Clinical trial NCT01543321: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Tardive Dyskinesia
Keywords: tetrabenazine
movement disorders
tardive disorders
Lead sponsor: Centre Hospitalier Universitaire, Amiens
Sponsor class: OTHER
First posted: 2012-03-02
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Changes in ESRS: Extrapyramidal Symptoms Rating Scale
timeFrame: 10 weeks after randomization
Secondary outcomes:
measure: Changes in Sub-score ESRS-II
timeFrame: At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1)
measure: CGI amelioration
timeFrame: At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1)
measure: Tolerance
timeFrame: within the 14 weeks of the patients' participation
measure: Changes in Quality of life
timeFrame: At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1)
measure: AIMS improvement
timeFrame: At baseline (V1), V4 (7 weeks after V1), V6 (10 weeks after V1) and V7 (14 weeks after V1)
measure: Changes in intermediate ESRS and post-treatment ESRS
timeFrame: 7 weeks after randomization and 14 weeks after randomization
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU Amiens
state: Picardie
city: Aix en Provence
country: France
facility: CH Aix en Provence
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Caen
country: France
facility: CHU Caen
city: Clermont-ferrand
country: France
facility: CHU Clermont-Ferrand
city: Lille
country: France
facility: CHRU Lille
city: Limoges
country: France
facility: CHU Limoges
city: Lyon
country: France
facility: CH des Charpennes
city: Marseille
country: France
facility: AP-HM Hopital de la Timone
city: Montpellier
country: France
facility: CHU Montpellier
city: Nantes
country: France
facility: CHU Nantes
city: Nice
country: France
facility: CHU Nice
city: Nimes
country: France
facility: CHRU de Nimes
city: Paris
country: France
facility: CHU Saint Antoine
city: Poitiers
country: France
facility: CHU Poitiers
city: Rennes
country: France
facility: CHU de Rennes
city: Rouen
country: France
facility: CHU Rouen
city: Strasbourg
country: France
facility: CHU Strasbourg
city: Toulouse
country: France
facility: CHU Toulouse
Study officials:
affiliation: University Hopsital of Amiens
name: Pierre Krystkowiak, MD-PhD
role: PRINCIPAL_INVESTIGATOR
References: