Alcohol Dependence, Alcoholism, Alcohol Use Disorder
Conditions
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.
Interventions
DRUGVarenicline Tartrate 1 mg b.i.d
Capsules for oral use
DRUGBupropion Hydrochloride 150 mg b.i.d
Capsules for oral use
Capsules for oral use
OTHERPlacebo for bupropion
Capsules for oral use
Sponsors
Vastra Gotaland Region
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes 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.
Eligibility
Sex/Gender
ALL
Age
25 Years to 70 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Alcohol Consumption as Measured by Phosphatidylethanol (PEth) in Blood | PEth is calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value) | 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. |
| Alcohol Consumption as Measured by Heavy Drinking Days (HDD) | 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. | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| GGT | GGT calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value) | The indirect alcohol marker gamma glutamyl transferase |
| Self-reported Alcohol Consumption Measured by Time-lime-follow-back | CDT is calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value) | Mean grams of alcohol per day * Number of drinking days * Number of drinks per drinking days * Number of abstaining days |
| Self-reported Alcohol Craving | 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) | Alcohol craving as measured by a Visual Analogue Scale (VAS) |
| Nicotine Use | 77 day-interval. Mean difference between cotinine concentration assessed at Day o and Day 77 | Nicotine use measured by the nicotine saliva marker cotinine in saliva |
| Alcohol Use Identification Test | Mean difference between total score obtained at baseline and visit 1 | Total score of Alcohol Use Identification Test |
| The Continous Performance Test + Activity Test | 77 day-interval. Mean difference between outcome measure assessed at Day o and Day 7. | A neuropsychiatric tool addressing inattention, impulsivity and activity |
| Plasma Concentration of Varenicline (ng/ml) | 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 | Mean concentration of values obtained at visit 4 and visit 6 |
| Plasma Concentration of Bupropion (ng/ml) | 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 | Mean concentration of values obtained at visit 4 and visit 6 |
| The Temporal Experience of Pleasure Scale (TEPS) | 77 day-interval. Mean difference between total scale score assessed at Day 0 and Day 77 | 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. |
| CDT | CDT is calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value) | The indirect alcohol marker carbohydrate deficient transferrin |
Countries
Sweden
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
Varenicline Tartrate 1 mg b.i.d: Capsules for oral use
Bupropion Hydrochloride 150 mg b.i.d: Capsules for oral use | 100 |
| 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)
Varenicline Tartrate 1 mg b.i.d: Capsules for oral use
Placebo for bupropion: Capsules for oral use | 96 |
| 3) Bupropion + Placebo for Varenicline Investigational medicinal product (IMP) 2: Bupropion SR 150 mg and Placebo capsule for IMP 1 (varenicline)
Bupropion Hydrochloride 150 mg b.i.d: Capsules for oral use
Placebo for varenicline: Capsules for oral use | 91 |
| 4) Placebo for Varenicline + Placebo for Bupropion Placebo capsule for IMP 1 (varenicline) and Placebo capsule for IMP 2 (bupropion)
Placebo for varenicline: Capsules for oral use
Placebo for bupropion: Capsules for oral use | 97 |
| Total | 384 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 13 | 14 | 5 | 4 |
| Overall Study | Alcohol treatment | 0 | 4 | 3 | 2 |
| Overall Study | concomitant medication | 0 | 0 | 0 | 1 |
| Overall Study | covid | 1 | 1 | 2 | 1 |
| Overall Study | incorrectly randomized or did not commence study drug | 1 | 1 | 2 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 | 5 | 5 |
| Overall Study | non-compliance | 0 | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 6 | 8 | 3 |
Baseline characteristics
| Characteristic | 1) Varenicline + Bupropion | Total | 4) Placebo for Varenicline + Placebo for Bupropion | 3) Bupropion + Placebo for Varenicline | 2) Varenicline + Placebo for Bupropion |
|---|---|---|---|---|---|
| Age at Alcohol debut | 15 years STANDARD_DEVIATION 3 | 16 years STANDARD_DEVIATION 3.9 | 16 years STANDARD_DEVIATION 5.3 | 15 years STANDARD_DEVIATION 2.7 | 15 years STANDARD_DEVIATION 4.1 |
| Age, Continuous | 56 years STANDARD_DEVIATION 8.3 | 56 years STANDARD_DEVIATION 9.2 | 56 years STANDARD_DEVIATION 9.9 | 56 years STANDARD_DEVIATION 9.2 | 56 years STANDARD_DEVIATION 9.7 |
| Heavy Drinking Days (HDD) | 0.72 proportion STANDARD_DEVIATION 0.3 | 0.74 proportion STANDARD_DEVIATION 0.27 | 0.74 proportion STANDARD_DEVIATION 0.28 | 0.75 proportion STANDARD_DEVIATION 0.26 | 0.76 proportion STANDARD_DEVIATION 0.25 |
| Heredity for alcohol problems | 25 Participants | 73 Participants | 16 Participants | 17 Participants | 15 Participants |
| Phosphatidylethanol (B-PEth) | 1.2 mikromol/L STANDARD_DEVIATION 0.66 | 1.2 mikromol/L STANDARD_DEVIATION 0.65 | 1.2 mikromol/L STANDARD_DEVIATION 0.55 | 1.3 mikromol/L STANDARD_DEVIATION 0.62 | 1.2 mikromol/L STANDARD_DEVIATION 0.76 |
| Race and Ethnicity Not Collected | — | 0 Participants | — | — | — |
| Sex: Female, Male Female | 28 Participants | 107 Participants | 34 Participants | 18 Participants | 27 Participants |
| Sex: Female, Male Male | 72 Participants | 277 Participants | 63 Participants | 73 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 96 | 0 / 100 | 0 / 91 | 0 / 97 |
| other Total, other adverse events | 92 / 96 | 98 / 101 | 82 / 91 | 84 / 97 |
| serious Total, serious adverse events | 3 / 96 | 2 / 100 | 3 / 91 | 3 / 97 |
Outcome results
Primary
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
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.
Population: modified ITT (mITT), defined as subjects taken at least one dose of study drug and documented at least one data entry.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2) Varenicline + Placebo for Bupropion | Alcohol Consumption as Measured by Heavy Drinking Days (HDD) | -0.322 proportion | Standard Error 0.028 |
| 1) Varenicline + Bupropion | Alcohol Consumption as Measured by Heavy Drinking Days (HDD) | -0.314 proportion | Standard Error 0.031 |
| 3) Bupropion + Placebo for Varenicline | Alcohol Consumption as Measured by Heavy Drinking Days (HDD) | -0.298 proportion | Standard Error 0.035 |
| 4) Placebo for Varenicline + Placebo for Bupropion | Alcohol Consumption as Measured by Heavy Drinking Days (HDD) | -0.217 proportion | Standard Error 0.031 |
Primary
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.
Time frame: PEth is calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value)
Population: modified ITT (mITT), defined as participants taken at least one dose of study drug and documented at least one data entry
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 2) Varenicline + Placebo for Bupropion | Alcohol Consumption as Measured by Phosphatidylethanol (PEth) in Blood | -0.406 mikromol/litre | Standard Error 0.057 |
| 1) Varenicline + Bupropion | Alcohol Consumption as Measured by Phosphatidylethanol (PEth) in Blood | -0.417 mikromol/litre | Standard Error 0.041 |
| 3) Bupropion + Placebo for Varenicline | Alcohol Consumption as Measured by Phosphatidylethanol (PEth) in Blood | -0.315 mikromol/litre | Standard Error 0.054 |
| 4) Placebo for Varenicline + Placebo for Bupropion | Alcohol Consumption as Measured by Phosphatidylethanol (PEth) in Blood | 0.250 mikromol/litre | Standard Error 0.044 |
Secondary
Alcohol Use Identification Test
Total score of Alcohol Use Identification Test
Time frame: Mean difference between total score obtained at baseline and visit 1
Secondary
CDT
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)
Secondary
GGT
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)
Secondary
Nicotine Use
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
Secondary
Plasma Concentration of Bupropion (ng/ml)
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
Secondary
Plasma Concentration of Varenicline (ng/ml)
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
Secondary
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
Time frame: CDT is calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value)
Secondary
Self-reported Alcohol Craving
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)
Secondary
The Continous Performance Test + Activity Test
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.
Secondary
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.
Time frame: 77 day-interval. Mean difference between total scale score assessed at Day 0 and Day 77