Xenazine in Late Dyskinetic Syndrome With Neuroleptics (Xeladys)

• Changes in ESRS: Extrapyramidal Symptoms Rating Scale [ Time Frame: 10 weeks after randomization ] [ Designated as safety issue: No ]
  Changes in ESRS from Baseline and V6 (10 weeks after randomization) are assessed at the end of the 10 weeks of treatment.
  
  

• Changes in Sub-score ESRS-II [ Time Frame: At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1) ] [ Designated as safety issue: No ]

  ESRS-II is calculated as the ESRS total score minus ESRS sub-part II (worst score=0, best score=158).

  The choice of this sub-score is justified because of the possibility of improving the total ESRS can be masked by the induction of parkinsonian syndrome represented by part II of the ESRS that we chose to subtract in order to achieve the ESRS 2.

  
  
• CGI amelioration [ Time Frame: At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1) ] [ Designated as safety issue: No ]
  Clinical Global Impression is an ordinal scale in eight categories: unevaluated = 0; much worsened = 7
  
  
• Tolerance [ Time Frame: within the 14 weeks of the patients' participation ] [ Designated as safety issue: Yes ]

  Tolerance includes:

  • neurological consultation
  • global clinical examination: ECG (QT), BP, pulse, orthostatic hypotension, weight
  
  
• Changes in Quality of life [ Time Frame: At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1) ] [ Designated as safety issue: No ]
  Quality of life will be investigated with the SF36 questionnaire.
  
  
• AIMS improvement [ Time Frame: At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1) ] [ Designated as safety issue: No ]
  Expected reduction of dyskinesia during the study will be investigated with the Abnormal Involuntary Movement Scale (AIMS).
  
  
• Changes in intermediate ESRS and post-treatment ESRS [ Time Frame: 7 weeks after randomization and 14 weeks after randomization ] [ Designated as safety issue: No ]
  Changes in ESRS are assessed between baseline and the end of the titration period (7 weeks after randomization) and after the wash-out period (14 weeks after randomization).
  
  

Tetrabenazine is classified as a central monoamine depleting agent. In vitro studies have shown that it is an inhibitor of the vesicular monamine transporter 2 (VMAT2), resulting in synaptic dopamine depletion. This effect explains the reduction of hyperkinetic movement disorders.

Although tetrabenazine enjoys a reputation of very good efficacy in tardive syndromes, with good tolerance, it is still yet to empiricism because studies are few andf most importantly, of low level of evidence according the criteria of Evidence Based Medicine.

This is a randomized, multicenter, parallel group, double-blind placebo (tetrabenazine/placebo: 1/1), in two comparative conditions before and after 10 weeks of treatment with tetrabenazine (5-week titration to a maximum dose of 200 mg/day and 5 weeks at stable dose).

Study enrollment is proposed to patients fulfilling inclusion criteria.

The study should process as follows:

1. Patients give their informed consent for participation after presentation of the study by the investigator.
2. Visit V0: Given the patient's signed consent, global clinical examination, blood sampling, vital signs (weight, height, arterial tension, ECG are performed as well as a neurological examination (MMS). For women in childbearing potential, a urinary pregnancy test will be realized. It is noteworthy that a psychiatric consultation dating less than one month is required.

3. Visit V1: patient is randomized in one of the two arms: tetrabenazine or placebo. Some tests are performed at baseline:

   • Neurologic: ESRS, AIMS, CGI, UPDRSIII, MMS;
   • Quality of life auto-questionnaires: SF36, Epworth; The treatment is prescribed following a titration phase during 5 weeks, a stable dose during 5 weeks, and a wash-out period during 2 weeks.
4. At V2 (1 week after V1), V3 (3 weeks after V1) and V5 (7 weeks after V1): global clinical examination is performed and prescription observance is checked.
5. At V4 (5 weeks after V1), V6 (10 weeks after V1) and V7 (12 weeks after V1): neurological (ESRS, AIMS, CGI, UPDRSIII, auto questionnaire SF36, Epworth, neuropsychological examination (MADRS), psychiatric examination (only at V6), vital signs and prescription observance.