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

NCT ID: NCT02134002

Last Updated: 2014-12-09

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE4
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-06-30
• Study Completion Date: 2016-12-31

Brief 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.

Detailed 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.

"

Conditions

Cocaine Dependence

Keywords

cocaine; disulfiram; beta-dopamine hydroxylase

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Disulfiram

disulfiram 250 mg/day

Group Type: EXPERIMENTAL

Disulfiram

Intervention Type: DRUG

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

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

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.

Intervention Type: DRUG

Other Intervention Names

Placebo of disulfiram

Eligibility Criteria

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 )"

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

National Research Agency, France

OTHER

Sponsor Role: collaborator

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Henri-Jean AUBIN, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Paris

Locations

Paul Brousse Hospital

Villejuif, , France

Countries

France

Other Identifiers

P121006

Identifier Type: -

Identifier Source: org_study_id