Study of Memantine for Gait Disorders And Attention Deficit In Parkinson's Disease
Condition: Parkinson's Disease; Gait Disorders, Neurologic
MeSH terms: Parkinson Disease; Nervous System Diseases; Gait Disorders, Neurologic
Study type: Interventional
Phase: Phase 4

Summary: 
      Along with cognitive and psychobehavioural disorders, gait disorders represent a major
      problem in the treatment of advanced Parkinson's disease (PD). PD can be considered to be a
      hyperglutamatergic disease because dopaminergic depletion induces hyperactivity of the
      subthalamic nucleus (STN) and the internal pallidum (GPi), with glutamatergic hyperactivity
      of the STN's efferent pathway, i.e., the subthalamopallidal, subthalamonigral and
      subthalamo-entopeduncular pathways (projecting to the pedunculopontine nucleus (PPN)). Excess
      glutamate in the PPN has also been observed in the 6-OHDA rat model of PD. Reduction of this
      glutamatergic hyperactivity within the PPN via the systemic or intra-peduncular
      administration of glutamate antagonists improves akinesia in drug-induced murine and primate
      models of PD, via the NMDA and AMPA receptors. High doses of memantine (10 mg/kg) improve
      locomotion in reserpine- and alpha-methyl-p-tyrosine-treated rats. In humans, the PPN may
      play a key role in gait, posture control, axial rigidity and attention. It is also involved
      in the gating of sensory information involved in the startle reflex, which can be studied via
      prepulse inhibition (PPI) of the blink reflex. At present, two uncompetitive NMDA receptor
      antagonists are approved for use in humans: amantadine and memantine. Reviews of the recent
      literature on these drugs have identified no published studies specifically on severe gait
      and attention disorders in PD. Memantine is a partial blocker of open NMDA channels. The
      value of memantine relates to the fact that it decreases excessive glutamatergic transmission
      by lowering the synaptic noise due to excessive activation of NMDA receptors. In this
      double-blind study, the investigators shall seek to demonstrate the presence or absence of an
      effect of memantine on gait and attention disorders. In order to study the interaction
      between glutamatergic hyperactivity and the dopaminergic system, the investigators shall
      study the phenomena both in the absence of L-dopa and following acute administration of the
      latter. Twenty eight volunteer, non-demented, late-stage PD patients displaying severe gait
      disorders will receive memantine (20 mg/day) or placebo for 3 months. The investigators
      expect to see a reduction in gait and attention disorders, together with an improvement in
      the blink reflex with PPI under memantine. This pilot study could subsequently be turned into
      a double-blind, placebo-controlled multicenter study.
    

Detailed description: 
      Overall study duration: 2 years. Planned inclusion period: 12 months. Study duration for
      individual patients: 4 months and 2 weeks(2 weeks between screening and randomization, 3
      months of double-blind treatment and then a 4-week wash-out period).

      Primary objective (V1 and V4):

      To assess efficacy of memantine treatment on severe gait disorders assessed on stride length
      by gait analysis with an optoelectronic system (VICON®) in patients with advanced Parkinson's
      disease under subthalamic stimulation

      Additional Efficacy Endpoints (V1 and V4):

        -  Kinematic and Kinetic parameters (stride length, stride time, velocity, and cadence) of
           the gait initiation and the stabilized gait using the optoelectronic system (VICON®)

        -  Gait and motor symptoms: the "Freezing Of Gait trajectory", the UPDRS scores (part III),
           the dyskinesia rating scale,

        -  Axial rigidity : measured by passive flexion on isokinetic dynamometer (Cybex 6000)

        -  Axial strength : measured by active flexion on isokinetic dynamometer (Cybex 6000)

        -  Attention: simple and complex reactions times

        -  The inhibition of the presynaptic dopamine transporter by memantine was assessed by the
           mean DAT density of the bilateral striatum (putamen and caudate nuclei) using
           [99mTc]TRODAT-1 SPECT

      Safety and Tolerability Endpoints (V1, V2, V3 and V4):

        -  Drowsiness: Epworth and Parkinson's disease Sleep Scales

        -  Apathy Lille Apathy Rating Scale

        -  Depression : MADRS,

        -  Pharmacokinetic properties of memantine were analyzed by the lowest plasmatic
           concentrations of memantine before the morning intake of the blinded treatment at 7:00
           h, during the steady state after 3 months (blind secondary analyse).

        -  Safety : Recording of all serious and non serious adverse events reported by the
           patients, electrocardiogram, blood pressure and biological analyzes (blood counts,
           ionogram, urea, creatinemia, transaminases, alkaline phosphatase, bilirubinemia, gamma
           GT, magnesium)

        -  Tolerability Number of subjects (%) who discontinue the study Number of subjects (%) who
           discontinue the study due to AEs Safety Measures AE incidence Safety laboratory values
           Vital signs Blood pressure monitoring ECG Physical and neurological examination

      Study Design

      Monocentric study: 12-week double blind, placebo-controlled phase. After being found eligible
      to participate in the study, subjects will be allocated in a 1:1 ratio into one of the
      following two treatment groups based on a randomization scheme with blocks stratified:

      one memantine

        1. st week: 5 mg per day in the morning

        2. nd week: 10 mg per day in the morning

        3. rd week: 15 mg per day in the morning

        4. th week: 20 mg per day in the morning

      one placebo during 3 months same as memantine

      Schedule: 5 visits : screening (V0), randomization (V1, 15 days after V0), (V2) visit after 1
      months, (V3) visit after 2 months and termination (V4, 3 months after randomization)

      Patients : 28 subjects with Parkinson's disease duration of more than 5 years, without
      dementia (Mattis Dementia Rating Scale ≥ 130, MMSE ≥ 27 and DSM IV), without major depression
      (MADRS < 18) who have severe gait disorders including freezing of gait (defined by an answer
      2 or 3 at the 3rd question of the autoquestionnaire of Giladi: Do your gait disorders impede
      your daily living activities and your independence: answer: yes, moderately or severely. But
      the patient requires no physical assistance to walk) despite an optimal dopaminergic
      treatment and optimal and stable subthalamic stimulation parameters. No additional therapy
      will be permitted during the study.

      Centre : LILLE :

      Department of Neurology, University Hospital of Lille : Pr L. Defebvre, Pr K. Dujardin, Dr D.
      Devos, Pr Destee, Mme Delliaux. Dr A Kreisler, Dr C Simonin, Dr C. Moreau, Dr A. Delval
      Department of Pharmacology, Faculté de Médecine, Lille II.
    

Intervention name(s): memantine; placebo
Intervention type(s): Drug; Drug
Intervention description(s): 2 tablets of 10 mg of memantine 1 time a day in the morning; 2 tablets of placebo 1 time a day in the morning
Other intervention name(s): EBIXA
Intervention MeSH terms: Memantine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Parkinson's disease; Freezing of Gait; Memantine; NMDA receptor; glutamate; No Dementia