Xenazine in Late Dyskinetic Syndrome With Neuroleptics (Xeladys)
Recruitment status was Recruiting
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 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|
- 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.
- 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 ]
- 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).
|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)|
Experimental: Tetrabenazine group
Tetrabenazine is a drug that is administered orally. This is 25 mg tablets, divisible into 2.
Treatment with tetrabenazine consists in:
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
Treatment with placebo consists in:
The treatment will be blinded for patients and investigators
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:
- Patients give their informed consent for participation after presentation of the study by the investigator.
- 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.
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.
- 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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01543321
|Contact: Pierre Krystkowiak, MD-PhD||+333 22 66 82 email@example.com|
|Contact: Loïc Fin, PhD||+333 22 66 80 firstname.lastname@example.org|
|Amiens, Picardie, France, 80000|
|Contact: Pierre Krystkowiak, MD-PhD +33322668240 email@example.com|
|Contact: Loïc Fin, PhD +333 22 66 80 60 firstname.lastname@example.org|
|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 email@example.com|
|Principal Investigator: François VIALLET, MD|
|Bordeaux, France, 33076|
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|Principal Investigator: Pierre BURBAUD, MD|
|Principal Investigator: Dominic GUEHL, MD|
|CHU Caen||Active, not recruiting|
|Caen, France, 14033|
|Clermont-ferrand, France, 63003|
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|Principal Investigator: Franck DURIF, MD|
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|Lille, France, 59037|
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|Principal Investigator: Luc DEFEBVRE, Pr|
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|Limoges, France, 87042|
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|Lyon, France, 69100|
|AP-HM Hopital de la Timone||Recruiting|
|Marseille, France, 13385|
|Contact: Jean-Pierre Azulay, MD-PhD +334-91-38-43-33 firstname.lastname@example.org|
|Principal Investigator: Jean-Pierre Azulay, MD-PhD|
|Sub-Investigator: Tatiana Witjas, MD|
|Sub-Investigator: Frédérique Fluchère, MD-PhD|
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|Montpellier, France, 34295|
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|Nantes, France, 44093|
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|Nice, France, 06002|
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|Nimes, France, 30900|
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|Principal Investigator: Giovanni Castelnovo, MD|
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|Paris, France, 75012|
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|Poitiers, France, 86021|
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|Rennes, France, 35033|
|Contact: Marc Vérin, MD-PhD firstname.lastname@example.org|
|Principal Investigator: Marc Vérin, MD-PhD|
|Sub-Investigator: Sophie Drapier, MD|
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|Rouen, France, 76031|
|Contact: David MALTETE, Dr David.Maltete@chu-rouen.fr|
|Principal Investigator: David MALTETE, MD|
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|Strasbourg, France, 67091|
|Toulouse, France, 31059|
|Contact: Christine BREFEL-COURBON email@example.com|
|Principal Investigator: Christine BREFEL-COURBON, MD|
|Principal Investigator:||Pierre Krystkowiak, MD-PhD||University Hopsital of Amiens|