A PET Exploration of the Mechanism of Action of Dopamine Beta-hydroxylase Inhibition in Cocaine Addicts

Cocaine Dependence Clinical Trial

— RAPID  

Official title:

Dopamine Beta-hydroxylase Inhibition Induced Blunting of Dopaminergic Response to Psychostimulant Administration. A PET Exploration of the Mechanism of Action of a New Therapeutic Strategy in Cocaine Addicts

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT02134002
• Other study ID #: P121006
• Status: Withdrawn
• Phase: Phase 4
• First received: May 7, 2014
• Last updated: December 7, 2014
• Start date: June 2014
• Est. completion date: December 2016

Study information

• Verified date: December 2014
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

This study represents a randomized, double blind placebo-controlled trial. Thirty cocaine dependant patients will be included in this study during their hospitalization for withdrawal. After the inclusion visit, they will be randomized to receive disulfiram 250 mg/day or placebo over the 15 days of their hospitalization. Main outcome criteria will be evaluated during two TEP imaging sessions with 11Craclopride, before and after stimulation by methylphenidate, 8 to 15 days after randomization.

Description:

"Dopamine beta-hydroxylase (DHB) inhibition represents a promising approach to treating cocaine dependence. DBH is the enzyme responsible for hydroxylation of dopamine into noradrenaline. Its inhibition suppresses noradrenaline secretion. In animal studies, the efficacy of DBH inhibition in psychostimulants use could be linked to a reduced dopaminergic response, possibly in association with post synaptic dopaminergic receptor hypersensitivity. In humans, the clinical efficacy of DBH inhibition, in particular following disulfiram administration, is in the process of being established. However, its particular mode of action remains unclear: some publications suggest an increased aversive reaction to cocaine, whereas others report decreased positive effects. To date, the impact of DBH inhibition on dopaminergic response to psychostimulants has yet to be studied in humans.

This study represents a randomized, double blind placebo-controlled trial. Thirty cocaine dependant patients will be included in this study during their hospitalization for withdrawal. After the inclusion visit, they will be randomized to receive disulfiram 250 mg/day or placebo over the 15 days of their hospitalization. Main outcome criteria will be evaluated during two TEP imaging sessions with 11Craclopride, before and after stimulation by methylphenidate, 8 to 15 days after randomization. The main outcome criterion will be the variations in linkage rates of 11Craclopride in the nucleus accumbens between baseline TEP measurement and TEP measurement following administration of 20 mg of methylphenidate.

The primary objective of this trial is to show that in abstinent cocaine patients, DBH inhibition by disulfiram induces reduced dopaminergic response following methylphenidate administration. The secondary objectives of this trial are:

1. to show that methylphenidate stimulation induces less craving and more aversive responses in the disulfiram vs placebo condition;

2. to show that DBH inhibition by disulfiram elevates D2 dopaminergic receptor availability (in the absence of methylphenidate stimulation);

3. to show that the availability of D2 dopaminergic receptors (in the absence of methylphenidate stimulation) is linked to DBH activity;

4. to confirm that in abstinent cocaine patients, disulfiram reduces DBH activity vs placebo;

5. to confirm that subjects with weak DBH activity have more aversive reactions to cocaine.

Currently, disulfiram is the only drug on the market that inhibits DBH. Another more specific DBH inhibitor is currently under development. It is possible that other inhibitors could soon be developed by the pharmaceutical industry in the area of psychoactive drug addiction or other psychiatric or somatic disorders. The development of this new therapeutic approach requires a better understanding of its action mechanism.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: December 2016
• Est. primary completion date: April 2016
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• men aged 18 years ans less than or equal 65

• diagnosis of cocaine dependence according to DSM IV

• hospitalization for cocaine withdrawal

• ability to understand and give informed consent orally ans in writing

• affiliation to a social security

• patient with a normal ECG and normal blood pressure

Exclusion Criteria:

• Psychiatric comorbidity : psychotic disorder, manic episode , major depressive current , high suicide risk , assessed by structured interview of the Mini International Neuropsychiatric Interview

• Neurological histories: neurological deficit focused, organic cerebral disorder , epilepsy, dementia

• Severe hepatic insufficiency

• Severe renal insufficiency

• Severe respiratory

• Diabetes

• Hypersensitivity disulfiram or any of the other components

• Neuropsychological disorder

• Preexisting cardiovascular disorders

• Hypersensitivity to methylphenidate or any of the excipients

• Hyperthyroidism or thyrotoxicosis

• Glaucoma

• Pheochromocytoma

• Preexisting cerebrovascular disorders

• Patient presenting an allergy to the wheat

• HIV or HCV seropositivity

• Family or personal history of motor tics, and syndrome of Gilles Tourette

• Any disorder that may interfere with adherence to treatment

• Pharmacological treatment interfering with catecholamines

• Participation in another clinical trial or exclusion period of a previous clinical trial

• Contraindications to magnetic resonance imaging

• People under placement measure

• Hypersensitivity to any component of NIQUITIN

• Skin disorder that may interfere with the use of a transdermal patch

• Patient under treatment with irreversible inhibitors of mono- amine oxidase inhibitors (MAOIs ) , and for at least 14 days following the stop of the treatment by an IMAO.

• Diagnosis or history of bipolar disorders (affective ) episodic and severe ( type 1 )"

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cocaine Dependence

Intervention

Drug:
• Disulfiram
Thirty cocaine dependant patients will be included in this study during their hospitalization for withdrawal. After the inclusion visit, they will be randomized to receive disulfiram 250 mg/day or placebo over the 15 days of their hospitalization.
• Placebo
Thirty cocaine dependant patients will be included in this study during their hospitalization for withdrawal. After the inclusion visit, they will be randomized to receive disulfiram 250 mg/day or placebo over the 15 days of their hospitalization.

Locations

Country	Name	City	State
France	Paul Brousse Hospital	Villejuif

Sponsors (2)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	National Research Agency, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Variations in linkage rates of 11Craclopride in the nucleus accumbens between baseline TEP measurement and TEP measurement following administration of 20 mg of methylphenidate.	The primary objective of this trial is to show that in abstinent cocaine patients, DBH inhibition by disulfiram induces reduced dopaminergic response following methylphenidate administration.	up to 15 days after randomization	Yes
Secondary	DBH activity as measured directly, and indirectly by the DHPG / DOPAC report.		Before and after stimulation by methylphenidate, 8 to 15 days after randomization.	Yes
Secondary	Measurement of craving in cocaine by a simple Likert scale.		Before and after stimulation by methylphenidate, 8 to 15 days after randomization.	Yes
Secondary	Measure of aversion to cocaine by a simple Likert scale.		before and after stimulation by methylphenidate, 8 to 15 days after randomization.	Yes