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.

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:

1. Signed informed consent
2. Blood alcohol level below <0.1‰ (0.1 g/L) at signing informed consent
3. 25-70 years of age at screening
4. Moderate and severe AUD according to DSM-V (meeting ≥4 out of 11 criteria)
5. B-PEth levels of ≥0.5 µmol/L at screening visit (visit 1)
6. 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
7. Available phone number for contact
8. Ability to speak and write in Swedish

Exclusion Criteria:

1. Total abstinence between screening and randomization visit
2. Treatment of alcohol withdrawal within 30 days of study initiation
3. 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
4. Non-pharmacological treatment within 3 months of study initiation and during the study period that may affect alcohol consumption
5. Current continuous use of antidepressants, opioid analgesics, benzodiazepines, zopiclone, zolpidem, hydroxyzine, alimemazine, propiomazine, or other sedatives. (The sporadic use of these compounds is accepted.)
6. 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.)
7. 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
8. Blood pressure ≥180/110 at screening
9. 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.
10. Diabetes mellitus type 1 and diabetes mellitus type 2 in need of insulin treatment
11. Any current psychiatric or somatic disorder or condition that may affect assessments or compromise participant's safety during the trial
12. ASRS- v1.1, part A score ≥4 in the marked cut-off section
13. MADRS score ≥ 20
14. Current depression that is not mild (mild depression is accepted)
15. Suicidality
16. Current illicit drug use based on urine-toxicity test and DUDIT
17. History of delirium tremens or abstinence-induced seizures within 5 years of study initiation
18. Epilepsy or seizures other than alcohol-induced, lifetime
19. Severe sleep disturbances
20. Need of alcohol detoxification
21. Living conditions not appropriate to fulfil study requirements
22. Use of herbal drugs/tea and supplementations possibly affecting outcome or safety
23. Previous randomization in this trial or participation in another trial within 3 months of enrollment into this trial.
24. Additional factors that render the participant unable to complete the study, as judged by the investigator

Analysis population mITT (modified Intention to Treat) defined as subjects that have taken at least one dose of study drug and documented at least one data entry

from inclusion (at informed consent) until last Follow-up at 30 days after study drug termination

safety population is equal to mITT population, subjects receiving at least one dose of study drug, N=384

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.