Study of the Effects on Motor Recovery of Early Post-stroke Spasticity Treatment
Condition: Muscle Spasticity
MeSH terms: Muscle Spasticity
Study type: Interventional
Phase: Phase 4

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.
    

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.
    

Intervention name(s): botulinum A toxin; Baclofen; Placebo toxin; placebo baclofen
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): botulinum toxin injection; baclofen oral tablet; placebo injection; placebo oral tablet
Other intervention name(s): Drug injection; Drug; placebo injection; placebo drug
Intervention MeSH terms: Baclofen; Botulinum Toxins, Type A; abobotulinumtoxinA
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Supportive Care
Keywords: Spasticity; Post stroke motor recovery; Botulinum toxin; Baclofen; Pharmacological modulation