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
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 388
- 试验地点
- 4
- 主要终点
- Alcohol Consumption as Measured by Phosphatidylethanol (PEth) in Blood
研究概览
简要总结
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.
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 25 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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
干预措施: Varenicline Tartrate 1 mg b.i.d (Drug)
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
干预措施: Bupropion Hydrochloride 150 mg b.i.d (Drug)
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)
干预措施: Varenicline Tartrate 1 mg b.i.d (Drug)
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)
干预措施: Placebo for bupropion (Other)
3) Bupropion + Placebo for Varenicline
Investigational medicinal product (IMP) 2: Bupropion SR 150 mg and Placebo capsule for IMP 1 (varenicline)
干预措施: Bupropion Hydrochloride 150 mg b.i.d (Drug)
3) Bupropion + Placebo for Varenicline
Investigational medicinal product (IMP) 2: Bupropion SR 150 mg and Placebo capsule for IMP 1 (varenicline)
干预措施: Placebo for varenicline (Other)
4) Placebo for Varenicline + Placebo for Bupropion
Placebo capsule for IMP 1 (varenicline) and Placebo capsule for IMP 2 (bupropion)
干预措施: Placebo for varenicline (Other)
4) Placebo for Varenicline + Placebo for Bupropion
Placebo capsule for IMP 1 (varenicline) and Placebo capsule for IMP 2 (bupropion)
干预措施: Placebo for bupropion (Other)
结局指标
主要结局
Alcohol Consumption as Measured by Phosphatidylethanol (PEth) in Blood
时间窗: 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)
时间窗: 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
次要结局
- 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)
- 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))
- The Temporal Experience of Pleasure Scale (TEPS)(77 day-interval. Mean difference between total scale score assessed at Day 0 and Day 77)
- 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)
- CDT(CDT is calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value))
- GGT(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(Mean difference between total score obtained at baseline and visit 1)
- 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))
- Nicotine Use(77 day-interval. Mean difference between cotinine concentration assessed at Day o and Day 77)
- The Continous Performance Test + Activity Test(77 day-interval. Mean difference between outcome measure assessed at Day o and Day 7.)