Varenicline and Bupropion for Alcohol Use Disorder

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

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.

Study Overview

• Status: Completed
• Conditions: Alcohol Dependence; Alcoholism; Alcohol Use Disorder
• Intervention / Treatment: Drug: Varenicline Tartrate 1 mg b.i.d; Drug: Bupropion Hydrochloride 150 mg b.i.d; Other: Placebo for bupropion; Other: Placebo for varenicline

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.

• Study Type: Interventional
• Enrollment (Actual): 388
• Phase: Phase 2

Contacts and Locations

Study Locations

• Sweden
  • Gothenburg, Sweden
    • Beroendekliniken, Sahlgrenska University Hospital, Västra Götalandsregionen
  • Region Skåne
    • Malmö, Region Skåne, Sweden
      • Beroendecentrum Malmö
  • Region Östergötland
    • Linköping, Region Östergötland, Sweden
      • Linköping University Hospital
  • Stockholms Läns Sjukvårdområde
    • Stockholm, Stockholms Läns Sjukvårdområde, Sweden
      • Stockholm Centre for Dependency Disorders,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 25 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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. Analysed as mean reduction of PEth per treatment arm, mITT.	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 as ≥70 grams for men and ≥56 grams for women according to FDA's guidelines. Analysed as mean reduction in HDD share per treatment arm, for mITT	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)
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)
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
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)
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 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

Collaborators and Investigators

• Sponsor: Vastra Gotaland Region
• Investigators: Principal Investigator: Bo Söderpalm, Prof, MD, Sahlgrenska University Hospital, Västra Götaland

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2019
• Primary Completion (Actual): December 15, 2022
• Study Completion (Actual): December 15, 2022

Study Registration Dates

• First Submitted: September 30, 2019
• First Submitted That Met QC Criteria: November 14, 2019
• First Posted (Actual): November 18, 2019

Study Record Updates

• Last Update Posted (Actual): June 7, 2024
• Last Update Submitted That Met QC Criteria: December 14, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Alcohol Drinking; Alcoholism; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Enzyme Inhibitors; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Cytochrome P-450 Enzyme Inhibitors; Nicotinic Agonists; Cholinergic Agonists; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Dopamine Uptake Inhibitors; Bupropion; Varenicline
• Other Study ID Numbers: COMB-BO8; 2018-000048-24 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No