Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy? (WE)

Norwegian University of Science and Technology, The Hospital of Vestfold, University Hospital of North Norway, Oslo University Hospital, Haukeland University Hospital, Fondation Lenval, Mazowieckie Centrum Neuropsychiatrii, Warszawa

In Norway, about 60% of all children with cerebral palsy (CP) are being treated with botulinum toxin A (BoNT-A) at 6 years of age, mainly in the legs. Despite this widespread use of the drug, the evidence for a positive effect on walking is insufficient. Moreover, large variation in effect is seen by clinicians. The main objective of the present study is to investigate whether injections with BoNT-A in the calf muscles make walking easier in children with spastic CP within 6 months, reflected by reduced energy cost during walking.

This is an industry independent multicentre clinical trial. The randomization will be done by a computer number random generator and will be carried out and held by the unit of Applied Clinical Research at NTNU. Two strata: age and center. The study will be conducted according to Consort guidelines and guidelines for Good Clinical Practice. It is approved by the local Ethical committee (REK Nord) and the Norwegian Drug Agency. Primary research question is: Do BoNT-A injections in the calf muscles make walking easier in children with CP? Secondary research questions: 1) Do BoNT-A injections in the calf muscles increase activity? 2) Do BoNT-A injections in the calf muscles improve walking capacity 3) Do BoNT-A injections in the calf muscles improve perceived performance and satisfaction related to mobility tasks and 4) Do BoNT-A injections in the calf muscles reduce recurrent musculoskeletal pain? The participants will receive the treatment with both local anaesthesia and conscious sedation with oral or nasal benzodiazepines.Outcome measures are made at baseline and 4, 12 and 24 weeks after treatment, with primary endpoint at 12 weeks. Data will be analyzed using a linear mixed model (LMM). The difference in change in the primary outcome measure (energy cost during walking) between the treated and placebo groups will be done using a post hoc test following the LMM. Secondary, the same model will be used to test for an effect also at 4 and 24 weeks post injection. Age, GMFCS Level, number of prior BoNT-A treatments and study center will be considered as potential covariates. A substudy will be conducted within the frames of this RCT, aiming to identify characteristics of those who respond to the treatment compared to those who do not respond (outcome measures 6, 7,8 and 9).

Botox® (onabotulinumtoxin A),injections in the calf muscles. The total maximum body dose of Botox® in this study will be 420 Units. Maximum dose per injection site will be 50 Units. The gastrocnemius muscle will receive 5-6 Units Botox® per kg, but maximum 180 Units in each leg. The soleus muscle will receive 2 Units Botox® per kg with maximum dose 60 Units in each leg. Dilution: 100 Units Botox® in 1 ml 0.9% sodium chloride, and the maximum volume per injection site will be 0,5 ml in both study groups. The route of administration is intramuscular injection.

Sterile 0,9% Sodium Chloride injection The placebo dose will be the same dose in ml as the reconstituted Botox

Will be measured by a 5 minutes walk test (overground walking at comfortable speed) with simultaneous gas exchange.

Assessed by the Child Health Questionnaire (Norwegian version), and elements from the Brief Pain Inventory (Norwegian version)

Assessed with OMNI-RPE (OMNI Rating of Perceived Exertion) and a 1 Minute walk test at maximal gait speed

Will be assessed by the use of Tardieu scale. On a subset of participants, concurrent velocity, position and muscle activation will be measured.

A qualitative interview will be conducted on a subset of the participants at baseline and post 1 (4 weeks post injection)

Inclusion criteria: Diagnosed with unilateral or bilateral CP GMFCS level I and II Signed informed consent expected cooperation of the patients for the treatment and follow up. Exclusion Criteria: BoNT-A injections in the lower legs in the last 6 months before intervention history of adverse reactions to BoNT-A Known hypersensitivity to BoNT-A or to any of the excipients Orthopedic surgery in the legs in the last 2 years Major cognitive impairments (must be able to take verbal instructions and conduct the test procedure) infection at the proposed injection site(s) Subclinical or clinical evidence of defective neuromuscular transmission e.g. myasthenia gravis or Lambert-Eaton Syndrome in patients with peripheral motor neuropathic diseases (e.g. amyotrophic lateral sclerosis or motor neuropathy) other underlying neurological disorders that may be affected by BoNT-A injections Use of aminoglycoside antibiotics or spectinomycin, or other medicinal products that interfere with neuromuscular transmission (e.g. neuromuscular blocking agents) Pregnant or breast-feeding Childbearing potential not using contraception any reason why, in the opinion of the investigator, the patient should not participate Children needing deep sedation under treatment

Braendvik SM, Roeleveld K, Andersen GL, Raftemo AE, Ramstad K, Majkic-Tajsic J, Lamvik T, Lund B, Follestad T, Vik T. The WE-Study: does botulinum toxin A make walking easier in children with cerebral palsy?: Study protocol for a randomized controlled trial. Trials. 2017 Feb 6;18(1):58. doi: 10.1186/s13063-016-1772-8.