Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05783739 |
| Other study ID # |
TAL |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 2000 |
| Est. completion date |
December 2013 |
Study information
| Verified date |
March 2023 |
| Source |
Region Skane |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
The goal of this study is to compare passive ankle and knee range of motion (ROM) development
after surgery to the gastrocsoleus complex, in children with cerebral palsy (CP).
The analysis will compare knee and ankle ROM development between types and levels of surgery
performed to achieve lengthening of the gastrosoleus complex. Also, associations between
treatment outcomes and Gross Motor Classification System level (GMFCS-level) as well as
CP-subtype will be evaluated.
This is a retrospective longitudinal study on the effects of gastrocsoleus complex
lengthening on ROM development. The study is based on data from the Swedish Surveillance
Program for Cerebral Palsy (CPUP)
Description:
The objective of the current study is to analyze the development of ankle and knee range of
motion (ROM) related to type and level of surgery, age at surgery and CP-subtype.
Materials and methods
Scope of the analyses The analysis will compare knee and ankle ROM development between types
and levels of surgery performed to achieve lengthening of the gastrosoleus complex. Also,
associations between treatment outcomes and GMFCS-level as well as CP-subtype will be
evaluated.
Study Objectives To determine which, if any, surgery at muscular level (zone 1 and 2), open
surgery at tendinous level (zone 1) and percutaneous surgery at tendinous level (zone1) is
more advantageous in terms of subsequent knee and ankle ROM development. We hypothesize that
children with BSCP having surgery on the Achilles tendon is more prone to develop exaggerated
dorsiflexion in the ankle as well as knee contractures.
Endpoints
Primary endpoints
• Polynomial regression coefficients describing mean ankle ROM development over follow-up
time.
Secondary endpoints
Polynomial regression coefficients describing mean knee ROM development over follow-up time.
Composite endpoint: the proportion of patients with failure is defined as dorsiflexion of the
ankle ≥ 20°, or dorsiflexion of the ankle ≤ 0 degrees defining recurrent equinus. Subjects
will be followed from date of surgery to failure, the last assessment or end of study, 31 dec
2022.
Each component endpoint: Dorsiflexion of the ankle ≥ 20° dorsiflexion of the ankle ≤ 0
degrees or flexion contracture in the knee ≥10°, . Subjects will be followed from date of
primary surgery to failure, the last assessment or end of study, at year 2022.
General Study Design and Plan
This is a retrospective longitudinal superiority study on the effects of gastrocsoleus
complex lengthening on ROM development. The study is based on data from the Swedish
Surveillance Program for Cerebral Palsy (CPUP) registry that covers >95% of children with CP
in Sweden(Alriksson-Schmidt et al. 2017). In CPUP the diagnosis is confirmed at the age of 4
by a neuropaediatrician (Westbom et al. 2007, Hollung et al. 2020). All families and
guardians had given informed verbal consent to use data for research before inclusion in the
CPUP registry. In Sweden the multidisciplinary habilitation units are responsible for
children with CP and the child's physiotherapist perform regular assessments of clinical
variables necessary to evaluate the health status of the child, including range of motion
(ROM). Assessments are performed twice a year, once a year or every second year, depending on
the GMFCS-level and age. The assessments are performed in standardized position of the child
and goniometer arms according to the CPUP-manual (http://www.cpup.se).
Children treated with gastrocsoleus lengthening and at least 7-year follow-up will be
collected from the CPUP registry. Type and level of surgery performed will be validated from
the patient records of the child. Treated children will be stratified into 3 groups depending
on the type and level of gastrocsoleus surgery: (surgery at muscular level (Zone 1 and 2),
versus open surgery at tendinous level (Zone 1), versus percutaneous surgery at tendinous
level (Zone1)). Groups are then followed for a minimum of 7 years (last date of surgery
December31, 2014) or until possible reoperation with respect to ROM development. Depending on
the distribution of GMFCS levels of each child, this will entail a varying number of
measurements but typically around 8-10.
Between-group comparisons will be performed using mean ROM measurements over the entire
follow up by means of statistical modeling and hazard rate ratios (HR) and 95% confidence
intervals for complication rates.
Inclusion-Exclusion Criteria and General Study Population
All children born 2000 - 2011 who accepted inclusion into the CPUP follow-up program and
registry at any age from the year 2000 and onwards, with an isolated gastrocsoleus complex
lengthening performed between 2000 and 2013, to allow for at least 7 years of follow-up.
Children treated with other surgical procedures (soft tissue surgery to the foot, leg, knee
and hamstrings and osteotomies or arthrodesis to all lower extremity) or where the type of
gastrocsoleus lengthening could not be verified, will be excluded from the analysis but
described using summary statistics.
Children with no ROM measurements before or after surgery will be excluded as well as
children treated with intrathecal baclofen and dorsal selective rhizotomy.
Study Assessments
Frequency of ROM - measurements in CPUP: Children in GMFCS I < age 6 is assessed once every
year and children < age 6 in GMFCS II-V twice every year. Children in GMFCS I > age 6 is
assessed once every second year and children > age 6 in GMFCS II-V once every year.
Variables
Type and level of surgery (TLS) - Collected from the CPUP registry and validated through
patient records. Takes on the values "TAL", "Open TAL", "Gastrocsoleus lengthening in zone 1
and 2".
Two indicator variables derived from the TLS variable; one indicator for the "Open Z" group,
and one for the "Zone 1 and 2"; they take on the value 1 when a child is part of the group
and 0 when it is not.
GMFCS level - ordinal scale of levels I through V. Type of spastic CP - indicator variable
taking on the value 0 for USCP and 1 for BSCP and is empty for any other CP type.
Age at surgery - derived as the difference in years between date of surgery and birth date.
ROM measured by means of goniometer
Knee extension, takes on values between 0 and -90 Ankle dorsiflexion, takes on values between
-45 and 45 Three dichotomized failure variables
An indicator variable for knee extension ≤ -10° An indicator variable for ankle dorsiflexion
≥ 20° An indicator variable for ankle dorsiflexion ≤ 0 Spasticity measured according to the
Ashworth scale 0 to 4(Bohannon et al. 1987).
Sample Size
As this is a register-based study the sample size is set by design. From reviewing register
data, we guestimate that about 200 children will fulfill the inclusion criteria. With an
approximate standard deviation in ankle dorsiflexion of 11 degrees we will be able to detect
a mean difference between groups of 3.1 degrees, at the alpha level of 0.05 for a two-sided
T-test, with 80 percent power. This is below the minimal clinical important difference (MICD)
as well as below the measurement error of the goniometer, i.e. 5 degrees(Konor et al. 2012).
For failure rates, we guestimate that there will be approximately 100 events for our
secondary composite endpoint, which means we will be able to detect a hazard rate ratio of
1.8 at the alpha level of 0.05 for a log rank test, with a power of 0.8.
Timing of Analyses
Final analysis of the data will be initiated when
Data has been extracted from the CPUP register, including all visit up until the day of
extraction.
Type and level of surgery has been validated by a subject matter expert using patient
records.
Remaining data has been validated and cleaned by a subject matter expert. Data has been
transferred to an analysis file and submitted to the statistician.
Covariates and Subgroups
Covariates Covariates assumed to influence the primary and secondary endpoints are sex,
age-at-surgery, baseline knee and ankle ROM, baseline spasticity level: Ashworth, GMFCS level
and CP-subtype: unilateral spastic cerebral palsy (USCP) vs bilateral spastic cerebral palsy
(BSCP).
Confounders The set of covariates used for confounding adjustment is selected according to
the disjunctive cause criterion. Here, covariates that influence outcome and/or exposure,
i.e. choice of surgery, (age-at-surgery, baseline ROM, baseline spasticity, GMFCS-level) and
covariates assumed to influence exposure, i.e. choice of surgery, (age-at-surgery, baseline
ROM, baseline spasticity, GMFCS-level and subdiagnosis) will be included in the final model.
Subgroups Surgery results are hypothesized to depend on the specific CP-subtype of the child,
operationalized in the current study as either USCP or BSCP. Therefore, interaction analysis
intended to identify modifiers of treatment effects are performed using the CP-suptype,
grouped accordingly . However, this analysis will be exploratory in nature, as the study is
likely underpowered to detect these interaction effects.
Missing covariate data will be ignored if, when combined over all covariates, the proportion
missing in any covariate constitute less than 5 percent. If the missing proportion exceeds 5
percent, a sensitivity analysis will be performed using multiple imputation by chained
equations imputing missing covariate and outcome data.
Multiple Testing
No adjustment for multiplicity will be performed in the current study, as it is observational
and exploratory in nature(Bender et al. 2001).
Derived Variables
Two variables will be derived from study data
The primary surgical grouping variable will be created based on data extracted from the CPUP
register, where surgical information is recorded including date and type of surgery. Here all
data on all visits up until the day of extraction will be included. Type and level of surgery
have recently been validated. The patients will be divided into 3 subgroups depending on the
type and level of gastrocsoleus surgery.
The outcome variable, "failure", used for the secondary composite endpoint; "the proportion
of patients with failure", will be created using the dichotomized variables based on knee
extension, ankle dorsiflexion as defined, from any of the valid assessments for each study
participant. If any of the variables from any of the valid assessments indicated failure, the
variable takes on the value 1, if they did not, it takes on the value 0. Valid assessments
were defined as any assessment between the day of surgery and end of follow-up, that does not
follow a previous assessment where failure was detected.
Analyses
Baseline data will be summarized stratified by surgical group. N, Mean, Standard Deviation,
Minimum and Maximum will summarize continuous variables, whereas number and percent will
summarize categorical efficacy variables. ROM outcome data will be described using spagehetti
plots with added group means and survival outcomes described using failure curves. Outcome
data summaries will be stratified by subdiagnosis groups, USCP and BSCP, for the purpose of
exploratory analysis of differences in surgical results.
Analyses of continuous primary outcomes, knee flexion and ankle dorsiflexion, will be
performed using linear mixed effects modelling as described below. Differences in mean
development over follow-up time will be tested using a one tailed likelihood ratio test at
the 5% significance level.
Secondary endpoints will be evaluated using methods of survival analysis, such as Kaplan
Meier estimates of failure curves together with confidence intervals and Cox regression
analyses, as described below, will be tested using a one tailed likelihood ratio test at the
5% significance level.
Variation in differences between surgical groups comparing USCP and BSCP subgroups, will be
explored in an interaction analysis using linear mixed effects regression analysis, also
defined below.
