Xenazine in Late Dyskinetic Syndrome With Neuroleptics (Xeladys)

This study is currently recruiting participants.
Verified April 2013 by Centre Hospitalier Universitaire, Amiens
Sponsor:
Information provided by (Responsible Party):
Centre Hospitalier Universitaire, Amiens
ClinicalTrials.gov Identifier:
NCT01543321
First received: February 22, 2012
Last updated: April 22, 2013
Last verified: April 2013
  Purpose

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 2013
Estimated Primary Completion Date: December 2013 (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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01543321

Contacts
Contact: Pierre Krystkowiak, MD-PhD +333 22 66 82 40 krystkowiak.pierre@chu-amiens.fr
Contact: Loïc Fin, PhD +333 22 66 80 60 fin.loic@chu-amiens.fr

Locations
France
CHU Amiens Recruiting
Amiens, Picardie, France, 80000
Contact: Pierre Krystkowiak, MD-PhD    +33322668240    krystkowiak.pierre@chu-amiens.fr   
Contact: Loïc Fin, PhD    +333 22 66 80 60    fin.loic@chu-amiens.fr   
Principal Investigator: Pierre Krystkowiak, MD-PhD         
Sub-Investigator: Cécile Duru, MD         
CH Aix en Provence Recruiting
Aix en Provence, France, 13100
Contact: François VIALLET, Dr       fviallet@ch-aix.fr   
Principal Investigator: François VIALLET, MD         
CHU Bordeaux Recruiting
Bordeaux, France, 33076
Contact: Pierre BURBAUD       Pierre.Burbaud@u-bordeaux2.fr   
Principal Investigator: Pierre BURBAUD, MD         
Principal Investigator: Dominic GUEHL, MD         
CHU Caen Active, not recruiting
Caen, France, 14033
CHU Clermont-Ferrand Recruiting
Clermont-ferrand, France, 63003
Contact: Franck DURIF    04 73 75 47 90    fdurif@chu-clermontferrand.fr   
Principal Investigator: Franck DURIF, MD         
CHRU Lille Not yet recruiting
Lille, France, 59037
Contact: Luc DEFEBVRE, Pr       ldefebvre@chru-lille.fr   
Principal Investigator: Luc DEFEBVRE, Pr         
CHU Limoges Active, not recruiting
Limoges, France, 87042
CH des Charpennes Active, not recruiting
Lyon, France, 69100
AP-HM Hopital de la Timone Recruiting
Marseille, France, 13385
Contact: Jean-Pierre Azulay, MD-PhD    +334-91-38-43-33    jean-philippe.azulay@ap-hm.fr   
Principal Investigator: Jean-Pierre Azulay, MD-PhD         
Sub-Investigator: Tatiana Witjas, MD         
Sub-Investigator: Frédérique Fluchère, MD-PhD         
CHU Montpellier Not yet recruiting
Montpellier, France, 34295
Contact: Christian GENY       c-geny@chu-montpellier.fr   
Principal Investigator: Christian GENY, MD         
CHU Nantes Active, not recruiting
Nantes, France, 44093
CHU Nice Active, not recruiting
Nice, France, 06002
CHRU de Nimes Recruiting
Nimes, France, 30900
Contact: Giovani CASTELNOVO, MD       giovanni.castelnovo@chu-nimes.fr   
Principal Investigator: Giovanni Castelnovo, MD         
CHU Saint Antoine Not yet recruiting
Paris, France, 75012
Contact: Valerie MESNAGE, MD       valerie.mesnage@sat.aphp.fr   
Principal Investigator: Valerie MESNAGE, MD         
CHU Poitiers Active, not recruiting
Poitiers, France, 86021
CHU de Rennes Recruiting
Rennes, France, 35033
Contact: Marc Vérin, MD-PhD       marc.verin@chu-rennes.fr   
Principal Investigator: Marc Vérin, MD-PhD         
Sub-Investigator: Sophie Drapier, MD         
CHU Rouen Not yet recruiting
Rouen, France, 76031
Contact: David MALTETE, Dr       David.Maltete@chu-rouen.fr   
Principal Investigator: David MALTETE, MD         
CHU Strasbourg Active, not recruiting
Strasbourg, France, 67091
CHU Toulouse Recruiting
Toulouse, France, 31059
Contact: Christine BREFEL-COURBON       brefel@cict.fr   
Principal Investigator: Christine BREFEL-COURBON, MD         
Sponsors and Collaborators
Centre Hospitalier Universitaire, Amiens
Investigators
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: April 22, 2013
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

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

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

ClinicalTrials.gov processed this record on April 15, 2014