Xenazine in Late Dyskinetic Syndrome With Neuroleptics

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Brief Title

Xenazine in Late Dyskinetic Syndrome With Neuroleptics

Official Title

Study of Efficacy and Acceptability of Tetrabenazine in the Late Dyskinetic Syndrome With Neuroleptics: A Randomized, Parallel Group, Double-blind Placebo Controlled Multicentre Trial

Brief Summary

      Late dyskinetic syndrome with neuroleptics, or tardive dyskinesia, is the appearance of
      abnormal involuntary movements (AIM) in patients treated with antipsychotics for at least
      three months. This important public health issue arises for 15-20% of patients treated with
      neuroleptics, the most prescribed psychotropic drugs in mental disorders in France, and
      seriously impacts the patients' quality of life. In over 50% of cases, it is
      irreversible-that is to say that he will persist despite discontinuation of the offending
      drug.

      Risk factors have been described: the age and female gender are established, a higher dosage
      of antipsychotic, a long-term treatment, a psychiatric condition other than schizophrenia are
      likely risk factors, intermittent treatment, previous acute dyskinesia, neuroleptics or
      powerful, longer term use of corrective treatments including anticholinergics are still
      discussed.

      Apart from preventive treatment, which consists in using antipsychotics as being coerced,
      support is disappointing: the etiological treatment, which is to stop the offending
      antipsychotic, is effective only in less than 50% of cases, the syndrome is most often late
      irreversible. Must still have the possibility to interrupt the treatment, which is usually
      impossible in the risk of decompensation of the mental illness for which the neuroleptic was
      prescribed. Remains symptomatic treatment: functional neurosurgery is only for extreme cases,
      because it is not without risk, in terms of morbidity and mortality. So it's the medication
      that is most often offered: many drugs have been proposed, a direct result of the
      multiplicity of neurotransmitter systems implicated.

      However, in the vast majority of cases, this approach is disappointing not to say
      ineffective. The only exception is the tetrabenazine, marketed under the name of Xenazine®.
      Empirically, neurologists specializing in pathology of the movement are almost unanimous: its
      efficiency is very good, with good tolerance. Some preliminary studies have reinforced this
      impression. However, their level of evidence remains low and that is why the investigators
      propose to implement a prospective multicenter clinical trial, double-blind with placebo
      which will include two groups of 27 patients.
    

Detailed Description

      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.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Changes in ESRS: Extrapyramidal Symptoms Rating Scale

Secondary Outcome

 Changes in Sub-score ESRS-II

Condition

Tardive Dyskinesia

Intervention

Tetrabenazine

Study Arms / Comparison Groups

 Tetrabenazine group
Description:  Tetrabenazine is a drug that is administered orally. This is 25 mg tablets, divisible into 2.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

54

Start Date

May 14, 2012

Completion Date

August 2017

Primary Completion Date

May 18, 2017

Eligibility Criteria

        Inclusion Criteria:

          1. Adult (age over 18) or adult under judicial protection (tutor or curator).

          2. Patient with late dyskinetic syndrome with neuroleptics yielding functional disability
             and/or impact in every day's life, according to the investigator, and/or the patient
             and/or the patient's family.

          3. Patient with persistent late dyskinetic syndrome, even if the neuroleptic has been
             stopped for more than 6 months or patient with late dyskinetic syndrome under
             neuroleptic treatment unchanged for at least 3 months and which would a priori not
             need any dose variation during the study time.

          4. MADRS < 18

          5. QTc < 450 ms for men and < 470 for women.

        Exclusion Criteria:

          1. Lack of social insurance

          2. Neuroleptic treatment less than 3 months

          3. Insanity according to the DSM IV and MMS < 24

          4. Predominant akathisia

          5. Psychiatric disease not stabilized for more than 6 months and/or which could require a
             neuroleptic treatment adaptation during study time.

          6. Pregnancy and lactating

          7. Women in genital activity without efficient contraception method (IUD or
             estrogen-progestin pill)

          8. Hypersensitivity to tetrabenazine

          9. Renal failure

         10. Drugs: Non-selective MAOIs, dopaminergic (or other antiparkinsonian)

         11. Other severe pathology

         12. Patient non compliant to protocol, at the investigator's appreciation

         13. Simultaneous participation to other clinical trial

         14. Congenital galactosemia, glucose malabsorption or lactase deficiency
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Pierre Krystkowiak, MD-PhD, , 

Location Countries

France

Location Countries

France

Administrative Informations


NCT ID

NCT01543321

Organization ID

PI11-PR-KRYSTKOWIAK

Secondary IDs

2011-004211-23

Responsible Party

Sponsor

Study Sponsor

Centre Hospitalier Universitaire, Amiens


Study Sponsor

Pierre Krystkowiak, MD-PhD, Principal Investigator, University Hopsital of Amiens


Verification Date

September 2017