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Varenicline and Bupropion for Alcohol Use Disorder

Primary Purpose

Alcohol Use Disorder, Alcoholism, Alcohol Dependence

Status

Unknown status

Phase

Phase 2

Locations

Sweden

Study Type

Interventional

Intervention

Varenicline Tartrate 1 mg b.i.d

Bupropion Hydrochloride 150 mg b.i.d

Placebo for varenicline

Placebo for bupropion

About this trial

This is an interventional treatment trial for Alcohol Use Disorder

Eligibility Criteria

25 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Signed informed consent
Blood alcohol level below <0.1‰ (0.1 g/L) at signing informed consent
25-70 years of age at screening
Moderate and severe AUD according to DSM-V (meeting ≥4 out of 11 criteria)
B-PEth levels of ≥0.5 µmol/L at screening visit (visit 1)
Continuous high alcohol consumption over the last 3 months prior to screening as defined by at least 2 HDD per week on a typical week
Available phone number for contact
Ability to speak and write in Swedish

Exclusion Criteria:

Total abstinence between screening and randomization visit
Treatment of alcohol withdrawal within 30 days of study initiation
Pharmacological treatment within 3 months of study initiation and during the study period that may affect alcohol consumption, including but not exclusive to, varenicline, bupropion, disulfiram, acamprosate, naltrexone, nalmefene, baclofen, topiramate, ondansetron, mirtazapine, methylphenidate, dexamphetamine, atomoxetine, pregabalin, buprenorphine and methadone
Non-pharmacological treatment within 3 months of study initiation and during the study period that may affect alcohol consumption
Current continuous use of antidepressants, opioid analgesics, benzodiazepines, zopiclone, zolpidem, hydroxyzine, alimemazine, propiomazine, or other sedatives. (The sporadic use of these compounds is accepted.)
Any concurrent medication that may affect the results of the trial or is considered to compromise the safety of the participants in the trial. (See SmPCs for possible interactions.)
Laboratory hepatic values of >3 times the upper limit of the normal range, creatinine clearance <30 ml/min, or other clinically significant abnormalities in the screening laboratory values
Blood pressure ≥180/110 at screening
Pregnancy, breast-feeding and for premenopausal women, not using one of the contraceptive methods oral contraceptive, intrauterine contraceptive device (copper or hormonal) or subcutaneous inplant.
Diabetes mellitus type 1 and diabetes mellitus type 2 in need of insulin treatment
Any current psychiatric or somatic disorder or condition that may affect assessments or compromise participant's safety during the trial
ASRS- v1.1, part A score ≥4 in the marked cut-off section
MADRS score ≥ 20
Current depression that is not mild (mild depression is accepted)
Suicidality
Current illicit drug use based on urine-toxicity test and DUDIT
History of delirium tremens or abstinence-induced seizures within 5 years of study initiation
Epilepsy or seizures other than alcohol-induced, lifetime
Severe sleep disturbances
Need of alcohol detoxification
Living conditions not appropriate to fulfil study requirements
Use of herbal drugs/tea and supplementations possibly affecting outcome or safety
Previous randomization in this trial or participation in another trial within 3 months of enrollment into this trial.
Additional factors that render the participant unable to complete the study, as judged by the investigator

Sites / Locations

Psykiatrin Halland
Linköping University Hospital
Stockholm Centre for Dependency Disorders,Recruiting
Psykiatrin Borås/Vuxenpsykiatrisk mottagning beroende, Borås, Västra Götalandsregionen
Beroendekliniken, Sahlgrenska University Hospital, Västra GötalandsregionenRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Arm Label

1) Varenicline + Bupropion

2) Varenicline + Placebo for Bupropion

3) Bupropion + Placebo for Varenicline

4) Placebo for Varenicline + Placebo for Bupropion

Arm Description

Investigational medicinal product (IMP) 1: Varenicline 0.5 mg and 1.0 mg and Investigational medicinal product (IMP) 2: Bupropion SR 150 mg

Investigational medicinal product (IMP) 1: Varenicline 0.5 mg and 1.0 mg and Placebo capsule for IMP 2 (bupropion)

Investigational medicinal product (IMP) 2: Bupropion SR 150 mg and Placebo capsule for IMP 1 (varenicline)

Placebo capsule for IMP 1 (varenicline) and Placebo capsule for IMP 2 (bupropion)

Outcomes

Primary Outcome Measures

Alcohol consumption as measured by phosphatidylethanol (PEth) in blood

B-PEth: Objective marker for alcohol consumption measured in blood,measured at every study visit

Alcohol consumption as measured by heavy drinking days (HDD)

HDD is obtained by the time Line Follow Back procedure, defined in two ways; as ≥60 grams for men and ≥40 for women according to EMA's guideline and as ≥70 grams for men and ≥56 grams for women according to FDA's guidelines

Secondary Outcome Measures

CDT

The indirect alcohol marker carbohydrate deficient transferrin

GGT

The indirect alcohol marker gamma glutamyl transferase

Self-reported alcohol consumption measured by time-lime-follow-back

Mean grams of alcohol per day Number of drinking days Number of drinks per drinking days Number of abstaining days

Alcohol Use Identification Test

Total score of Alcohol Use Identification Test

Self-reported Alcohol Craving

Alcohol craving as measured by a Visual Analogue Scale (VAS)

Nicotine use

Nicotine use measured by the nicotine saliva marker cotinine in saliva

The Temporal Experience of Pleasure Scale (TEPS)

A 17-item scale with anticipatory and consummatory components of the experience of pleasure. The scale is used as a proxy to assess a hypodopaminergic state. Worse Outcome: A lower score indicates low experience of pleasure (=proxy for hypodopaminergic state). Better outcome:A high score indicates high experience of pleasure.

The Continous Performance Test + Activity test

A neuropsychiatric tool addressing inattention, impulsivity and activity

Plasma concentration of varenicline (ng/ml)

Mean concentration of values obtained at visit 4 and visit 6

Plasma concentration of bupropion (ng/ml)

Mean concentration of values obtained at visit 4 and visit 6

Full Information

NCT ID

NCT04167306

First Posted

September 30, 2019

Last Updated

November 26, 2019

Sponsor

Vastra Gotaland Region

1. Study Identification

Unique Protocol Identification Number

NCT04167306

Brief Title

Varenicline and Bupropion for Alcohol Use Disorder

Official Title

A Randomized, Double-blind, Placebo-controlled Multicenter Trial on the Efficacy of Varenicline and Bupropion in Combination and Alone, for Treatment of Alcohol Use Disorder

Study Type

Interventional

2. Study Status

Record Verification Date

November 2019

Overall Recruitment Status

Unknown status

Study Start Date

March 4, 2019 (Actual)

Primary Completion Date

December 30, 2022 (Anticipated)

Study Completion Date

December 30, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Vastra Gotaland Region

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

The COMB study is a randomized double-blind placebo-controlled multicenter trial in Sweden on the efficacy of varenicline and bupropion, in combination and alone, for treatment of alcohol use disorder (AUD). Study design overview: A 13-weeks (91 days) multicenter clinical trial with four parallel groups. 95 subjects per treatment arm will be randomized into the study. 380 subjects with AUD will be randomized in total.

Detailed Description

Varenicline (Champix®) and bupropion (Zyban®, patent time expired) are approved and marketed in Europe and US for smoking cessation in nicotine use disorder, and for treatment of major depression (bupropion). There is clinical evidence of an additive effect of the drug combination of varenicline and bupropion on smoking cessation. Varenicline has been shown in two RCTs to reduce also alcohol intake in subjects with AUD. It is hypothesized that bupropion will enhance the effect of varenicline and that the combined effect size will be greater than that of approved therapies for AUD. As efficacy endpoint, the trial uses the alcohol specific biomarker for alcohol intake, phosphatidylethanol in blood (B-PEth). Outcome will also be measured by self-reported alcohol consumption, the standard effect measure in AUD trials.This will be the first trial using the biomarker B-PEth as primary outcome variable. The use of a specific objective marker is expected to increase chances for detecting treatment effects. Development phase: II Number of randomized subjects: 380 subjects with AUD. 95 subjects per treatment arm will be randomized into the study. Number of sites: Approximately 5 study sites in Sweden Investigational medicinal products, dosages and administration: There will be two separate study kits for IMP 1 and IMP 2 Investigational medicinal product 1 (IMP1): Varenicline 1 mg x 2 p.o. daily. The pharmaceutical formulation will be encapsulated tablets for oral use. Varenicline will be escalated from 0.5 to 2 mg daily during the first week. Investigational medicinal product 2 (IMP 2): Bupropion SR 150 mg x 2 p.o. daily. The pharmaceutical formulation will be encapsulated sustained release (SR) tablets for oral use. Bupropion will be escalated from 150 to 300 mg daily during the first week. IMP 1 and IMP 2 are distributed at 7 occasions: Day 0, Day 7, Day 21, Day 35, Day 49, Day 63 and Day 77. The doses and route of administration for varenicline and bupropion are those approved and recommended as oral formulations for smoking cessation. The trial comprises 9 study visits over 91 days: Screening visit,Day 0, Day 7, Day 21, Day 35, Day 49, Day 63, Day 77 and Day 91. Randomization is carried out according to block randomization and eligible subjects are randomized to one of the below described intervention arms. The study will be performed in accordance with the study protocol, with the latest version of the Declaration of Helsinki, in accordance with GCP principles (ICH-GCP E6-R2), and applicable regulatory requirements in Sweden . The study is approved by competent authority (the Swedish Medical Product Agency) and the Etics committee. The trial is monitored by an independent monitor according to GCP principles.

