Clinical Trials Register

Summary
EudraCT Number:	2018-000048-24
Sponsor's Protocol Code Number:	COMB-BO8
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-10-24
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Sweden - MPA

A.2

EudraCT number

2018-000048-24

A.3

Full title of the trial

A RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED MULTICENTER TRIAL ON THE EFFICACY OF VARENICLINE AND BUPROPION, IN COMBINATION AND ALONE, FOR THE TREATMENT OF ALCOHOL USE DISORDER

En randomiserad dubbel-blind placebo-kontrollerad multicenter prövning aveffekterna av vareniklin och bupropion, i kombination och var för sig, vid behandling av alkoholberoende

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A STUDY OF THE EFFECT OF VARENICLINE AND BUPROPION, IN COMBINATION AND ALONE, FOR THE TREATMENT OF ALCOHOL USE DISORDER

En läkemedelstudie av effekterna av vareniklin och bupropion, i kombination och var för sig, vid behandling av alkoholberoende

A.3.2

Name or abbreviated title of the trial where available

The COMB study

COMB studien

A.4.1

Sponsor's protocol code number

COMB-BO8

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Sahlgrenska University Hospital/VGR
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Vetenskapsrådet/Swedish Research Council
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Svenska Läkaresällskapet
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Systembolagets Alkoholforskningsråd
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	Hjärnfonden
B.4.2	Country	Sweden
B.4.1	Name of organisation providing support	ALF Agreement for Clinical Research
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Sahlgrenska University Hospital
B.5.2	Functional name of contact point	Helga Lidö, Clinical Trial Manager
B.5.3	Address:
B.5.3.1	Street Address	Psychiatry/SU, Blå Stråket 15
B.5.3.2	Town/ city	Gothenburg
B.5.3.3	Post code	41345
B.5.3.4	Country	Sweden
B.5.4	Telephone number	00460709179311
B.5.6	E-mail	helga.lido@gu.se

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Champix
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Champix
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	varenicline
D.3.9.1	CAS number	375815-87-5
D.3.9.3	Other descriptive name	VARENICLINE TARTRATE
D.3.9.4	EV Substance Code	SUB22601
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	2
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Bupropion Sandoz
D.2.1.1.2	Name of the Marketing Authorisation holder	Sandoz AS
D.2.1.2	Country which granted the Marketing Authorisation	Sweden
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Bupropion
D.3.2	Product code	50226
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BUPROPION HYDROCHLORIDE
D.3.9.1	CAS number	31677-93-7
D.3.9.4	EV Substance Code	SUB00432MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	300
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Alcohol Use Disorder

E.1.1.1

Medical condition in easily understood language

Alcohol Use Disorder

Alkoholberoende

E.1.1.2

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary objective: To assess the effects of the smoking-cessation drugs varenicline and bupropion in combination and alone for reducing alcohol consumption in individuals with AUD.
Two primary efficacy end-points will be used.
1) Alcohol consumption as measured by the objective alcohol marker B-PEth
2) Alcohol consumption as measured by heavy drinking days (HDD*) by using the Time Line Follow Back (TLFB) procedure
*HDD is defined as ≥60 grams ethanol for men and ≥40 grams ethanol for women. The baseline proportion of heavy drinking days is obtained at the screening visit.

E.2.2

Secondary objectives of the trial

Secondary objectives:
1)To assess the effects of the smoking-cessation drugs varenicline and bupropion in combination and alone for reducing alcohol consumption in individuals with AUD by using
-The alcohol marker carbohydrate deficient transferrin
-The alcohol marker gamma glutamyltransferase
-Temporal experience of pleasure scale
-OPATUS®CPTA test
-Self-reported alcohol consumption by using the TLFB procedure and measured by:
-Mean grams alcohol per day
-Number of drinking days, drinks per drinking days and abstaining days

2) To assess the effects of varenicline and bupropion in combination and alone on other clinical relevant efficacy endpoints:
-Total score of Alcohol Use Identification Test
-Alcohol craving measured by Visual analogue scale
-Nicotine use measured by nicotine saliva marker cotinine

3)To assess the relationships beteen the above described outcome measures and and plasma drug IMP concentrations measured at visit 4 and 6

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

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

E.4

Principal 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, hydroxizin, alimemazin, propiomazin, 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 clearence <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) Epilepsia or seizures other than alcohol-induced, lifetime
19) Severe sleep disturbances
20) Need of alcohol detoxification
21) Living conditions not appropriate to fulfill 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 enrolment into this trial.
24) Additional factors that render the participant unable to complete the study, as judged by the investigator

E.5 End points

E.5.1

Primary end point(s)

Two primary efficacy end-points will be used.
1) Alcohol consumption as measured by the objective alcohol marker phosphatidyl ethanol in blood
2)Alcohol consumption as measured by heavy drinking days (HDD*) by using the Time Line Follow Back (TLFB) procedure
*HDD is defined as ≥60 grams for men and ≥40 for women according to EMA’s guideline and as ≥70 grams for men and ≥56 grams for women according to FDA’s guideline on the development of medicinal products for the treatment of alcohol dependence.

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary outcome measures will be collected at each study visit, 9 in total.

E.5.2

Secondary end point(s)

1)To assess the effects of varenicline and bupropion in combination and alone for reducing alcohol consumption in individuals with AUD by using
•The indirect alcohol marker carbohydrate deficient transferrin (CDT)
•The indirect alcohol marker gamma glutamyltransferase (GGT)
•Self-reported alcohol consumption as measured by TLFB:
oMean grams of alcohol per day
oNumber of drinking days
oNumber of drinks per drinking days
oNumber of abstaining days
2)Total score of Alcohol Use Identification Test (AUDIT)
3)Alcohol craving as measured by a Visual Analogue Scale (VAS)
4)Nicotine use measured by the nicotine saliva marker cotinine
5)Temporal Experience of Pleasure Scale (TEPS)
6)The Continous Performance Test + Activity test (CPTA)
7)To assess the relationships beteen the above described outcome measures and plasma drug concentrations of bupropion and varenicline measured at visits 4 + 6

E.5.2.1

Timepoint(s) of evaluation of this end point

A. Will be collected at each study visit, 9 in total.
B. Will be collected at baseline and at end of treatment

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

End-of-Study is defined as last visit of the last subject (LVLS).LVLS is scheduled to March 2023

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

320

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

F.3.2

Patients

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

380

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-12-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-06-01

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-12-15

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials