Upper-limb Active Function and Botulinum Toxin A

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Toulouse

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Decision date (initial)

2024-10-31

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-518147-37-00

EudraCT number

2018-000941-38

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Evaluer l’effet d’injections de toxine botulique A dans les fléchisseurs du coude sur la réduction des cocontractions spastiques au cours d’un mouvement d’extension active de coude chez des patients hémiplégiques vasculaires chroniques.

Secondary objectives 9

1. Comparison of ICCS between T1 (before TBA injection) and T2 (4 weeks after TBA injection into the elbow flexors) for two subgroups of patients: those with ICCS greater than non-pathological values, and those with ICCS consistent with non-pathological values ​​(values ​​of matched control subjects).
2. To assess the stability of the ICCS measurement over time, without intercurrent intervention, by comparing the ICCS measurement of the paretic arm between T0 (Visit carried out between 15 days and 1 month before T1) and T1: this is a study of the variability of the ICCS over time.
3. Establish an efficacy curve of TBA on the patient's experience in terms of achieving objectives, as well as on the reduction of CCS and spasticity. To establish this efficacy curve, clinical intercurrent assessments will be carried out every 3 weeks from the first TBA injection (T1) until the next injection (T3).
4. Determine a range of non-pathological values ​​of the ICCS. This range of non-pathological values ​​will allow a subgroup analysis to be performed, to situate the level of increase in the ICCS in patients with brain damage on the paretic side and on the non-paretic side at T0, T1, T2, T3 and T6, and to characterize a possible evolution towards a value considered non-pathological.
5. To study the changes over time of the following parameters: - Clinical parameters: ICCS, spasticity (Tardieu) and strength (Held) of the elbow flexors; motor skills (Fugl-Meyer); function (WMFT); limitation of active amplitude of elbow extension (LAMA); - Spectral modulation of cortical activity (EEG): ipsilesional ERD, ERS quotient and amount of interhemispheric coherence. - Cortico-spinal excitability (curve of variation of MEP amplitude as a function of stimulation intensity) assessed by TMS. Comparisons will be made between T1 (before TBA) and T2 (efficacy period at 4 weeks after TBA injection) to study the effect of TBA injection, between T1 and T3 (18 weeks after TBA injection) to study short-term plasticity, and between T1 and T6 (18 weeks after the 3rd TBA injection) to study long-term plasticity. A repeated measures analysis will assess the effect size of botulinum toxin injection in relation to short- and long-term plasticity.
6. Describe the link between ICCS and spasticity (Tardieu) at T0, T1, T2, T3 and T6
7. To describe the association between ICCS and spasticity on the one hand, and the parameters LAMA, WMFT, ipsilesional ERD, ERS quotient, interhemispheric coherence quantity, cortical excitability and motor pathway lesions on the other hand at T1, T2, T3 and T6.
8. To describe the association between the variation of the ICCS and spasticity on the one hand, and the variation of the parameters LAMA, WMFT, ipsilesional ERD, ERS quotient and quantity of inter-hemispheric coherence on the other hand between T1-T2 (TBA effect), T1-T3 (short-term plasticity), and T1-T6 (long-term plasticity).
9. For objectives 5 to 8, a subgroup analysis will also be performed to separately evaluate patients with an ICCS higher than non-pathological values ​​and those with an ICCS consistent with non-pathological values ​​(i.e. similar to those of the group of matched healthy control subjects). Knowledge of the integrity or not of the encephalic motor pathways (T1 and diffusion MRI) will allow for better analysis of EEG activations (30) and to place TMS above the motor cortex.

