Phase: NA
Conditions: Cerebral Palsy, Spastic
Sponsor: Universitaire Ziekenhuizen KU Leuven

Progressive Supervised Home-based Strength Training in 
Children With Spastic Cerebral Palsy 
NCT number: NCT03863197 
Protocol data: 1 November 2021 
 
Study protocol 
Study outline 
A waitlist randomized controlled trial (RCT) will be conducted to define the effects of a progressive 
resistance training (PRT) program for the knee extensor, knee flexor and plantar flexor muscle groups 
in children with spastic cerebral palsy (CP). A minimization technique will be used to divide 
participants in an intervention group, performing a 12-week PRT program and a waitlist control 
group, continuing usual care for 12 weeks first. After the control period, the participants were offered 
to participate in the intervention.  
Participants 
Participants will be recruited across Flanders in Belgium, through the CP reference center of the 
University Hospitals Leuven, pediatric physiotherapists, and special needs schools. Written informed 
consent will be obtained from the children’s parents or legal guardian prior to the first assessment. 
The study is registered at Clinicaltrials.gov (NCT03863197) and was approved by local medical ethical 
committees of University Hospitals Leuven (s59945) and Ghent (EC/2017/0526). The inclusion criteria 
for participation are 1) a diagnosis of SCP, 2) age at baseline between 5 and 11 years and 3) level of I, 
II or III on the gross motor function classification system (GMFCS) (Palisano et al., 2008) . Exclusion 
criteria were 1) botulinum neuro-toxin A injections and/or lower leg casts in the past 6 months, 2) 
lower limb bony surgery in the past 2 years, 3) lower limb muscular surgery or selective dorsal 
rhizotomy at any time point, 4) inability to communicate in Dutch or English and 5) inability to 
understand instructions and cooperate during assessments and training.  
For comparison of baseline data, a convenience sample of typically developing (TD) children will be 
recruited via hospital co-workers and students within the same age range of 5–12 years. The TD 
children could not have any known neurological or orthopedic lower limb problems. The TD children 
will only participate in one assessment of isometric strength, 3D freehand ultrasonography and 
functional strength (see below). 
Study design  
After enrollment and prior to the first assessment, participants will be assigned to the intervention or 
the control group through randomization by minimization. MinimPy will be used to randomize the 
participants based on age (2 levels: <8 years and >8 years) and GMFCS score (3 levels: I, II and III) 
(Saghaei, 2011). The allocation ratio will be 1:1 with probability set at 0.75. The biased coin 
minimization will be used as probability method and marginal balance as distance measure.  
Assessments are planned in the University Hospitals and special needs schools, at baseline (PRE) and 
after the 12-week control or intervention period (POST). Training and assessments will always be 

conducted on different days. Participants in the intervention group start training within 2 weeks after 
the baseline assessment. For both groups, the POST assessments will be performed within 1 week 
after the 12-week period. Blinding is not completely possible since participants and trainers are 
aware of group allocation. Assessors are also aware of group allocation during assessments but data 
will be anonymized before processing and analyses. The participants will be assessed by the same 
assessors (PRE and POST) and the data of one participant will be processed by the same processer.  
Piloting for the feasibility of the measurements and parameter extraction was done through prior and 
parallel investigations. The exercises used during the training were piloted through iterations with 
strength and conditioning specialists to ensure correct exercise selection and also with senior 
pediatric physiotherapists and their patients to ensure the applicability in targeted population of 
children with SCP.   
Sample size  
At the moment of trial design (2018), no data were available on an RCT investigating changes in 
muscle size after PRT in a population of children with SCP. Therefore, effect sizes (d) of systematic 
reviews and meta-analyses reporting muscle strength outcomes after PRT were used. Reported effect 
sizes were moderate (d=0.53) (Ryan et al., 2017) and large (d=1.050 and d=1.105) (Park & Kim, 2014). 
Based on a large effect size of d=0.8 with the probability of making a type I error set equal to or less 
than 1% (p≤0.01) and a power of 80%, an independent samples t-test with common standard 
deviation required 39 independent observations per group to compare the evolution over time 
between the intervention and control groups. To account for the possibility of clustered legs in 
bilaterally affected participants a design effect (Killip et al., 2004) was calculated resulting in an 
estimated sample size of clustered observations per group with following formulas:   
Design effect = 1 + ρ*(m-1),  
where ρ is the intraclass correlation and m the cluster size, and,   
Estimated sample size of clustered legs = estimated sample size of independent observations * design 
effect = m * number of participants  
With a cluster size of m=2 (2 legs per bilaterally affected participant) and an intraclass correlation 
coefficient of ρ=0.1 , based on literature of general health parameters (Adams et al., 2004), the 
estimated design effect was 1.1, resulting in 43 clustered legs, or 22 bilaterally affected participants 
per group. A group including both uni- and bilaterally affected children would require a sample size 
between 39 and 43.  
Intervention  
Participants assigned to the control group will continue their usual care. Participants assigned to the 
intervention group will undertake 3 to 4 PRT sessions per week (alternating), on non-consecutive 
days, for 12 weeks, resulting in a total of 42 scheduled sessions. The PRT program will be explained 
during a visit to the physiotherapist(s) and parent(s). After a familiarization phase of up to 3 sessions, 
the official PRT starts. At least 1 session per week will be performed under the supervision of the 
physiotherapist(s). The remaining sessions will be completed at home under the supervision of a 
parent or guardian. We will create a patient-specific PRT program through the online software 
platform Skill-Up (www.Skill-up.com) and ask the participants to log each PRT session in a training 
diary. Throughout the 12-week period, the PRT program will be supervised through phone calls, e-
mails, and targeted visits to check adherence and progress exercises by trainers with a background in 
human movement sciences. Participants in the intervention group were invited for an interim 

