Varenicline and Bupropion for Alcohol Use Disorder

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.

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