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Early Intervention in Infants With Cerebral Palsy (CONTRACT)

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ClinicalTrials.gov Identifier: NCT04250454
Recruitment Status : Not yet recruiting
First Posted : January 31, 2020
Last Update Posted : April 22, 2020
Sponsor:
Collaborator:
Elsass Foundation
Information provided by (Responsible Party):
Maria Willerslev-Olsen, University of Copenhagen

Tracking Information
First Submitted Date  ICMJE January 29, 2020
First Posted Date  ICMJE January 31, 2020
Last Update Posted Date April 22, 2020
Estimated Study Start Date  ICMJE June 2020
Estimated Primary Completion Date December 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 29, 2020)
Muscle growth rate [ Time Frame: 48 months ]
The primary outcome measure is the rate of muscle growth in the children evaluated from the start of the study until the final end point measurement at 48 month. Researchers with high experience in the use of ultrasound (US) examines the entire length of the MG muscle to assess muscle volume. Height, weight, circumference of the widest part of the crus and fibula length is measured. US is performed on the most affected leg or if possible, on both legs, with the infant's ankle fixed in a neutral angle. To estimate muscle thickness and fascicle length one recording is performed with the probe positioned longitudinally at the mid-belly of the MG, with the infant's ankle fixed in a 90-degree angle. The probe was hand-held and fixed vertically with the lower leg for all images.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 29, 2020)
Evaluation of passive stiffness and reflex stiffness [ Time Frame: 48 months ]
Passive and reflex-mediated stiffness of the ankle plantar-flexors will be objectively assessed according to the methods described in Lorentzen et al. (Lorentzen et al 2010) and Willerslev-Olsen et al (Willerslev-Olsen et al 2018). Data will be sampled at a rate of 512Hz and transferred to a computer via Bluetooth for further analysis in Matlab (Mathworks, Natick, MA, USA). With the use of the device the researcher will move the ankle joint from maximal plantar flexed position to maximal dorsiflexion in order for the devise to estimate the ROM. Manual movements will then be performed by the researcher at either a slow velocity (~<20deg/sec) or as fast as possible through the entire ROM. EMG activity is sampled from bipolar surface EMG electrodes (0.5mm diameter, 2cm between electrodes; Ambu Blue Sensor NF-00-S/12; Ambu, Ballerup, Denmark) placed over the soleus muscle at the distal part of the gastrocnemius muscles and the Tibialis Anterior muscle. The device is equipped with strain
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Early Intervention in Infants With Cerebral Palsy
Official Title  ICMJE Protocol of a Two-group Open-label Randomized Clinical Trial With Blinded Assessment for Prevention of Contractures in Infants With High Risk of Cerebral Palsy.
Brief Summary Contractures are a frequent cause of reduced mobility in children with Cerebral palsy (CP) already at the age of 2-3 years. Reduced muscle use and muscle growth have been suggested as key factors in the development of contractures, suggesting that efficient early prevention will have to involve stimuli that can facilitate muscle growth already before the age of 1 year. The present study protocol was developed to assess the effectiveness of an early intervention program, CONTRACT, on muscle growth and mobility in children at very high risk of CP compared with best standard care.
Detailed Description

Cerebral palsy (CP) is the most common cause of motor and cognitive disabilities in childhood affecting around 1 out of 500 newborn infants. Contractures and joint deformities are frequent complications, which limit the functional abilities of the children from an early age and are a main life-long challenge for social integration and participation. The functional limitations imposed by the combination of weak paretic muscles and contractures in early childhood also reduce the child´s possibilities of active exploration of its environment and social interaction with its peers. This may have secondary impact on cognitive development and cognitive performance later in life.

Therefore, early intervention to prevent contractures is pivotal in helping motor and cognitive development in children with CP and thereby enable social integration and optimal cognitive and motor performance throughout their life time. The importance of prevention of contractures is also emphasized by the realization that none of the surgical, medical or physical therapies that we have available provide an efficient treatment of contractures once they have become manifest and interfere with joint mobility.

There is growing evidence that reduced growth of muscles is a key factor in the development of contractures. If muscles fail to grow at the same rate as bones they will be subjected to abnormal tension. This and the lack of muscle use may stimulate growth of connective tissue in the muscles causing a stiffer extracellular matrix. Growth of the medial gastrocnemius muscle in infants with CP deviates from that of typically developing (TD) infants around the age of 12-15 month. Pathologically increased stiffness of the muscle tissue is seen some months later consistent with a causal relation between reduced growth and increased stiffness. These findings indicate that efficient prevention of contractures will have to take place before the age of one years and will need to focus on stimulation of muscle growth as a key factor.

