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

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ClinicalTrials.gov Identifier: NCT02134002
Recruitment Status : Withdrawn (Too selective recrutment criteria, none eligible patients)
First Posted : May 8, 2014
Last Update Posted : December 9, 2014
Sponsor:
Collaborator:
National Research Agency, France
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE May 7, 2014
First Posted Date  ICMJE May 8, 2014
Last Update Posted Date December 9, 2014
Study Start Date  ICMJE June 2014
Estimated Primary Completion Date April 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 7, 2014)
Variations in linkage rates of 11Craclopride in the nucleus accumbens between baseline TEP measurement and TEP measurement following administration of 20 mg of methylphenidate. [ Time Frame: up to 15 days after randomization ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 7, 2014)
  • DBH activity as measured directly, and indirectly by the DHPG / DOPAC report. [ Time Frame: Before and after stimulation by methylphenidate, 8 to 15 days after randomization. ]
  • Measurement of craving in cocaine by a simple Likert scale. [ Time Frame: Before and after stimulation by methylphenidate, 8 to 15 days after randomization. ]
  • Measure of aversion to cocaine by a simple Likert scale. [ Time Frame: before and after stimulation by methylphenidate, 8 to 15 days after randomization. ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A PET Exploration of the Mechanism of Action of Dopamine Beta-hydroxylase Inhibition in Cocaine Addicts
Official Title  ICMJE 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
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.

"

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cocaine Dependence
Intervention  ICMJE
  • 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.
  • 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.
    Other Name: Placebo of disulfiram
Study Arms  ICMJE
  • Experimental: Disulfiram
    disulfiram 250 mg/day
    Intervention: Drug: Disulfiram
  • Placebo Comparator: Placebo
    Placebo
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Withdrawn
Actual Enrollment  ICMJE
 (submitted: December 7, 2014)
0
Original Estimated Enrollment  ICMJE
 (submitted: May 7, 2014)
80
Estimated Study Completion Date  ICMJE December 2016
Estimated Primary Completion Date April 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 )"
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02134002
Other Study ID Numbers  ICMJE P121006
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE National Research Agency, France
Investigators  ICMJE
Principal Investigator: Henri-Jean AUBIN, MD, PhD Assistance Publique - Hôpitaux de Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date December 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP