Xenazine in Late Dyskinetic Syndrome With Neuroleptics

Phase 3

Completed

• Conditions: Tardive Dyskinesia
• Interventions: Drug: Tetrabenazine; Drug: Placebo

• Registration Number: NCT01543321
• Lead Sponsor: Centre Hospitalier Universitaire, Amiens

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 Timeline

• Study First Submitted: 2012-02-22
• Study First Submitted QC: 2012-02-27
• Study First Posted: 2012-03-02
• Study Start: 2012-05-14
• Primary Completion: 2017-05-18
• Study Completion: 2017-08
• Status Verified: 2017-09
• Last Update Submitted: 2017-09-11
• Last Update Posted: 2017-09-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 54

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tetrabenazine group	Tetrabenazine	Tetrabenazine is a drug that is administered orally. This is 25 mg tablets, divisible into 2.
Plagebo group	Placebo	Patients will receive a buccal tablet identical to the experimental product

Primary Outcome Measures

Name	Time	Method
Changes in ESRS: Extrapyramidal Symptoms Rating Scale	10 weeks after randomization	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

Name	Time	Method
Changes in Sub-score ESRS-II	At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1)	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	At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1)	Clinical Global Impression is an ordinal scale in eight categories: unevaluated = 0; much worsened = 7
Tolerance	within the 14 weeks of the patients' participation	Tolerance includes: * neurological consultation; * global clinical examination: ECG (QT), BP, pulse, orthostatic hypotension, weight
Changes in Quality of life	At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1)	Quality of life will be investigated with the SF36 questionnaire.
AIMS improvement	At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1)	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	7 weeks after randomization and 14 weeks after randomization	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).

Trial Locations

Locations (19)

CHU Strasbourg; 🇫🇷 Strasbourg, France

CH des Charpennes; 🇫🇷 Lyon, France

CHU Toulouse; 🇫🇷 Toulouse, France

CHU Nantes; 🇫🇷 Nantes, France

CHU Rouen; 🇫🇷 Rouen, France

AP-HM Hopital de la Timone; 🇫🇷 Marseille, France

CHU de Rennes; 🇫🇷 Rennes, France

CHU Caen; 🇫🇷 Caen, France

CHRU de Nimes; 🇫🇷 Nimes, France

CHU Poitiers; 🇫🇷 Poitiers, France

CH Aix en Provence; 🇫🇷 Aix en Provence, France

CHU Clermont-Ferrand; 🇫🇷 Clermont-ferrand, France

CHU Nice; 🇫🇷 Nice, France

CHU Saint Antoine; 🇫🇷 Paris, France

CHU Limoges; 🇫🇷 Limoges, France

CHU Montpellier; 🇫🇷 Montpellier, France

CHU Amiens; 🇫🇷 Amiens, Picardie, France

CHU Bordeaux; 🇫🇷 Bordeaux, France

CHRU Lille; 🇫🇷 Lille, France