Varenicline and Bupropion for Alcohol Use Disorder
الكلمات الدالة
نبذة مختصرة
وصف
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.
تواريخ
| آخر التحقق: | 10/31/2019 |
| تم الإرسال لأول مرة: | 09/29/2019 |
| تم إرسال التسجيل المقدر: | 11/13/2019 |
| أول نشر: | 11/17/2019 |
| تم إرسال آخر تحديث: | 11/25/2019 |
| آخر تحديث تم نشره: | 11/28/2019 |
| تاريخ بدء الدراسة الفعلي: | 03/03/2019 |
| تاريخ الإنجاز الأساسي المقدر: | 12/29/2022 |
| التاريخ المتوقع لانتهاء الدراسة: | 12/29/2022 |
حالة أو مرض
التدخل / العلاج
Drug: Varenicline Tartrate 1 mg b.i.d
Drug: Bupropion Hydrochloride 150 mg b.i.d
Other: Placebo for varenicline
Other: Placebo for bupropion
مرحلة
مجموعات الذراع
| ذراع | التدخل / العلاج |
|---|---|
| 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 | |
| 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) | |
| Experimental: 3) Bupropion + Placebo for Varenicline Investigational medicinal product (IMP) 2: Bupropion SR 150 mg and Placebo capsule for IMP 1 (varenicline) | |
| Placebo Comparator: 4) Placebo for Varenicline + Placebo for Bupropion Placebo capsule for IMP 1 (varenicline) and Placebo capsule for IMP 2 (bupropion) |
معايير الأهلية
| الأعمار المؤهلة للدراسة | 25 Years إلى 25 Years |
| الأجناس المؤهلة للدراسة | All |
| يقبل المتطوعين الأصحاء | نعم |
| المعايير | 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 |
النتيجة
مقاييس النتائج الأولية
1. 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)]
2. 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.]
مقاييس النتائج الثانوية
1. CDT [CDT is calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value)]
2. GGT [GGT calculated as the mean value over the active steady state period (Day 21-Day77) compared to baseline (=screening visit value)]
3. 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)]
4. Alcohol Use Identification Test [Mean difference between total score obtained at baseline and visit 1]
5. 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)]
6. Nicotine use [77 day-interval. Mean difference between cotinine concentration assessed at Day o and Day 77]
7. The Temporal Experience of Pleasure Scale (TEPS) [77 day-interval. Mean difference between total scale score assessed at Day 0 and Day 77]
8. The Continous Performance Test + Activity test [77 day-interval. Mean difference between outcome measure assessed at Day o and Day 7.]
9. 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]
10. 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]
