Parkinson's Disease Clinical Trial
— FOGG-IOfficial 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
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.
Status | Completed |
Enrollment | 28 |
Est. completion date | October 2010 |
Est. primary completion date | September 2010 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 30 Years to 80 Years |
Eligibility |
Inclusion Criteria: - Parkinson's disease of more than 5 years - Subthalamic nucleus stimulation - Gait disorders impeding moderately to severely the activities of daily living - gait disorders including freezing of gait - able to walk without physical assistance Exclusion Criteria: - Dementia (MMSE < 27 et score de Mattis < 130) - Requiring dopatherapy modification - Requiring subthalamic stimulation parameters adaptation - Psychiatric disorders: hallucinations, unstable thymic disorders, psychosis) - Cardiac disorders: dysrhythmia or unstable arterial hypertension - Unstable or severe medical illness - intolerance or contraindication to memantine |
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
France | Devos | Lille |
Lead Sponsor | Collaborator |
---|---|
University Hospital, Lille |
France,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | stride length by gait analysis with an optoelectronic system (VICON®) | 3 months of treatment | No | |
Secondary | 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®) | 3 months | No | |
Secondary | Gait and motor symptoms: the "Freezing Of Gait trajectory",the UPDRS motor score (part III), the dyskinesia rating scale, | 3 months | No | |
Secondary | Attention: simple and complex reactions times | 3 months | No | |
Secondary | hypertonia of axial flexor and extensor | 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) | 3 months | No |
Secondary | Drowsiness: Epworth and Parkinson's disease Sleep Scales | 3 months | Yes | |
Secondary | Apathy Lille Apathy Rating Scale | 3 months | Yes | |
Secondary | Depression: MADRS | 3 months | Yes | |
Secondary | Safety and Tolerability Endpoints | 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 |
3 months | Yes |
Secondary | strength of axial flexor and extensor | 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 | 3 months | No |
Secondary | DaT scan | 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. | 3 months | No |
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