Clinical Trial: Study of Memantine for Gait Disorders And Attention Deficit In Parkinson's Disease

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Study of Memantine to Treat Gait Disorders And Attention Deficit In Parkinson's Disease: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Monocentric Trial

Brief 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 b

Detailed Summary:

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
  • Apa
    Sponsor: University Hospital, Lille

    Current Primary Outcome: stride length by gait analysis with an optoelectronic system (VICON®) [ Time Frame: 3 months of treatment ]

    Original Primary Outcome: stride lenght by gait analysis with an optoelectronic system (VICON®) [ Time Frame: 3 months of treatment ]

    Current Secondary Outcome:

    • Kinematic and Kinetic parameters (stride length, stride time, velocity, cadence and variability of these parameters) of the gait initiation and the stabilised gait using the optoelectronic system (VICON®) [ Time Frame: 3 months ]
    • Gait and motor symptoms: the "Freezing Of Gait trajectory",the UPDRS motor score (part III), the dyskinesia rating scale, [ Time Frame: 3 months ]
    • Attention: simple and complex reactions times [ Time Frame: 3 months ]
    • hypertonia of axial flexor and extensor [ Time Frame: 3 months ]
      hypertonia of axial flexor and extensor measured on mean and total work at 30°/s (Joules) by passive flexion and extension on isokinetic dynamometer (Cybex 6000)
    • Drowsiness: Epworth and Parkinson's disease Sleep Scales [ Time Frame: 3 months ]
    • Apathy Lille Apathy Rating Scale [ Time Frame: 3 months ]
    • Depression: MADRS [ Time Frame: 3 months ]
    • Safety and Tolerability Endpoints [ Time Frame: 3 months ]
      • Safety : Recording of all serious and non serious adverse events reported by the patients, electrocardiogram, blood pressure and biological analyzes (blood counts, ionogramme, 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
    • strength of axial flexor and extensor [ Time Frame: 3 months ]
      strength of axial flexor and extensor measured on mean and total work of 3 repetitions at 30°/s (Joules) and of 5 repetitions at 120°/s (Joules) by active flexion and extension on isokinetic dynamometer
    • DaT scan [ Time Frame: 3 months ]
      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 before and after 3 months of treatment.


    Original Secondary Outcome:

    • Kinematic and Kinetic parameters (stride length, stride time, velocity, cadence and variability of these parameters) of the gait initiation and the stabilised gait using the optoelectronic system (VICON®) [ Time Frame: 3 months ]
    • Gait and motor symptoms: the "Freezing Of Gait trajectory", RGSE scale, the UPDRS scores (partI, II, III, IV), the dyskinesia rating scale, Achiron scales auto-questionnaires of Giladi, ABC scale and PDQ 39 [ Time Frame: 3 months ]
    • Attention: simple and complex reactions times [ Time Frame: 3 months ]
    • Axial rigidity: measured by passive flexion on isokinetic dynamometer (Cybex 6000),and indirectly by amplitude of active flexion and measures of the spine and pelvis during gait on Vicon® [ Time Frame: 3 months ]
    • Blink reflex with Prepulse Inhibition: percentage of inhibition [ Time Frame: 3 months ]
    • Drowsiness: Epworth and Parkinson's disease Sleep Scales [ Time Frame: 3 months ]
    • Apathy Lille Apathy Rating Scale [ Time Frame: 3 months ]
    • Depression: MADRS [ Time Frame: 3 months ]
    • Safety and Tolerability Endpoints [ Time Frame: 3 months ]
      • Safety : Recording of all serious and non serious adverse events reported by the patients, electrocardiogram, blood pressure and biological analyzes (blood counts, ionogramme, 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


    Information By: University Hospital, Lille

    Dates:
    Date Received: July 20, 2009
    Date Started: October 2009
    Date Completion:
    Last Updated: March 23, 2012
    Last Verified: July 2009