assessment after 6 weeks, which was also used as an additional moment to evaluate and adjust the 
intensity of the training program.  
The PRT program, targeting strength and hypertrophy of knee extensors, knee flexors and plantar 
flexors, will be prescribed in close consultation with the personal physiotherapist(s) to ensure 
feasibility for each participant. The general session design recommendations include a 5-minute 
dynamic warm-up and a 5-minute cool-down. Depending on the participants’ abilities, the PRT will 
start with 1-3 functional multi-joint exercises, followed by 2-3 single-joint exercises targeting the 
specific muscle groups, all performed without orthotics. Following international guidelines for youth 
resistance training of the National Strength and Conditioning Association, as well as CP-specific 
recommendations, the initial exercises start at a training volume of 3 sets of 10 repetitions, aiming at 
an exercise intensity of 60 to 80% of the estimated 1-repetition maximum, with a rest period in 
between sets of at least 1 minute (Faigenbaum et al., 2009; Lloyd et al., 2014; Noorduyn et al., 2011; 
Verschuren et al., 2016). The most difficult exercise that could be performed, with the maximal load 
that could be lifted, for the defined number of repetitions and sets was defined through trial and 
error (Moreau, 2020). Throughout the training program, exercise difficulty was increased. Thereto, 
physiotherapists will be encouraged to regularly test the difficulty of the exercises, i.e. at least 
biweekly, by asking a maximum performance in the last set, based on exercise execution and fatigue. 
The intensity will be modified by the trainers or the physiotherapist(s) if the last set exceeded 15 well-
executed repetitions. Exercise modification options are dependent on the exercise and include 
addition of weight in a weighted vest (0.5kg increments up to 10kg), use of a stronger resistance band 
(5 colors ranging from light to very heavy), increase of ankle weight (1.0, 1.5 or 2.0kg), or selection of 
a more challenging exercise. The number of sets and repetitions performed, modifications or 
compensations, perceived fatigue at the end of the session and potential adverse events will be 
noted in the training diary.   
Assessments and outcome measures   
1. Participant characteristics  
Age, body mass and height will be recorded for the participants at each assessment. Usual care and 
treatment history will be recorded at the PRE-assessment using standardized in-house 
questionnaires. A routine clinical examination regarding the investigated muscle groups will be 
performed, including passive joint range of motion, spasticity, manual muscle strength and selective 
motor control (SMC), based on standard clinical scales (Bohannon & Smith, 1987; Boyd, 1999; Gage 
et al., 2009; Matthews, 1977). These clinical examination parameters will be used to define the most 
affected leg for bilaterally affected children. If both sides are equally affected, the right leg will be 
used. Lower limb SMC will be assessed with the selective control assessment of the lower extremity 
total limb score (Fowler et al., 2009). Assessments will be performed in the same order, starting with 
clinical examination and muscle morphology, followed by isometric and functional strength and lastly 
gross motor function and walking capacity.  
2. Isometric strength assessments  
Knee extensor, knee flexor and plantar flexion maximum voluntary isometric contractions were 
collected with a fixed dynamometer in a previously described, custom-designed chair (Goudriaan et 
al., 2018). The dynamometer is positioned at 75% of the lower leg and foot length, and the level arm 
distance is measured between this position and the joint axis. After a test trial, we aim to collect 3 
well executed maximum voluntary isometric contractions with a duration of 3 to 5 seconds. 
Standardized verbal encouragement and visual feedback will be provided throughout the isometric 
contraction. The protocol includes periods of rests of at least 10 seconds between repeated 

