BacloTox: Study of the Effects on Motor Recovery of Early Post-stroke Spasticity Treatment

Sponsor

University Hospital, Toulouse (Other)

Overall Status

Completed

CT.gov ID

NCT02462317

Collaborator

Merz Pharmaceuticals GmbH (Industry)

184

Enrollment

Locations

Arms

68.3

Actual Duration (Months)

9.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Stroke is the first cause of motor impairment and disability in adults. Then the main objective of rehabilitation during the first six months following stroke is to facilitate motor recovery. Many post-stroke hemiplegics develop spasticity which is responsible for an increase of disability. Then antispastic drugs are frequently prescribed to the patients even during the post-stroke recovery phase. Until recently most of french patients were treated by oral tablets of baclofen. Now the number of patients receiving intramuscular injections of botulinum A toxin is increasing. However in the literature, these drugs have been tested in post-stroke spasticity during the chronicle phase, after the sixth month and their action on motor recovery remain largely unknown. Then it is necessary to evaluate more accurately the effects of its drugs on motor recovery. The main criterion of its study is the time course of Fugl-Meyer Motor Assessment (FMA). Spastic patients with a single stroke, since less than two months, will be included in the try. They receive at the same time oral tablets for five months and intramuscular injections. Patients are randomized in three arms planned with a distribution balanced by group of 5 patients with a 2 -2- 1 model: botulinum toxin and placebo baclofen (120 patients), oral baclofen and placebo botulinum toxin (120 patients), placebo baclofen and placebo botulinum toxin (60 patients). The FMA score will be assessed before treatment start, one month and three months later. Spasticity, functional abilities, capacity in the activities of daily life, pain and quality of life will be also assessed during the study with Tardieu score, Rivermead Motor Assessment scale, Barthel index, Rankin score, Visual Analogic Scale and Reintegration to Normal Life Index respectively. A positive difference of 12 points in the time course of FMA in the botulinum toxin group in comparison with the baclofen group will be considered as the minimum relevant effect. 300 patients have been planned to be included in 20 centers during the 2 years of trial.

Condition or Disease	Intervention/Treatment	Phase
Muscle Spasticity	Drug: botulinum A toxin Drug: Baclofen Drug: Placebo toxin Drug: placebo baclofen	Phase 4

Detailed Description

Background: Stroke is the first cause of motor impairment and disability in adults. 80% of post-stroke survivors have a motor weakness resulting in hemiplegia. Post-stroke patients partially recover from their motor impairments . These patients reach their maximum motor score round the first 20 weeks. In all cases, motor recovery period is considered completed beyond the sixth month. There is a consensus of epidemiological studies and of more fundamental works on brain plasticity, for the positive effect of rehabilitation on post stroke motor recovery. Then the main objective of rehabilitation during the first six months following stroke is to facilitate motor recovery.

There are many arguments in animals and humans for the pharmacological modulation of post-stroke motor recovery. In animals, the experimental data suggesting efficacy of amphetamine in motor recovery after brain injury, are numerous. The administration of amphetamine in rats dramatically improves motor recovery after brain injury. This action appears to be related to the α noradrenergic activity of amphetamines and their properties of norepinephrine precursor. In contrast molecules that reduce the release of norepinephrine, which increase its metabolism, or blocking its post-synaptic effects such as gabaergic drugs or clonidine have a deleterious effect on motor recovery after brain injury.

In humans, the results of studies concerning the action of amphetamine are much more contrasted. A study in functional imaging has shown that a single dose of methylphenidate was able to modulate brain plasticity in post-stroke patients by increasing the activity of substitute neural networks in the lesioned hemisphere. However, if some clinical studies confirm the positive result, others at the opposite show no behavioral effect on recovery as compared to placebo group.

In humans, there is also some arguments for the positive effect of serotonin reuptake inhibitors (SRI) drugs. Functional neuroimaging studies have shown the SRI modulating action on brain plasticity of sensorimotor cortex. Single dose SRI is responsible for an increase in neuronal activity of sensorimotor cortex correlated with an improvement in behavioral tests in healthy subjects as in post-stroke patients. In small clinical trial, Dam et al has shown a positive effect on motor recovery after prescription of fluoxetine associated with rehabilitation, irrespective of antidepressant activity of this molecule. A randomized controlled multicentre trial (FLAME), comparing the effects on post-stroke motor recovery assessed by the Fugl-Meyer score, of a treatment with fluoxetine or with placebo was published. This trial confirms the positive effect of fluoxetine on recovery of motor function in post stroke hemiplegics.

Regarding the deleterious drug GABAergic and especially diazepam has been tested in animal models of recovery after brain injury. The administration of these molecules has a negative impact on functional recovery. Golsdtein studied the impact on motor recovery of prescription of GABAergic drugs with benzodiazepine or neuroleptic during the recovery phase of brain injured patients. It shows that regardless of the indications of drugs there is a negative effect on the recovery of patients.

Conjointly 15% to 40% of post-stroke hemiplegics develop a spasticity which is responsible for an increase of disability. Spasticity is a symptom characterized by an increase of resistance to passive mobilization in relation to a post-stroke exaggeration of spinal reflexes and to a later muscular component. Usual antispastic drugs have an action on the reflex component and not on the muscular one. Then many physicians want to treat spasticity early after stroke even during the recovery phase, before development of the muscular changes. Until recently in France, most of patients were treated by oral tablets of baclofen. Now the number of patients receiving intramuscular injections of botulinum A toxin is increasing. However in the literature, these drugs have been tested in post-stroke spasticity during chronicle phase, after the sixth month and their action on motor recovery remain largely unknown. Botulinum toxin can increase weakness of injected muscles and baclofen belongs to the family of gabaergic drugs which have demonstrated a deleterious effect in animal models of recovery.