6. Conditions and Keywords

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

Alcohol Use Disorder, Alcoholism, Alcohol Dependence

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Appointed manufacturer produces, packs and labels the IMPs in two separate IMP kits and uses a blinding procedure accordance with internal standard operating procedure. IMP 1 and IMP 2, will have an unique Randomization Number generated randomly. For each randomization number, a sealed emergency code envelope will follow the shipment.

Allocation

Randomized

Enrollment

380 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

1) Varenicline + Bupropion

Arm Type

Experimental

Arm Description

Investigational medicinal product (IMP) 1: Varenicline 0.5 mg and 1.0 mg and Investigational medicinal product (IMP) 2: Bupropion SR 150 mg

Arm Title

2) Varenicline + Placebo for Bupropion

Arm Type

Experimental

Arm Description

Investigational medicinal product (IMP) 1: Varenicline 0.5 mg and 1.0 mg and Placebo capsule for IMP 2 (bupropion)

Arm Title

3) Bupropion + Placebo for Varenicline

Arm Type

Experimental

Arm Description

Investigational medicinal product (IMP) 2: Bupropion SR 150 mg and Placebo capsule for IMP 1 (varenicline)

Arm Title

4) Placebo for Varenicline + Placebo for Bupropion

Arm Type

Placebo Comparator

Arm Description

Placebo capsule for IMP 1 (varenicline) and Placebo capsule for IMP 2 (bupropion)

Intervention Type

Drug

Intervention Name(s)

Varenicline Tartrate 1 mg b.i.d

Other Intervention Name(s)

Champix

Intervention Description

Capsules for oral use

Intervention Type

Drug

Intervention Name(s)

Bupropion Hydrochloride 150 mg b.i.d

Other Intervention Name(s)

Bupropion Sandoz

Intervention Description

Capsules for oral use

Intervention Type

Other

Intervention Name(s)

Placebo for varenicline

Intervention Description

Capsules for oral use

Intervention Type

Other

Intervention Name(s)

Placebo for bupropion

Intervention Description

Capsules for oral use

Primary Outcome Measure Information:

Title

Alcohol consumption as measured by phosphatidylethanol (PEth) in blood

Description

B-PEth: Objective marker for alcohol consumption measured in blood,measured at every study visit

Time Frame

PEth is calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value)

Title

Alcohol consumption as measured by heavy drinking days (HDD)

Description

Time Frame

Number of HDD by 14 days is defined as a mean over the 8-week steady state active treatment period (Day 21-Day77) . ( D21-D77)/4 in order to get a 14 day-period measurment.

Secondary Outcome Measure Information:

Title

CDT

Description

The indirect alcohol marker carbohydrate deficient transferrin

Time Frame

CDT is calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value)

Title

GGT

Description

The indirect alcohol marker gamma glutamyl transferase

Time Frame

GGT calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value)

Title

Self-reported alcohol consumption measured by time-lime-follow-back

Description

Mean grams of alcohol per day Number of drinking days Number of drinks per drinking days Number of abstaining days

Time Frame

CDT is calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value)

Title

Alcohol Use Identification Test

Description

Total score of Alcohol Use Identification Test

Time Frame

Mean difference between total score obtained at baseline and visit 1

Title

Self-reported Alcohol Craving

Description

Alcohol craving as measured by a Visual Analogue Scale (VAS)

Time Frame

Scale range: 0-100 mm. Minimum value: 0 = No craving. Maxumum value: 100 Maximum= Very strong craving. Craving is calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value)

Title

Nicotine use

Description

Nicotine use measured by the nicotine saliva marker cotinine in saliva

Time Frame

77 day-interval. Mean difference between cotinine concentration assessed at Day o and Day 77

Title

The Temporal Experience of Pleasure Scale (TEPS)

Description

Time Frame

77 day-interval. Mean difference between total scale score assessed at Day 0 and Day 77

Title

The Continous Performance Test + Activity test

Description

A neuropsychiatric tool addressing inattention, impulsivity and activity

Time Frame

77 day-interval. Mean difference between outcome measure assessed at Day o and Day 7.

