Brief Title
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
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 Phase
Phase 3
Study Type
Interventional
Primary Outcome
Changes in ESRS: Extrapyramidal Symptoms Rating Scale
Secondary Outcome
Changes in Sub-score ESRS-II
Condition
Tardive Dyskinesia
Intervention
Tetrabenazine
Study Arms / Comparison Groups
Tetrabenazine group
Description: Tetrabenazine is a drug that is administered orally. This is 25 mg tablets, divisible into 2.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
54
Start Date
May 14, 2012
Completion Date
August 2017
Primary Completion Date
May 18, 2017
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
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Pierre Krystkowiak, MD-PhD, ,
Location Countries
France
Location Countries
France
Administrative Informations
NCT ID
NCT01543321
Organization ID
PI11-PR-KRYSTKOWIAK
Secondary IDs
2011-004211-23
Responsible Party
Sponsor
Study Sponsor
Centre Hospitalier Universitaire, Amiens
Study Sponsor
Pierre Krystkowiak, MD-PhD, Principal Investigator, University Hopsital of Amiens
Verification Date
September 2017