Xenazine in Late Dyskinetic Syndrome With Neuroleptics (Xeladys)

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

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.

Study Overview

• Status: Completed
• Conditions: Tardive Dyskinesia
• Intervention / Treatment: Drug: Tetrabenazine; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Aix en Provence, France, 13100
    • CH Aix en Provence
  • Bordeaux, France, 33076
    • CHU Bordeaux
  • Caen, France, 14033
    • CHU Caen
  • Clermont-ferrand, France, 63003
    • CHU Clermont-Ferrand
  • Lille, France, 59037
    • CHRU Lille
  • Limoges, France, 87042
    • CHU Limoges
  • Lyon, France, 69100
    • CH des Charpennes
  • Marseille, France, 13385
    • AP-HM Hopital de la Timone
  • Montpellier, France, 34295
    • CHU Montpellier
  • Nantes, France, 44093
    • CHU Nantes
  • Nice, France, 06002
    • CHU NICE
  • Nimes, France, 30900
    • CHRU de Nîmes
  • Paris, France, 75012
    • CHU Saint Antoine
  • Poitiers, France, 86021
    • CHU Poitiers
  • Rennes, France, 35033
    • CHU de Rennes
  • Rouen, France, 76031
    • CHU Rouen
  • Strasbourg, France, 67091
    • CHU Strasbourg
  • Toulouse, France, 31059
    • CHU Toulouse
  • Picardie
    • Amiens, Picardie, France, 80000
      • CHU Amiens

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in ESRS: Extrapyramidal Symptoms Rating Scale	Changes in ESRS from Baseline and V6 (10 weeks after randomization) are assessed at the end of the 10 weeks of treatment.	10 weeks after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Sub-score ESRS-II	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.	At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1)
CGI amelioration	Clinical Global Impression is an ordinal scale in eight categories: unevaluated = 0; much worsened = 7	At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1)
Tolerance	Tolerance includes: neurological consultation; global clinical examination: ECG (QT), BP, pulse, orthostatic hypotension, weight	within the 14 weeks of the patients' participation
Changes in Quality of life	Quality of life will be investigated with the SF36 questionnaire.	At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1)
AIMS improvement	Expected reduction of dyskinesia during the study will be investigated with the Abnormal Involuntary Movement Scale (AIMS).	At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1)
Changes in intermediate ESRS and post-treatment ESRS	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).	7 weeks after randomization and 14 weeks after randomization

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire, Amiens
• Investigators: Principal Investigator: Pierre Krystkowiak, MD-PhD, University Hopsital of Amiens

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2012
• Primary Completion (Actual): May 18, 2017
• Study Completion (Actual): August 1, 2017

Study Registration Dates

• First Submitted: February 22, 2012
• First Submitted That Met QC Criteria: February 27, 2012
• First Posted (Estimate): March 2, 2012

Study Record Updates

• Last Update Posted (Actual): September 12, 2017
• Last Update Submitted That Met QC Criteria: September 11, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: movement disorders; tetrabenazine; tardive disorders
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Movement Disorders; Dyskinesia, Drug-Induced; Dyskinesias; Tardive Dyskinesia; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Adrenergic Uptake Inhibitors; Tetrabenazine
• Other Study ID Numbers: PI11-PR-KRYSTKOWIAK; 2011-004211-23 (EudraCT Number)