Clinical trial NCT05093296: Oxytocin and Naltrexone: Investigation of Combined Effects on Stress- and Alcohol Cue-induced Craving in Alcohol Use Disorder
Official title: Oxytocin and Naltrexone: Investigation of Combined Effects on Stress- and Alcohol Cue-induced Craving in Alcohol Use Disorder - a Randomized Double-blind Placebo-controlled Parallel-group Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Alcohol Use Disorder
Alcoholism
Alcohol Addiction
Lead sponsor: Central Institute of Mental Health, Mannheim
Sponsor class: OTHER
Collaborators: name: Heidelberg University - Institute of Medical Biometry (IMBI)
name: Heidelberg University - Coordination Centre for Clinical Trials (KKS) of Heidelberg University
name: German Federal Ministry of Education and Research
First posted: 2021-10-26
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Alcohol use disorder (AUD) is a chronic relapsing disorder. Alcohol craving, a hallmark symptom of AUD that drives relapse in patients, is only insufficiently treated by existing medication. One promising new compound is Oxytocin (OXY), which showed beneficial effects on alcohol craving in preliminary clinical studies. Additionally, OXY seems to enhance effects of established medication, specifically Naltrexone (NTX), an opioid-antagonist which is approved for AUD treatment via positive synergism on neurotransmitter levels. The proposed two-armed, 1:1 randomized, double-blind, parallel group trial seeks to test the putative synergistic effects of combined intranasal OXY spray (24 IU) + oral NTX (50mg) against Placebo spray + oral NTX (50mg) on alcohol craving (primary outcome) in male and female patients with AUD that suffer from high alcohol craving, within the framework of a validated alcohol cue-and stress-exposure task (i.e. a combined Trier Stress Test and alcohol cue-exposure) that was established for screening new medications in AUD and determine their effects on craving and relapse risk. Treatment effects on additional neurobiological and biochemical markers of craving that show strong associations to individual relapse risk, will serve as secondary outcomes. Collection and analysis of follow-up data (90 days) will be performed to determine whether treatment effects relate to patient outcome.

The clinical trial period for an individual participant consists of a screening visit (visit 1), a baseline visit (visit 2) and two treatment visits (visits 3 and 4)(all within equal or less than ten days) followed by a 90 days (+/- 7 days) follow-up phase with two visits (visits 5 and 6) at day 30 (± 7 days) and day 90 (± 7 days). Visits 1 to 4 will be conducted while participants are undergoing standard in-patient treatment at the Department of Addictive Behavior and Addiction medicine at the Central Institute of Mental Health (CIMH) in Mannheim, Germany, for the medical condition under investigation.


Eligibility criteria: Inclusion Criteria:

* Age between 18 and 70 years
* Patients meeting the diagnosis of an alcohol dependence according to the Internation Clasification of Diseases 10th revision (ICD10)
* Patients with at least moderate craving, i.e. either \>=15 points on the Alcohol Urge Questionnaire (AUQ, range 8 to 56 points) craving scale or increase in AUQ scores by \>= 50% after exposure to visual alcohol cues (i.e. minimum increase of \>=4 points after cue exposure)
* Ability of the individual to understand the character and the individual consequences of the clinical trial
* Written informed consent (must be available before enrollment in the study)
* Consent to random assignment
* For women with childbearing potential, use of a highly effective birth control method until 24 hours after Visit 4 and negative pregnancy test

Exclusion Criteria:

* Subjects presenting with any of the following criteria will not be included in the clinical trial: Current psychotic or bipolar disorder or current severe depressive episode with suicidal ideations
* Current treatment with any of the following substances: Any investigational medicinal product, Opioid-containing Analgesics, Anorexics, Anticonvulsants, Opioid-containing Antidiarrheal Agents, Antineoplastics, Antipsychotics (exception: episodic use of melperone, pipamperone and quetiapine are allowed), Antidepressants (exception: allowed, when being taken in stable dose for a minimum of 14 days prior to enrolment and/or doxepin in low doses \[max. 75mg daily\]), Opioid-containing Cough/cold agents, systemic Steroids
* Positive drug screening (amphetamines/ecstasy, opiates, cocaine, barbiturates)
* Pregnancy, lactation or breastfeeding
* Current severe somatic comorbidities: liver cirrhosis \[CHILD B or C\] or impaired renal function \[glomerular filtration rate (GFR)\<15ml/Min\] \[each determined by physical examination and/or laboratory testing\], severe heart insufficiency \[determined by assessment of medical history\], pre-existing epilepsy \[determined by assessment of medical history\], long-QT syndrome or cardial arrhythmia \[determined by ECG\]
* History of hypersensitivity to the investigational medicinal product Oxytocin (Syntocinon®) and/or Naltrexone (trade names: Adepend, Naltrexon-Hcl neuraxpharm, Naltrexonhydrochlorid Accord) or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product Oxytocin (Syntocinon®) and/or Naltrexone
* Participation in other clinical trials or observation period of competing clinical trials, respectively.
* Acute suicidal tendency or acute endangerment of self and others

