Study of Methylphenidate to Treat Gait Disorders And Attention Deficit In Parkinson's Disease (PARKGAIT-II)
Condition: Parkinson's Disease; Gait Disorders, Neurologic; Dementia
MeSH terms: Parkinson Disease; Nervous System Diseases; Gait Disorders, Neurologic
Study type: Interventional
Phase: Phase 4

Summary: 
      Therapeutic management of gait disorders in very advanced Parkinson's disease (PD) patients
      can sometimes be disappointing, since dopaminergic drug treatments and subthalamic nucleus
      (STN) stimulation are more effective for limb-related Parkinsonian signs than for gait
      disorders. Gait disorders could be also partly related to noradrenergic system impairment,
      pharmacological modulation of both dopamine and noradrenaline pathways could potentially
      improve the symptomatology. The investigators have demonstrated using an open label study on
      17 advanced PD patients that chronic, high doses of methylphenidate (MPD) improved gait,
      freezing of gait, motor symptoms and attention in the absence of L-Dopa and increased the
      intensity of response of these symptoms to L-Dopa (Devos et al., 2007). The investigators
      aimed to confirm their results using a randomized, double-blind, placebo-controlled,
      parallel-group, multicentric trial. The investigators will assess the clinical value of
      chronic, high doses (1 mg/kg/day) of MPD vs placebo in 88 non demented PD patients suffering
      from severe gait disorders with freezing despite their use of optimal dopaminergic doses and
      eventually STN stimulation parameters. Efficacy will be assessed directly and on video in the
      absence of L-Dopa and again after acute administration of the drug, both before and after a
      3-month course of MPD, using Stand Walk Sit test (primary criteria), the "Freezing Of Gait
      trajectory", RGSE scale, the UPDRS scores, the dyskinesia rating scale, Achiron scales and
      using auto-questionnaires of Giladi, ABC scale and PDQ 39. Attention will be assessed using
      reactions times. Drowsiness will be assessed using Epworth and Parkinson's disease Sleep
      Scales. Apathy and depression will be monitored with Lille Apathy Rating Scale, MADRS, BPRS,
      MINI and psychiatric interview. Cardiologic and general tolerance will be also monitored.
      This study could lead to propose methylphenidate with a good efficacy/ risk balance in
      advanced PD patients suffering from severe gait disorders with freezing of gait, drowsiness
      and attention deficit.
    

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 methylphenidate treatment on severe gait disorders including freezing
      assessed by the Stand Walk Sit Test in patients with advanced Parkinson's disease without
      dementia or depression and under subthalamic stimulation

      Additional Efficacy Endpoints (V1 and V4):

        -  Gait and motor symptoms: the "Freezing Of Gait trajectory", RGSE scale, the UPDRS scores
           (partI, II, III, IV), the dyskinesia rating scale

        -  auto-questionnaires of Giladi, ABC scale and PDQ 39

        -  Attention: simple and complex reactions times

        -  Drowsiness: Epworth and Parkinson's disease Sleep Scales

        -  Apathy Lille Apathy Rating Scale

        -  Depression and other psychiatric disorders: MADRS, BPRS, MINI and psychiatric interview

      Safety and Tolerability Endpoints (V1, V2, V3 and V4):

      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:

      Multicentric 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 methylphenidate

        -  1st week: 1/2cp 3 times a day (morning, at noon and at 16h)

        -  2nd week: 1cp 3 times a day

        -  3rd week: 1cp + 1/2cp 3 times a day

        -  4th week: depending on the weight: 2 to 3 cp 3 times a day (1 mg/kg/day)

      During the 2 following month: 2 to 3 cp 3 times a day (1 mg/kg/day) one placebo during 3
      months same as methylphenidate

      Schedule: 10 visits Six short consultations: screening (V0), safety visits every 15 days (V2,
      V3, V4, V5, V6) and two last consultation for the decrease titration (V8, V9) Two long visits
      during an hospitalization of two days: randomization (V1, 15 days after V0) and visit of
      termination (V7, 3 months after randomization)

      Patients 76 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 if present stable subthalamic stimulation parameters. No additional therapy will
      be permitted during the study.

      Centres :

      LILLE :

      Neurological department, CHU de Lille, EA 2683, IFR 114 : 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, EA 1046, IFR 114 : R. Bordet.

      CHU AMIENS :Pr. P. KRYSTKOWIAK Place Victor PAUCHET - 80054 AMIENS Cedex 1. CH AIX EN
      PROVENCE : Dr F. VIALLET Avenue Tamaris - 13616 AIX-en-PROVENCE. APHP - HOPITAL DE LA PITIE
      SALPETRIERE : Pr M. VIDAILHET 47-83, Boulevard de l'Hôpital - 75 PARIS 13ème CHU BORDEAUX :
      Pr. F. TISON 1, Avenue Magellan - 33600 PESSAC CHU CLERMONT-FERRANT : Pr. F. DURIF 58, Rue
      Montalambert - 63000 CLERMONT-FERRRAND CHU CRETEIL : Pr. P. CESARO 51, Avenue du Maréchal de
      Lattre de Tassigny - 94000 CRETEIL CHU GRENOBLE : Pr P. POLLAK Bd de la Chantourne - BP 217 -
      38700 La Tronche. CHU MARSEILLE : Pr. JP AZULAY Hôpital de la Timone - 13385 MARSEILLE cedex
      05 CHU NANTES : Pr PH. DAMIER Hôtel-Dieu - Place Alexis Ricordeau - 44093 Nantes cedex 1 CHU
      POITIERS : Dr JL HOUETO 2, Rue de la Milétrie - 86000 POITIERS. CHU RENNES : Pr. M. VERIN CHU
      Pontchaillou , Rue H. Le Guilloux - 35033 Cedex 9. CHU ROUEN :DR D. MALTETE

      1, Rue Germont - 76000 ROUEN. CHU TOULOUSE : Pr. O. RASCOL Hôpital Purpan - Place du Docteur
      Baylac - TSA 40031 - 31059 Toulouse cedex 9. CHU STRASBOURG : Pr. C. TRANCHANT Hôpital civil
      - 1 place de l'hôpital BP 426 - 67091 Strasbourg cedex CHU CAEN : Pr. G. DEFER Avenue Côte de
      Nacre - 14000 CAEN. CHU NICE : M. BORG Hôpital Pasteur - 30, Avenue de la Voie Romaine -
      06000 NICE Promoteur de l'étude : CHRU de Lille
    

Intervention name(s): methylphenidate; placebo
Intervention type(s): Drug; Drug
Intervention description(s): 10 mg tablet of methylphenidate 3 times a day (1 mg/kg/day); tablets of placebo 3 times a day
Other intervention name(s): Concerta; Ritaline
Intervention MeSH terms: Methylphenidate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Parkinson's disease; Freezing of Gait; Methylphenidate; Dopamine transporter inhibitor; Noradrenaline