Varenicline and Bupropion for Alcohol Use Disorder

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Alcohol Use Disorder, Alcoholism, Alcohol Dependence

Intervention / Treatment
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* Drug: Varenicline Tartrate 1 mg b.i.d
* Drug: Bupropion Hydrochloride 150 mg b.i.d
* Other: Placebo for varenicline
* Other: Placebo for bupropion


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 25 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1) Varenicline + Bupropion<br>Investigational medicinal product (IMP) 1: Varenicline 0.5 mg and 1.0 mg and Investigational medicinal product (IMP) 2: Bupropion SR 150 mg | Drug: Varenicline Tartrate 1 mg b.i.d<br>* Capsules for oral use<br>* Other names: Champix;Drug: Bupropion Hydrochloride 150 mg b.i.d<br>* Capsules for oral use<br>* Other names: Bupropion Sandoz;|
| Experimental: 2) Varenicline + Placebo for Bupropion<br>Investigational medicinal product (IMP) 1: Varenicline 0.5 mg and 1.0 mg and Placebo capsule for IMP 2 (bupropion) | Drug: Varenicline Tartrate 1 mg b.i.d<br>* Capsules for oral use<br>* Other names: Champix;Other: Placebo for bupropion<br>* Capsules for oral use<br>|
| Experimental: 3) Bupropion + Placebo for Varenicline<br>Investigational medicinal product (IMP) 2: Bupropion SR 150 mg and Placebo capsule for IMP 1 (varenicline) | Drug: Bupropion Hydrochloride 150 mg b.i.d<br>* Capsules for oral use<br>* Other names: Bupropion Sandoz;Other: Placebo for varenicline<br>* Capsules for oral use<br>|
| Placebo Comparator: 4) Placebo for Varenicline + Placebo for Bupropion<br>Placebo capsule for IMP 1 (varenicline) and Placebo capsule for IMP 2 (bupropion) | Other: Placebo for varenicline<br>* Capsules for oral use<br>Other: Placebo for bupropion<br>* Capsules for oral use<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alcohol consumption as measured by phosphatidylethanol (PEth) in blood | B-PEth: Objective marker for alcohol consumption measured in blood,measured at every study visit | PEth is calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value) | 
| 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 | 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 Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CDT | The indirect alcohol marker carbohydrate deficient transferrin | CDT is calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value) | 
| GGT | The indirect alcohol marker gamma glutamyl transferase | GGT calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value) | 
| 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 | CDT is calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value) | 
| Alcohol Use Identification Test | Total score of Alcohol Use Identification Test | Mean difference between total score obtained at baseline and visit 1 | 
| Self-reported Alcohol Craving | Alcohol craving as measured by a Visual Analogue Scale (VAS) | 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) | 
| Nicotine use | Nicotine use measured by the nicotine saliva marker cotinine in saliva | 77 day-interval. Mean difference between cotinine concentration assessed at Day o and Day 77 | 
| 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. | 77 day-interval. Mean difference between total scale score assessed at Day 0 and Day 77 | 
| The Continous Performance Test + Activity test | A neuropsychiatric tool addressing inattention, impulsivity and activity | 77 day-interval. Mean difference between outcome measure assessed at Day o and Day 7. | 
| Plasma concentration of varenicline (ng/ml) | Mean concentration of values obtained at visit 4 and visit 6 | 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 | 
| Plasma concentration of bupropion (ng/ml) | Mean concentration of values obtained at visit 4 and visit 6 | 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 |