Xenazine in Late Dyskinetic Syndrome With Neuroleptics (Xeladys)

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
Centre Hospitalier Universitaire, Amiens
ClinicalTrials.gov Identifier:
First received: February 22, 2012
Last updated: July 28, 2015
Last verified: July 2015

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.

Condition Intervention Phase
Tardive Dyskinesia
Drug: Tetrabenazine
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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

Resource links provided by NLM:

Further study details as provided by Centre Hospitalier Universitaire, Amiens:

Primary Outcome Measures:
  • 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.

Secondary Outcome Measures:
  • 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).

Estimated Enrollment: 54
Study Start Date: March 2012
Estimated Study Completion Date: December 2015
Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Tetrabenazine group
Tetrabenazine is a drug that is administered orally. This is 25 mg tablets, divisible into 2.
Drug: Tetrabenazine

Treatment with tetrabenazine consists in:

  • 5-week titration to a maximum dose of 200 mg / day
  • 5 weeks at stable dose
  • 2 weeks in wash-out

The treatment will be blinded for patients and investigators

Other Name: Xenazine (tetrabenazine)
Placebo Comparator: Plagebo group
Patients will receive a buccal tablet identical to the experimental product
Drug: Placebo

Treatment with placebo consists in:

  • 5-week titration to a maximum dose of 200 mg / day
  • 5 weeks at stable dose
  • 2 weeks in wash-out

The treatment will be blinded for patients and investigators

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.

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01543321

CHU Amiens
Amiens, Picardie, France, 80000
CH Aix en Provence
Aix en Provence, France, 13100
CHU Bordeaux
Bordeaux, France, 33076
CHU Caen
Caen, France, 14033
CHU Clermont-Ferrand
Clermont-ferrand, France, 63003
CHRU Lille
Lille, France, 59037
CHU Limoges
Limoges, France, 87042
CH des Charpennes
Lyon, France, 69100
AP-HM Hopital de la Timone
Marseille, France, 13385
CHU Montpellier
Montpellier, France, 34295
CHU Nantes
Nantes, France, 44093
CHU Nice
Nice, France, 06002
CHRU de Nimes
Nimes, France, 30900
CHU Saint Antoine
Paris, France, 75012
CHU Poitiers
Poitiers, France, 86021
CHU de Rennes
Rennes, France, 35033
CHU Rouen
Rouen, France, 76031
CHU Strasbourg
Strasbourg, France, 67091
CHU Toulouse
Toulouse, France, 31059
Sponsors and Collaborators
Centre Hospitalier Universitaire, Amiens
Principal Investigator: Pierre Krystkowiak, MD-PhD University Hopsital of Amiens
  More Information

No publications provided

Responsible Party: Centre Hospitalier Universitaire, Amiens
ClinicalTrials.gov Identifier: NCT01543321     History of Changes
Other Study ID Numbers: PI11-PR-KRYSTKOWIAK, 2011-004211-23
Study First Received: February 22, 2012
Last Updated: July 28, 2015
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Centre Hospitalier Universitaire, Amiens:
movement disorders
tardive disorders

Additional relevant MeSH terms:
Central Nervous System Diseases
Movement Disorders
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Antipsychotic Agents
Adrenergic Agents
Adrenergic Uptake Inhibitors
Central Nervous System Agents
Central Nervous System Depressants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Neurotransmitter Uptake Inhibitors
Pharmacologic Actions
Physiological Effects of Drugs
Psychotropic Drugs
Therapeutic Uses
Tranquilizing Agents

ClinicalTrials.gov processed this record on November 30, 2015