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

• ClinicalTrials.gov Identifier: NCT02546999
• Recruitment Status: Completed
• First Posted: September 11, 2015
• Last Update Posted: January 11, 2022
• Sponsor: St. Olavs Hospital
• Collaborators: 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
• Information provided by (Responsible Party): St. Olavs Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cerebral Palsy; Muscle Spasticity	Drug: botox; Drug: placebo	Phase 4

Detailed Description:

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 61 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
• Study Start Date: September 2015
• Actual Primary Completion Date: October 15, 2021
• Actual Study Completion Date: October 15, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: botox; 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.	Drug: botox; The agent will be given only once at point zero in the time scheme for the project.; Other Name: botulinum toxin A
Placebo Comparator: placebo; Sterile 0,9% Sodium Chloride injection The placebo dose will be the same dose in ml as the reconstituted Botox	Drug: placebo; The agent will be given only once at point zero in the time scheme for the project.; Other Name: sodium chloride

Outcome Measures

Primary Outcome Measures :

1. Energy cost during walking [ Time Frame: 6 months ]
   Will be measured by a 5 minutes walk test (overground walking at comfortable speed) with simultaneous gas exchange.

Secondary Outcome Measures :

1. Activity [ Time Frame: 6 months ]
   Daily activity, measured by a body worn accelerometer over 4 periods of 7 consecutive days.
2. Perceived improved performance and satisfaction [ Time Frame: 6 months ]
   Assessed by The Canadian Occupational Performance Measure
3. Recurrent musculoskeletal pain [ Time Frame: 6 months ]
   Assessed by the Child Health Questionnaire (Norwegian version), and elements from the Brief Pain Inventory (Norwegian version)
4. Walking capacity [ Time Frame: 6 months ]
   Assessed with OMNI-RPE (OMNI Rating of Perceived Exertion) and a 1 Minute walk test at maximal gait speed

Other Outcome Measures:

1. Gait pattern [ Time Frame: 6 months ]
   3D gait analysis will be carried out on a subset of participants.
2. Ankle strength [ Time Frame: 6 months ]
   Isometric strength of ankle plantar- and dorsiflexors, will be made on a subset of the participants.
3. Spasticity [ Time Frame: 6 months ]
   Will be assessed by the use of Tardieu scale. On a subset of participants, concurrent velocity, position and muscle activation will be measured.
4. Self-perceived effect on walking [ Time Frame: 4 weeks ]
   A qualitative interview will be conducted on a subset of the participants at baseline and post 1 (4 weeks post injection)

Eligibility Criteria

• Ages Eligible for Study: 4 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

France

Lenval Foundation Children's Hospital

Nice, France

Norway

Haukeland University Hospital

Bergen, Norway, 5000

Oslo University Hospital

Oslo, Norway

University Hospital of North-Norway

Tromsø, Norway

Department of Orthopaedic Surgery, St. Olavs University Hospital

Trondheim, Norway

Vestfold Hospital trust

Tønsberg, Norway

Poland

Mazowieckie Centrum Neuropsychiatrii, Zagorze

Warsaw, Poland

Sponsors and Collaborators

St. Olavs Hospital

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

Investigators

• Study Director: Petter Aadahl, md prof; St. Olavs Hospital

More Information

Publications:

Brændvik 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.

• Responsible Party: St. Olavs Hospital
• ClinicalTrials.gov Identifier: NCT02546999
• Other Study ID Numbers: 2013/1195; 2014-002539-32 ( EudraCT Number )
• First Posted: September 11, 2015
• Last Update Posted: January 11, 2022
• Last Verified: January 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by St. Olavs Hospital:

Botulinum Toxins, Type A; Walking

Additional relevant MeSH terms:

Botulinum Toxins; Botulinum Toxins, Type A; Muscle Spasticity; Cerebral Palsy; Neurologic Manifestations; Nervous System Diseases; Brain Damage, Chronic; Brain Diseases; Central Nervous System Diseases; Muscular Diseases; Musculoskeletal Diseases; Muscle Hypertonia; Neuromuscular Manifestations; Acetylcholine Release Inhibitors; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Neurotransmitter Agents; Physiological Effects of Drugs; Neuromuscular Agents; Peripheral Nervous System Agents