Title

Plasma concentration of varenicline (ng/ml)

Description

Mean concentration of values obtained at visit 4 and visit 6

Time Frame

14 day-interval. Obtained twice, at Day 21 and Day 49 during IMP steady state. Correlation between plasma concentration of varenicline and above described outcome measures

Title

Plasma concentration of bupropion (ng/ml)

Description

Mean concentration of values obtained at visit 4 and visit 6

Time Frame

14 day-interval. Obtained twice, at Day 21 and Day 49 during IMP steady state. Correlation between plasma concentration of bupropion and above described outcome measures

10. Eligibility

Sex

All

Minimum Age & Unit of Time

25 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Signed informed consent Blood alcohol level below <0.1‰ (0.1 g/L) at signing informed consent 25-70 years of age at screening Moderate and severe AUD according to DSM-V (meeting ≥4 out of 11 criteria) B-PEth levels of ≥0.5 µmol/L at screening visit (visit 1) Continuous high alcohol consumption over the last 3 months prior to screening as defined by at least 2 HDD per week on a typical week Available phone number for contact Ability to speak and write in Swedish Exclusion Criteria: Total abstinence between screening and randomization visit Treatment of alcohol withdrawal within 30 days of study initiation Pharmacological treatment within 3 months of study initiation and during the study period that may affect alcohol consumption, including but not exclusive to, varenicline, bupropion, disulfiram, acamprosate, naltrexone, nalmefene, baclofen, topiramate, ondansetron, mirtazapine, methylphenidate, dexamphetamine, atomoxetine, pregabalin, buprenorphine and methadone Non-pharmacological treatment within 3 months of study initiation and during the study period that may affect alcohol consumption Current continuous use of antidepressants, opioid analgesics, benzodiazepines, zopiclone, zolpidem, hydroxyzine, alimemazine, propiomazine, or other sedatives. (The sporadic use of these compounds is accepted.) Any concurrent medication that may affect the results of the trial or is considered to compromise the safety of the participants in the trial. (See SmPCs for possible interactions.) Laboratory hepatic values of >3 times the upper limit of the normal range, creatinine clearance <30 ml/min, or other clinically significant abnormalities in the screening laboratory values Blood pressure ≥180/110 at screening Pregnancy, breast-feeding and for premenopausal women, not using one of the contraceptive methods oral contraceptive, intrauterine contraceptive device (copper or hormonal) or subcutaneous inplant. Diabetes mellitus type 1 and diabetes mellitus type 2 in need of insulin treatment Any current psychiatric or somatic disorder or condition that may affect assessments or compromise participant's safety during the trial ASRS- v1.1, part A score ≥4 in the marked cut-off section MADRS score ≥ 20 Current depression that is not mild (mild depression is accepted) Suicidality Current illicit drug use based on urine-toxicity test and DUDIT History of delirium tremens or abstinence-induced seizures within 5 years of study initiation Epilepsy or seizures other than alcohol-induced, lifetime Severe sleep disturbances Need of alcohol detoxification Living conditions not appropriate to fulfil study requirements Use of herbal drugs/tea and supplementations possibly affecting outcome or safety Previous randomization in this trial or participation in another trial within 3 months of enrollment into this trial. Additional factors that render the participant unable to complete the study, as judged by the investigator

Central Contact Person:

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

Helga Lidö, PhD, Pharm

Phone

+46709179311

helga.lido@gu.se

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

Andrea deBejczy, PhD, MD

Phone

+46735930501

andrea.debejczy@neuro.gu.se

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Bo Söderpalm, Prof, MD

Organizational Affiliation

Sahlgrenska University Hospital, Västra Götaland

Official's Role

Principal Investigator

Facility Information:

Facility Name

Psykiatrin Halland

City

Kungsbacka

State/Province

Region Halland

Country

Sweden

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Hans Ackerot, MD

Facility Name

Linköping University Hospital

City

Linköping

State/Province

Region Östergötland

Country

Sweden

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Markus Heilig, MD, Prof

Facility Name

Stockholm Centre for Dependency Disorders,

City

Stockholm

State/Province

Stockholms Läns Sjukvårdområde

Country

Sweden

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Johan Franck, MD, Prof

Facility Name

Psykiatrin Borås/Vuxenpsykiatrisk mottagning beroende, Borås, Västra Götalandsregionen

City

Borås

State/Province

VGR

Country

Sweden

Individual Site Status

Not yet recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Ulrika T. Ekman, MD

Facility Name

Beroendekliniken, Sahlgrenska University Hospital, Västra Götalandsregionen

City

Gothenburg

Country

Sweden

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Bo Söderpalm, MD, Prof

12. IPD Sharing Statement

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Varenicline and Bupropion for Alcohol Use Disorder

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