Conditions and MedDRA coding

Stroke

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Patient group: Ischemic or hemorrhagic stroke of more than 6 months, of cortical and/or subcortical location
2. Patient group: Indication for performing a TBA injection in the elbow flexor muscles according to the usual clinical criteria: presence of a functional or aesthetic complaint expressed by the patient, linked to muscular hyperactivity (spasticity or co-contraction) on the elbow flexor muscles, and requiring focal treatment by injection of botulinum toxin
3. Patient group: Being prescribed the molecule abobotulinumtoxinA (DYSPORT®, Ipsen-Pharma)
4. Patient group: Possibility of active elbow extension of at least 20°
5. Patient group: Limitation of active elbow extension movement by at least 15° or performance of a complete movement with a speed reduced by 50%
6. Patient group: TBA-naïve patients or more than 4 months after a first TBA injection, targeting the elbow flexors
7. Patient group: Age > 18 years
8. Patient group: Signing of informed consent
9. Patient group: Patient affiliated to a social security scheme.
10. Control group: Age > 18 years
11. Control group: Signing of informed consent.

Exclusion criteria 16

1. Patient group: Passive limitation of elbow extension > 30°
2. Patient group: Pain when performing active elbow flexion/extension movements
3. Patient group: Cognitive disorder limiting the understanding of three basic instructions (test type of the 3 MMS papers test)
4. Patient group: Boston Diagnostic Severity Aphasia Examination score ≤3
5. Patient group: Progressive or decompensated neurological pathology
6. Patient group: Unstable epilepsy
7. Patient group: General contraindication to the use of botulinum toxin: hypersensitivity to the active substance (toxin-haemagglutinin complex BoTX-A) or to one of the excipients (albumin solution), history of myasthenia, Lambert Eaton syndrome, history of neuromuscular disease, surgery with curarization for less than 1 month, treatment with aminoglycosides, aminoquinolines, cyclosporine or anticholinesterases, History or presence of swallowing disorders (choking on solids or liquids), History or presence of chronic respiratory disorders (known respiratory failure), presence of a skin infection or inflammation at the injection site
8. Patient group: Anticoagulant treatment at curative dose or haemostasis disorder (prolonged bleeding time) contraindicating intramuscular injections
9. Patient group: Claustrophobia or metallic foreign bodies contraindicating the performance of an MRI
10. Patient group: Legal incapacity (judicial protection, curatorship, guardianship)
11. Patient group: Pregnant or breastfeeding women
12. Patient group: Women who want to become pregnant within 18 months
13. Patient group: Premenopausal women (menopause being defined by an absence of menstruation for at least 12 months without medical intervention) not using one of the following methods of contraception considered to be very reliable: intrauterine device, estrogen-progestin or progestin contraception inhibiting ovulation delivered by an implanted subcutaneous device, or tubal ligation.
14. Control group: History or progressive orthopedic or neurological damage to the upper limbs
15. Control group: Subject expert in a sport requiring intensive use of the upper limbs (competition, at least departmental level)
16. Control group: Legal incapacity (judicial protection, curatorship, guardianship).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Measurement of the spastic cocontraction index (ICCS) during active elbow extension movement, obtained from the EMG signal of the elbow extensor and flexor muscles on the paretic side, between T1 and T2 (before versus 4 weeks after TBA injection)

Secondary endpoints 7

1. Spasticity of the elbow flexors according to Tardieu
2. Limitation of the active movement angle (LAMA) of elbow extension
3. Fugl-Meyer score (motor selectivity)
4. Functional abilities with the Wolf Motor Function Test (WMFT) score
5. EEG quantification of bilateral cortical activity during movement (real or imagined) to calculate the following indices: o desynchronization index (ERD) identifying hyperactivity in the ipsilesional cortex; o synchronization index quotient (ERS) to assess interhemispheric inhibition (inhibition laterality coefficient) o amount of interhemispheric coherence
6. Corticospinal excitability (curve of variation of MEP amplitude as a function of stimulation intensity) assessed by TMS
7. Anatomical lesions of the motor pathways (motor cortex and descending motor pathways) obtained from anatomical (T1) and diffusion-weighted MRI

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Toulouse

Sponsor organisation

Centre Hospitalier Universitaire De Toulouse

Address

2 Rue Viguerie

City

Toulouse

Postcode

31300

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Toulouse

Contact name

David GASQ

Public contact point

Organisation

Centre Hospitalier Universitaire De Toulouse

Contact name

Audrey TOMASIK

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 7 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications