Xenazine in Late Dyskinetic Syndrome With Neuroleptics

Tardive Dyskinesia Clinical Trial

— Xeladys  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01543321
• Other study ID #: PI11-PR-KRYSTKOWIAK
• Secondary ID: 2011-004211-23
• Status: Completed
• Phase: Phase 3
• First received: February 22, 2012
• Last updated: September 11, 2017
• Start date: May 14, 2012
• Est. completion date: August 2017

Study information

• Verified date: September 2017
• Source: Centre Hospitalier Universitaire, Amiens
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: August 2017
• Est. primary completion date: May 18, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Dyskinesias
• Movement Disorders
• Tardive Dyskinesia

Intervention

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
• 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

Locations

Country	Name	City	State
France	CH Aix en Provence	Aix en Provence
France	CHU Amiens	Amiens	Picardie
France	CHU Bordeaux	Bordeaux
France	CHU Caen	Caen
France	CHU Clermont-Ferrand	Clermont-ferrand
France	CHRU Lille	Lille
France	CHU Limoges	Limoges
France	CH des Charpennes	Lyon
France	AP-HM Hopital de la Timone	Marseille
France	CHU Montpellier	Montpellier
France	CHU Nantes	Nantes
France	CHU Nice	Nice
France	CHRU de Nimes	Nimes
France	CHU Saint Antoine	Paris
France	CHU Poitiers	Poitiers
France	CHU de Rennes	Rennes
France	CHU Rouen	Rouen
France	CHU Strasbourg	Strasbourg
France	CHU Toulouse	Toulouse

Sponsors (1)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire, Amiens

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	Tolerance	Tolerance includes: neurological consultation; global clinical examination: ECG (QT), BP, pulse, orthostatic hypotension, weight	within the 14 weeks of the patients' participation
Secondary	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)
Secondary	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)
Secondary	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