Muscle growth depends crucially on muscle use, which is the exact challenge that infants with CP are faced with. How do we get a child who has difficulty activating its muscles to do so when that child has no prior experience of using its muscles and limbs and has little verbal understanding of what it is we want it to do? There is now evidence to support that the early development of the motor system is highly plastic and depends crucially on activity-dependent interaction with the environment. Experimental evidence from kittens and rodents support the existence of a sensitive period soon after birth where descending connections from the motor cortex to the spinal cord are re-organized in an activity-dependent manner. Functional deficits in mature animals who have received central motor lesions prior to or in relation to birth appear to depend on the extent to which this activity-dependent re-organization takes place during the sensitive period. It is unknown whether a similar sensitive period exists in humans, but there is reason to believe that the first 5-6 month after birth constitute a period where the motor system undergo rapid changes that may resemble the sensitive period in rodents and kittens. This period is characterized in humans by so-called fidgety movements (FM) which may reflect a ´calibration´ of the sensori-motor system, where descending connections are re-organized similar to what is seen in animals. Children also acquire the ability of goal-directed movements using visual feedback during this period, which may be related to maturation of the connections from motor cortex to the spinal cord. There is also evidence that 5-6 month old children have acquired a sense of agency over their own movements and a basic understanding of how they may use their body to control their environment. Sensory feedback and reward that are associated to successful behavior play an important role in this early establishment of movement control. Thelen & Fissher showed that when infants at an very early age can activate a mobile by own spontaneous movements, movement of the infant increased. The initial 5-6 month after term may therefore provide a window of opportunity where it is possible to facilitate normal development of movement and thereby also prevent contractures through the concomitant muscle growth-stimulus. An intervention in which infants in that age group are stimulated to move by their parents at home under supervision by therapists has indeed been demonstrated to improve motor development in infants with high risk of cerebral palsy. Home-training technology that may facilitate the training and the interaction between therapists and the families are also now becoming available and have shown promising effects on motor development in preterm infants . Intensive goal-oriented training involving experiences of success and frequent reward within the first 5-6 month is therefore central in the intervention that we propose in the present protocol for prevention of contractures in infants at high risk of developing CP.

Muscle growth does not only depend on neural and mechanical stimuli, but also on nutritional and metabolic stimuli. It is therefore important also to consider the nutritional status of the infant and especially whether nutrients that have a specific muscle growth promoting effect are delivered in sufficient quantity to the infant either through breast feeding or breast milk substitutes. The polyunsaturated fatty acid, Docosahexaenic acid (DHA) is considered essential for maturation of the developing brain and may also facilitate muscle growth. Supplementation with DHA is not recommended for healthy term-born infants, but may be important for development of preterm infants and especially for infants with brain lesion. In addition, Vitamin D also plays a role in regulating muscle growth and deficiency of Vitamin D has been suggested to be of importance in neurodevelopmental disorders. It is not clear whether early Vitamin D supplementation has beneficial effects on neurodevelopment and muscle growth, but is recommended for newborns in countries with limited sun exposure because of its beneficial effects on bone metabolism. Information about the nutritional status of mother and infant and subsequent supplementation could therefore be of importance to enhance facilitation of muscle growth in the infants.

It should also be considered whether stimuli that may substitute the neural activation of the muscles such as electrical stimulation may be used when the child is not otherwise active (for instance during sleep) to help maintain muscle growth. Electrical muscle stimulation has been shown to diminish muscle atrophy in adults. The facilitation of muscle growth may help to postpone contracture development until communication with the (older) infant is easier and training goals may therefore be achieved more easily.

The purpose of the present paper is consequently to describe a study protocol for a two-group open-label randomized clinical trial with blinded assessment of an early intervention program directed towards prevention of contractures.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Cerebral Palsy
Intervention  ICMJE Behavioral: CONTRACT

The intervention will consist of four elements:

  1. Personal meeting - detailed information to the parents before the age of 15 weeks CA (1-3 days)
  2. Home Activity Plan (HAP)
  3. Home-based Feedback training
  4. Electrical muscle stimulation

Combination of these elements has been chosen in order to ensure that optimal muscle growth is achieved through multi-modal stimulation of the motor and cognitive development of the child.

Study Arms  ICMJE
  • No Intervention: Control
    Elsass Standard Care
  • Active Comparator: Intervention
    Enriched eviroment, Feed back training, Electrical stimulation, nutrition
    Intervention: Behavioral: CONTRACT
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: January 29, 2020)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2029
Estimated Primary Completion Date December 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Infants younger than 17 weeks CA with suspicion of brain lesion determined from a medical assessment, by MRI or ultrasound scan or abnormal general movements determined as part of General Movement Asessement (GMA) will be included. The brain lesion should be rated severe enough by the clinician to have informed the parents of the associated risk of CP.

Exclusion Criteria:

  • Infants otherwise eligible but with severe genetic abnormalties, severe heart problems, metabolic diseases, or still hospitalized will not be selected for the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 8 Weeks to 20 Weeks   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jens Nielsen, Professor +4528757450 jbnielsen@sund.ku.dk
Contact: Maria Willerslev-Olsen, Ph.D +4522834005 mwo@elsassfonden.dk
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04250454
Other Study ID Numbers  ICMJE CONTRACT333
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: The university of Copenhagen has a data server available for open acces to research data. We aim to make all annonymised data available through the server as soon as the study has been published in a peer reviewed scientific journal.
Supporting Materials: Study Protocol
Supporting Materials: Clinical Study Report (CSR)
Time Frame: When the study has been published in a peer reviewed scientific journal.
Access Criteria: University affiliation
Responsible Party Maria Willerslev-Olsen, University of Copenhagen
Study Sponsor  ICMJE University of Copenhagen
Collaborators  ICMJE Elsass Foundation
Investigators  ICMJE Not Provided
PRS Account University of Copenhagen
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP