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Oxytocin and Naltrexone: Investigation of Combined Effects on Stress- and Alcohol Cue-induced Craving in Alcohol Use Disorder (ON-ICE)

Primary Purpose

Alcohol Use Disorder, Alcoholism, Alcohol Addiction

Status

Recruiting

Phase

Phase 2

Locations

Germany

Study Type

Interventional

Intervention

Oxytocin nasal spray

Naltrexone Pill

Placebo

About this trial

This is an interventional treatment trial for Alcohol Use Disorder

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Central Institute of Mental HealthRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Oxytocin + Naltrexone

Placebo + Naltrexone

Arm Description

All patients will receive 50mg Naltrexone daily (NTX, oral tablet) in the course of standard in-patient treatment. In the experimental group, patients will receive a single dose of 24 I.U. oxytocin nasal spray at two study visits during in-patient treatment: Visit 2 - First Application of Oxytocin 40 minutes prior to a combined stress- and alcohol cue-exposure during visit 2 Visit 3 - Second Application of Oxytocin 40 minutes prior to an fMRI-based assessment of alcohol cue-reactivity

All patients will receive 50mg Naltrexone daily (NTX, oral tablet) in the course of standard in-patient treatment. In the comparator group, patients will receive a placebo nasal spray (same composition as the verum oxytocin spray except for the active ingredient oxytocin) at two study visits during in-patient treatment: Visit 2 - First Application of Placebo 40 minutes prior to a combined stress- and alcohol cue-exposure during visit 2 Visit 3 - Second Application of Placebo 40 minutes prior to an fMRI-based assessment of alcohol cue-reactivity

Outcomes

Primary Outcome Measures

Alcohol Urge Questionnaire (AUQ)

Subjective Alcohol Craving will be assessed at separate time points before and after Oxytocin Administration using the AUQ

Secondary Outcome Measures

Alcohol Urge Questionnaire (AUQ)

Subjective Alcohol Craving will be assessed at separate time points before and after Oxytocin Administration using the AUQ

Alcohol Urge Questionnaire (AUQ)

Subjective Alcohol Craving will be assessed at separate time points before and after Oxytocin Administration using the AUQ

Alcohol Urge Questionnaire (AUQ)

Subjective Alcohol Craving will be assessed at separate time points before and after Oxytocin Administration using the AUQ

Alcohol Urge Questionnaire (AUQ)

Subjective Alcohol Craving will be assessed at separate time points before and after Oxytocin Administration using the AUQ

Alcohol Urge Questionnaire (AUQ)

Subjective Alcohol Craving will be assessed at separate time points before and after Oxytocin Administration using the AUQ

Primary Appraisal secondary Appraisal Scale (PASA)

Perceived stress will be assessed using the Primary Appraisal secondary Appraisal Scale (PASA) at separate time points before and after Oxytocin Administration using the AUQ at Visit 3 and Visit 4

Primary Appraisal secondary Appraisal Scale (PASA)

Perceived stress will be assessed using the Primary Appraisal secondary Appraisal Scale (PASA) at separate time points before and after Oxytocin Administration using the AUQ at Visit 3 and Visit 4

Primary Appraisal secondary Appraisal Scale (PASA)

Perceived stress will be assessed using the Primary Appraisal secondary Appraisal Scale (PASA) at separate time points before and after Oxytocin Administration using the AUQ at Visit 3 and Visit 4

Primary Appraisal secondary Appraisal Scale (PASA)

Perceived stress will be assessed using the Primary Appraisal secondary Appraisal Scale (PASA) at separate time points before and after Oxytocin Administration using the AUQ at Visit 3 and Visit 4

Positive and Negative Affect Schedule (PANAS)

Positive and Negative Affect will be assessed using the Positive and Negative Affect Schedule (PANAS) at separate time points before and after Oxytocin Administration using the AUQ at Visit 3 and Visit 4

Positive and Negative Affect Schedule (PANAS)

Cortisol

Cortisol plasma levels will be determined using validated Enzyme-linked Immunosorbent Assay (ELISA) methods by the central laboratory at visit 3 after Oxytocin/Placebo administration

Oxytocin

Oxytocin plasma levels will be determined using validated ELISA methods by the central laboratory at visit 3 after Oxytocin/Placebo administration

Oxytocin

Oxytocin plasma levels will be determined using validated ELISA methods by the central laboratory at visit 3 after Oxytocin/Placebo administration

Alcohol Cue-induced neural brain activation during an Alcohol cue-reactivity functional magnetic resonance imaging (fMRI) task

Neural brain activation in the mesocorticolimbic system (whole-brain and Region-of-Interest Analyses (ROIs): ventral striatum, dorsal striatum, insula), measured using the blood oxygenated level dependent (BOLD) response, during presentation of alcohol cues will serve as secondary outcome

Neural Activation during a natural reward cue-reactivity fMRI task

Neural brain activation in the mesocorticolimbic system (whole-brain and ROIs: ventral striatum, dorsal striatum, insula), measured using the blood oxygenated level dependent (BOLD) response during the presentation of natural reward cues will serve as secondary outcome

Neural Activation during a Face-matching fMRI task

Neural brain activation in the mesocorticolimbic system (whole-brain and ROIs: ventral striatum, dorsal striatum, insula, amygdala), measured using the blood oxygenated level dependent (BOLD) response during the presentation of emotional faces and neutral shapes will serve as secondary outcome

Neural Activation during a Stop Signal fMRI Task

Neural brain activation in the mesocorticolimbic system (whole-brain and ROIs: ventral striatum, dorsal striatum, insula, dlPFC), measured using the blood oxygenated level dependent (BOLD) response during a stop signal fMRI task will serve as secondary outcome

Adverse Events (AEs)/Serious Adverse Events (SAEs) and Discontinuation rate

Rate of adverse events, serious adverse events and rate of discontinuation of the study due to an adverse event

Subjective quality of life index

Quality of life will be assessed using the WHO-QOL-BREF scores

Subjective quality of life index

Quality of life will be assessed using the World Health Organization (WHO) Quality of life assessment (WHO-QOL-BREF) scores

Time to relapse during the follow-up period of 90 days (+/- 7 days)

Time from randomization to relapse to alcohol use (in days)

Cumulative alcohol consumption during the follow-up period of 90 days (+/- 7 days)

Self-reported cumulative alcohol use (in gram)

Percent heavy drinking days during the follow-up period of 90 days (+/- 7 days)

Self-reported percent heavy drinking days (in %)

Full Information

NCT ID

NCT05093296

First Posted

October 13, 2021

Last Updated

March 30, 2023

Sponsor

Central Institute of Mental Health, Mannheim

Collaborators

Heidelberg University - Institute of Medical Biometry (IMBI), Heidelberg University - Coordination Centre for Clinical Trials (KKS) of Heidelberg University, German Federal Ministry of Education and Research

1. Study Identification

Unique Protocol Identification Number

NCT05093296

Brief Title

Oxytocin and Naltrexone: Investigation of Combined Effects on Stress- and Alcohol Cue-induced Craving in Alcohol Use Disorder

Acronym

ON-ICE

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

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Recruiting

Study Start Date

December 2, 2021 (Actual)

Primary Completion Date

April 1, 2024 (Anticipated)

Study Completion Date

September 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Central Institute of Mental Health, Mannheim

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alcohol Use Disorder, Alcoholism, Alcohol Addiction

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2, Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

62 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Oxytocin + Naltrexone

Arm Type

Experimental

Arm Description

Arm Title

Placebo + Naltrexone

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Oxytocin nasal spray

Intervention Description

24 I.U. Oxytocin nasal Spray will be administered twice on two separate trial days.

Intervention Type

Drug

Intervention Name(s)

Naltrexone Pill

Intervention Description

All participants will receive 50mg Naltrexone daily as oral tablet throughout the study

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Placebo nasal spray (same composition as the verum oxytocin spray except for the active ingredient oxytocin)

Primary Outcome Measure Information:

Title

Alcohol Urge Questionnaire (AUQ)

Description

Subjective Alcohol Craving will be assessed at separate time points before and after Oxytocin Administration using the AUQ

Time Frame

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 Outcome Measure Information:

Title

Alcohol Urge Questionnaire (AUQ)

Description

Subjective Alcohol Craving will be assessed at separate time points before and after Oxytocin Administration using the AUQ

Time Frame

35 minutes after oxytocin/placebo application at Visit 3

Title

Alcohol Urge Questionnaire (AUQ)

Description

Subjective Alcohol Craving will be assessed at separate time points before and after Oxytocin Administration using the AUQ

Time Frame

70 minutes after oxytocin/placebo application at Visit 3

Title

Alcohol Urge Questionnaire (AUQ)

Description

Subjective Alcohol Craving will be assessed at separate time points before and after Oxytocin Administration using the AUQ

Time Frame

80 minutes after oxytocin/placebo application at Visit 3

Title

Alcohol Urge Questionnaire (AUQ)

Description

Subjective Alcohol Craving will be assessed at separate time points before and after Oxytocin Administration using the AUQ

Time Frame

90 minutes after oxytocin/placebo application at Visit 3

Title

Alcohol Urge Questionnaire (AUQ)

Description

Subjective Alcohol Craving will be assessed at separate time points before and after Oxytocin Administration using the AUQ

Time Frame

85 minutes after oxytocin/placebo application, i.e. directly fMRI session at Visit 4

Title

Primary Appraisal secondary Appraisal Scale (PASA)

Description

Perceived stress will be assessed using the Primary Appraisal secondary Appraisal Scale (PASA) at separate time points before and after Oxytocin Administration using the AUQ at Visit 3 and Visit 4

Time Frame

35 minutes after oxytocin/placebo application at Visit 3

Title

Primary Appraisal secondary Appraisal Scale (PASA)

Description

Perceived stress will be assessed using the Primary Appraisal secondary Appraisal Scale (PASA) at separate time points before and after Oxytocin Administration using the AUQ at Visit 3 and Visit 4

Time Frame

60 minutes after oxytocin/placebo application at Visit 3

Title

Primary Appraisal secondary Appraisal Scale (PASA)

Description

Perceived stress will be assessed using the Primary Appraisal secondary Appraisal Scale (PASA) at separate time points before and after Oxytocin Administration using the AUQ at Visit 3 and Visit 4

Time Frame

90 minutes after oxytocin/placebo application at Visit 3

Title

Primary Appraisal secondary Appraisal Scale (PASA)

Description

Perceived stress will be assessed using the Primary Appraisal secondary Appraisal Scale (PASA) at separate time points before and after Oxytocin Administration using the AUQ at Visit 3 and Visit 4

Time Frame

85 minutes after oxytocin/placebo application, i.e. directly fMRI session at Visit 4

Title

Positive and Negative Affect Schedule (PANAS)

Description

Time Frame

60 minutes after oxytocin/placebo application at Visit 3

Title

Positive and Negative Affect Schedule (PANAS)

Description

Time Frame

85 minutes after oxytocin/placebo application, i.e. directly fMRI session at Visit 4

Title

Cortisol

Description

Cortisol plasma levels will be determined using validated Enzyme-linked Immunosorbent Assay (ELISA) methods by the central laboratory at visit 3 after Oxytocin/Placebo administration

Time Frame

65 minutes after oxytocin/placebo application at Visit 3

Title

Oxytocin

Description

Oxytocin plasma levels will be determined using validated ELISA methods by the central laboratory at visit 3 after Oxytocin/Placebo administration

Time Frame

30 minutes after oxytocin/placebo application at Visit 3

Title

Oxytocin

Description

Oxytocin plasma levels will be determined using validated ELISA methods by the central laboratory at visit 3 after Oxytocin/Placebo administration

Time Frame

65 minutes after oxytocin/placebo application at Visit 3

Title

Alcohol Cue-induced neural brain activation during an Alcohol cue-reactivity functional magnetic resonance imaging (fMRI) task

Description

Time Frame

During fMRI session at Visit 4, i.e. 40 to 85 minutes after Oxytocin/Placebo administration

Title

Neural Activation during a natural reward cue-reactivity fMRI task

Description

Time Frame

During fMRI session at Visit 4, i.e. 40 to 85 minutes after Oxytocin/Placebo administration

Title

Neural Activation during a Face-matching fMRI task

Description

Time Frame

During fMRI session at Visit 4, i.e. 40 to 85 minutes after Oxytocin/Placebo administration

Title

Neural Activation during a Stop Signal fMRI Task

Description

Time Frame

During fMRI session at Visit 4, i.e. 40 to 85 minutes after Oxytocin/Placebo administration

Title

Adverse Events (AEs)/Serious Adverse Events (SAEs) and Discontinuation rate

Description

Rate of adverse events, serious adverse events and rate of discontinuation of the study due to an adverse event

Time Frame

During Study Visits 1 to 6, including the 90 day (±7 day) follow-up period

Title

Subjective quality of life index

Description

Quality of life will be assessed using the WHO-QOL-BREF scores

Time Frame

At Visit 5, i.e. 30 days (+/- 7 days) after Visit 3

Title

Subjective quality of life index

Description

Quality of life will be assessed using the World Health Organization (WHO) Quality of life assessment (WHO-QOL-BREF) scores

Time Frame

At Visit 6, i.e. 90 days (+/- 7 days) after Visit 3

Title

Time to relapse during the follow-up period of 90 days (+/- 7 days)

Description

Time from randomization to relapse to alcohol use (in days)

Time Frame

During 90-day (± 7 days) Follow-up

Title

Cumulative alcohol consumption during the follow-up period of 90 days (+/- 7 days)

Description

Self-reported cumulative alcohol use (in gram)

Time Frame

During 90-day (± 7 days) Follow-up

Title

Percent heavy drinking days during the follow-up period of 90 days (+/- 7 days)

Description

Self-reported percent heavy drinking days (in %)

Time Frame

During 90-day (± 7 days) Follow-up

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Patrick Bach, MD

Phone

+49-621-1703-0

patrick.bach@zi-mannheim.de

First Name & Middle Initial & Last Name or Official Title & Degree

Sina Zimmermann, M.Sc.

Phone

+49-621-1703-0

sina.zimmermann@zi-mannheim.de

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Patrick Bach, MD

Organizational Affiliation

Central Institute of Mental Health, Mannheim

Official's Role

Study Director

Facility Information:

Facility Name

Central Institute of Mental Health

City

Mannheim

ZIP/Postal Code

68159

Country

Germany

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Patrick Bach, MD

Phone

+496211703

Ext

patrick.bach@zi-mannheim.de

First Name & Middle Initial & Last Name & Degree

Sina Zimmermann, M.Sc.

Phone

+496211703

Ext

sina.zimmermann@zi-mannheim.de

First Name & Middle Initial & Last Name & Degree

Patrick Bach, MD

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Individual de-identified data will be shared, specifically individual participant data that underlie the results of the trial (i.e. primary outcome data [AUQ scores]) will be made available with a respective data dictionary. Secondary Outcome data (e.g. fMRI data) will be made available on aggregated group level (e.g. for the purpose of meta-analyses). Related documents, specifically the study protocol, statistical analysis plan and analytic code will be shared in open-access online repositories. Aggregated data will be made available to publicly accessible repositories (Neurosynth.org), e.g. for the purpose of meta-analyses.

IPD Sharing Time Frame

Data will be available upon publication of the results until 3 years after that.

IPD Sharing Access Criteria

Individual data will be shared with researchers who provide a methodologically sound proposal (sent to the Principal Investigator/Study Chair of the Trial).

Citations:

PubMed Identifier

35410938

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.

Results Reference

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Oxytocin and Naltrexone: Investigation of Combined Effects on Stress- and Alcohol Cue-induced Craving in Alcohol Use Disorder

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