assessments and of at least 2 minutes between different muscle groups. Peak force is extracted from 
each trial with a custom-written MATLAB script and maximal joint torque (in Nm) will be calculated by 
multiplying peak force with the lever arm and taking the average of the 3 trials. Knee and plantar 
flexion maximal voluntary isometric contractions are corrected for gravity by subtracting the 
gravitational torque in rest from the outcomes. Maximal joint torque will be normalized by dividing it 
by body weight (Nm/kg).   
3. Three-dimensional freehand ultrasonography  
A previously validated 3-dimensional freehand ultrasonography technique will be used to evaluate 
muscle morphology, combining a 2-dimensional B-mode ultrasonography device (Telemed-
Echoblaster 128 Ext-1Z, with a 5.9 cm 10MHz linear ultrasound transducer, Telemed, Ltd, Lithuania) 
with a motion tracking system (Optitrack V120:Trio, NaturalPoint, Inc, Corvallis, Oregon, USA) (Cenni 
et al., 2016). Ultrasound settings will be kept constant throughout the study period, at a frequency of 
8MHz, with a focus of 3cm, a gain of 64%, a dynamic range of 56 dB and unaltered time-gain 
compensation. Depth can vary between 5cm and 7cm, adjusted to muscle size. The m. rectus femoris 
and m. tibialis anterior will be scanned in supine position with a triangular cushion underneath the 
calf, providing approximately 25 degrees of knee and hip flexion. The m. semitendinosus and m. 
medial gastrocnemius will be scanned in prone position with a triangular cushion underneath the 
shank, providing 25 degrees of knee flexion and an unconstrained ankle angle. STRADWIN software 
(version 6.0; Mechanical Engineering, Cambridge University, Cambridge, UK) will be used for data 
acquisition, generation of 3-D datasets, and data processing. Data processing will be performed by 
experienced processers, drawing equally spaced transverse plane segmentations throughout the 3-D 
datasets, which will be interpolated with an automatic cubic planimetry technique resulting in the 
muscle volume (in mL) (Treece et al., 1999). Muscle length (in mm) will be defined by calculating the 
linear distance between muscle origin and muscle tendon junction. Both muscle volume and muscle 
length will be normalized to fibula length to correct for skeletal growth (mL/cm and cm/cm). The 
echo-intensity (EI) from ultrasound images will be used as an indication of intrinsic muscle quality, 
with higher EI-values representing an increased ratio of non-contractile vs. contractile tissue (Pitcher 
et al., 2015; Young et al., 2015). EI (expressed in arbitrary units) will be computed as the average 
value throughout the interpolated reconstruction of the muscle.   
4. Functional strength assessments  
Endurance functional strength will be as assessed with 30-s repetition maximum tests including bi- 
and unilateral heel raise, sit-to-stand, and lateral step-up, as previously described (van Tittelboom et 
al., 2021). Participants completed as many repetitions as possible in 30 seconds. Each test will be 3 
times and the average taken as final score. Explosive strength will be evaluated with a standing long 
jump, with both feet together, which will also be repeated 3 times and the scores averaged. The use 
of orthoses will not be allowed, as the PRT program will also be performed without orthoses.  
5. Gross motor function and walking capacity  
Gross motor function will be evaluated with the Gross Motor Function Measure-Item Set (Brunton & 
Bartlett, 2011) and the Gross Motor Ability Estimator 2 used to estimate the final score. The 1-minute 
walk test, performed on an indoor 20-m track, will be used to assess walking capacity (Chrysagis et 
al., 2014; Mcdowell et al., 2009). The participant will be instructed to walk as fast as possible without 
running and the distance covered in 1 minute will be recorded. Both assessments will be performed 
without orthoses, but a kay-walker is allowed for the 1-minute walk test for children classified as 
GMFCS-level III.   

6. Statistics  
Descriptive statistics for all groups will summarized using appropriate summary indices. The 
comparison between TD children and children with CP will be performed with a Student's t-test (after 
confirming equality of variances) or the Mann–Whitney U-test. Associations between muscle 
morphology measures, muscle strength and participant characteristics will be evaluated with 
univariate linear regressions followed by a multivariate linear regression using a backward approach. 
The linear regressions in the TD cohort based on an anthropometric variable will be used to define 
the deficits in muscle strength and muscle morphology in CP children.  
To define the effects of the PRT intervention linear mixed models will be applied to evaluate the 
difference in evolution over time between the control and intervention group (time*group interaction 
effect) and between PRE and POST within each group (time effect). The random effects in these 
models can correct for the correlation between repeated observations within the same subject. 
Moreover, in the case of missing values that are completely at random, i.e. not related to any 
observed or unobserved outcomes, or at random, i.e. related to observed outcomes, linear mixed 
models provide valid inferences for missing observations. A covariance structure for repeated 
measurements to model longitudinal dependencies within the participant will be applied with a 
random intercept for participant (legs are nested within participants). The models will be adjusted for 
age and GMFCS level as covariates as these were used to allocate the children to the control or 
intervention group. Age was entered as a categorical variable (<8 years and >8 years). A full-factorial 
time*group mean model adjusted for age and GMFCS level, with a compound symmetry covariance 
matrix, unless an unstructured covariance matrix results in a better fit (Akaike information criterion 
decrease of >2). Adjustment for age (categorical variable: <8 years and >8 years) and GMFCS level will 
be included as these were used to allocate the children to the control or intervention group.  
The α-level will be adjusted to p≤0.01 since multiple parameters are evaluated for most research 
questions, with a maximum of 5 parameters (functional strength). All analyses will be performed with 
SPSS (Version 28, SPSS Inc., Chicago, Illinois).  
Finally, the data of the total intervention group (intervention + waitlist control group with delayed 
intervention) will be used to define the association between baseline properties and the changes in 
the outcome parameters after PRT with uni- or multivariate regression (mixed) models.  
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