• Purpose: In the specific population of post-stroke hemiplegics, antispastic drugs should reduce spasticity while at least respecting functional recovery. Then it study wants to compare the effect on motor recovery of two usual antispastic treatments administrated before the end of second month after stroke: botulinum toxin versus oral baclofen. Our hypothesis is that botulinum toxin is more respectful of motor recovery than Baclofen and may be promotes the functional recovery.

Study Design

Study Type:

Interventional

Actual Enrollment :

184 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Supportive Care

Official Title:

Study of the Effects on Motor Recovery of Early Post-stroke Spasticity Treatment: Double Blinded Comparison Between Botulinum Toxin and Baclofen.

Actual Study Start Date :

Apr 1, 2015

Actual Primary Completion Date :

Dec 9, 2019

Actual Study Completion Date :

Dec 9, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: botulinum A toxin Patients are injected with botulinum toxin in a standardized protocol and received placebo baclofen tablets (120 patients)	Drug: botulinum A toxin botulinum toxin injection Other Names: Drug injection Drug: placebo baclofen placebo oral tablet Other Names: placebo drug
Active Comparator: Baclofen Patients are injected with placebo in a standardized protocol and received baclofen tablets (120 patients)	Drug: Baclofen baclofen oral tablet Other Names: Drug Drug: Placebo toxin placebo injection Other Names: placebo injection
Placebo Comparator: double Placebo Patients are injected with placebo in a standardized protocol and received placebo baclofen tablets (60 patients)	Drug: Placebo toxin placebo injection Other Names: placebo injection Drug: placebo baclofen placebo oral tablet Other Names: placebo drug

Arm

Intervention/Treatment

Active Comparator: botulinum A toxin

Patients are injected with botulinum toxin in a standardized protocol and received placebo baclofen tablets (120 patients)

Drug: botulinum A toxin

botulinum toxin injection

Other Names:

Drug injection

Drug: placebo baclofen

placebo oral tablet

Other Names:

placebo drug

Active Comparator: Baclofen

Patients are injected with placebo in a standardized protocol and received baclofen tablets (120 patients)

Drug: Baclofen

baclofen oral tablet

Other Names:

Drug

Drug: Placebo toxin

placebo injection

Other Names:

placebo injection

Placebo Comparator: double Placebo

Patients are injected with placebo in a standardized protocol and received placebo baclofen tablets (60 patients)

Drug: Placebo toxin

placebo injection

Other Names:

placebo injection

Drug: placebo baclofen

placebo oral tablet

Other Names:

placebo drug

Outcome Measures

Primary Outcome Measures

Motor recovery with time course of Fugl-Meyer Assessment scale [month 3]
A positive difference of 12 points in the time of course of Fugl-Meyer motor Assessment scale (FMA) from inclusion to the third month, between the results obtained in the botulinum toxin group and those of the baclofen group will be considered as the minimum relevant effect.

Secondary Outcome Measures

none inferiority of motor recovery with time course of Fugl-Meyer Assessment scale [month 3]
A none inferiority of the FMA time course between the results of the botulinum toxin group and the placebo group will be researched.
Spasticity with Tardieu scale [Month 1 and 3]
A comparison of efficacy of the two treatments on spastic symptoms using Tardieu scale.
Function with Rivermead Motor Assessment score, [month 3]
Functional impact of early treatment of post-stroke spasticity: comparison of changes in the Rivermead Motor Assessment score during the three months of protocol between all groups.
Quality of life : Reintegration to Normal Life Index [month 3]
Pain : Visual Analogic Scale [Month 1 and 3]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

First single stroke ischaemic or haemorrhagic responsible of an hemiplegia
Stoke since less than 2 month
A sufficient understood
A spasticity : a Tardieu score upper or equal to 2 on at least one of the following muscle-triceps surae, flexors of fingers, of wrist and of elbow
A free consent

Exclusion Criteria:

Previous antispastic drugs
Contraindication for baclofen or toxin
Antecedent of epileptic seizure
Psychiatric antecedent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospital, Toulouse	Toulouse	Haute-Garonne	France	31059
2	CHU Jean Minjoz	Besançon		France	25030
3	Groupe Pellegrin, University Hospital Bordeaux	Bordeaux		France	33076
4	CHRU de Brest	Brest		France	29609
5	Centre de rééducation MARIENIA	Cambo Les Bains		France	64250
6	Centre Bouffard- Vercelli	Cerbere		France	66290
7	University Hospital Dijon	Dijon		France	21079
8	University Hospital Grenoble	Echirolles		France	38434
9	Hôpital R. Poincarré	Garches		France	92380
10	l'Institut Hélio Marin de la côte d'azur	Hyères		France	67082
11	Hôpital Swynghedauw	Lille		France	59000
12	Hôpital J Rebeyrol	Limoges		France	87042
13	CHU Gui de Chauliac	Montpellier		France	34295
14	University Hospital Carémeau	Nimes		France	30029
15	Hopital Rothschild	Paris		France	75012
16	GH Lariboisière F.Widal	Paris		France	75013
17	Groupe Hospitalier Pitié-Salpêtrière	Paris		France	75013
18	Université Reims Champagne Ardenne	Reims		France	51092
19	Pôle MPR St Hélier	Rennes		France	35000