Primary outcomes:
measure: Alcohol Urge Questionnaire (AUQ)
timeFrame: 60 minutes after oxytocin/placebo application and directly after the combined stress- and cue-exposure will serve as primary outcome measure at Visit 3
Secondary outcomes:
measure: Alcohol Urge Questionnaire (AUQ)
timeFrame: 35 minutes after oxytocin/placebo application at Visit 3
measure: Alcohol Urge Questionnaire (AUQ)
timeFrame: 70 minutes after oxytocin/placebo application at Visit 3
measure: Alcohol Urge Questionnaire (AUQ)
timeFrame: 80 minutes after oxytocin/placebo application at Visit 3
measure: Alcohol Urge Questionnaire (AUQ)
timeFrame: 90 minutes after oxytocin/placebo application at Visit 3
measure: Alcohol Urge Questionnaire (AUQ)
timeFrame: 85 minutes after oxytocin/placebo application, i.e. directly fMRI session at Visit 4
measure: Primary Appraisal secondary Appraisal Scale (PASA)
timeFrame: 35 minutes after oxytocin/placebo application at Visit 3
measure: Primary Appraisal secondary Appraisal Scale (PASA)
timeFrame: 60 minutes after oxytocin/placebo application at Visit 3
measure: Primary Appraisal secondary Appraisal Scale (PASA)
timeFrame: 90 minutes after oxytocin/placebo application at Visit 3
measure: Primary Appraisal secondary Appraisal Scale (PASA)
timeFrame: 85 minutes after oxytocin/placebo application, i.e. directly fMRI session at Visit 4
measure: Positive and Negative Affect Schedule (PANAS)
timeFrame: 60 minutes after oxytocin/placebo application at Visit 3
measure: Positive and Negative Affect Schedule (PANAS)
timeFrame: 85 minutes after oxytocin/placebo application, i.e. directly fMRI session at Visit 4
measure: Cortisol
timeFrame: 65 minutes after oxytocin/placebo application at Visit 3
measure: Oxytocin
timeFrame: 30 minutes after oxytocin/placebo application at Visit 3
measure: Oxytocin
timeFrame: 65 minutes after oxytocin/placebo application at Visit 3
measure: Alcohol Cue-induced neural brain activation during an Alcohol cue-reactivity functional magnetic resonance imaging (fMRI) task
timeFrame: During fMRI session at Visit 4, i.e. 40 to 85 minutes after Oxytocin/Placebo administration
measure: Neural Activation during a natural reward cue-reactivity fMRI task
timeFrame: During fMRI session at Visit 4, i.e. 40 to 85 minutes after Oxytocin/Placebo administration
measure: Neural Activation during a Face-matching fMRI task
timeFrame: During fMRI session at Visit 4, i.e. 40 to 85 minutes after Oxytocin/Placebo administration
measure: Neural Activation during a Stop Signal fMRI Task
timeFrame: During fMRI session at Visit 4, i.e. 40 to 85 minutes after Oxytocin/Placebo administration
measure: Adverse Events (AEs)/Serious Adverse Events (SAEs) and Discontinuation rate
timeFrame: During Study Visits 1 to 6, including the 90 day (±7 day) follow-up period
measure: Subjective quality of life index
timeFrame: At Visit 5, i.e. 30 days (+/- 7 days) after Visit 3
measure: Subjective quality of life index
timeFrame: At Visit 6, i.e. 90 days (+/- 7 days) after Visit 3
measure: Time to relapse during the follow-up period of 90 days (+/- 7 days)
timeFrame: During 90-day (± 7 days) Follow-up
measure: Cumulative alcohol consumption during the follow-up period of 90 days (+/- 7 days)
timeFrame: During 90-day (± 7 days) Follow-up
measure: Percent heavy drinking days during the follow-up period of 90 days (+/- 7 days)
timeFrame: During 90-day (± 7 days) Follow-up
Other outcomes:
Locations:
city: Mannheim
country: Germany
facility: Central Institute of Mental Health
Study officials:
affiliation: Central Institute of Mental Health, Mannheim
name: Patrick Bach, MD
role: STUDY_DIRECTOR
References:
citation: Zimmermann S, Thomas BC, Krisam J, Limprecht R, Klose C, Stenger M, Pourbaix M, Ries M, Vollstaedt-Klein S, Koopmann A, Lenz B, Kiefer F, Bach P. ON-ICE trial: Investigation of the combined effects of oxytocin and naltrexone on stress-induced and alcohol cue-induced craving in alcohol use disorder-Study protocol of a phase II randomised double-blind placebo-controlled parallel-group trial. BMJ Open. 2022 Apr 11;12(4):e059672. doi: 10.1136/bmjopen-2021-059672.