Clinical Trials Register

Summary
EudraCT Number:	2011-004692-36
Sponsor's Protocol Code Number:	VAR/01/011
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2011-10-13
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

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2011-004692-36

A.3

Full title of the trial

COMBIVAR. Randomized double-blind trial of two parallel groups design to evaluate the efficacy of smoking cessation with combined (varenicline plus nicotine patches) versus monotherapy (varenicline)

COMBIVAR. Ensayo clínico randomizado de dos grupos paralelos para evaluar la eficacia de la cesación tabáquica con tratamiento combinado (vareniclina y placebo) versus monoterapia (vareniclina)

A.3.1

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

COMBIVAR. Trial of two parallel groups to evaluate the efficacy of smoking cessation with combined versus monotherapy

COMBIVAR. Ensayo clínico de dos grupos paralelos para evaluar la eficacia de tratamiento combinado frente monoterapia en la cesación tabáquica

A.3.2

Name or abbreviated title of the trial where available

COMBIVAR

A.4.1

Sponsor's protocol code number

VAR/01/011

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	HOSPITAL UNIVERSITARI DE BELLVITGE
B.1.3.4	Country	Spain
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	PFIZER
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	HOSPITAL UNIVERSITARI DE BELLVITGE
B.5.2	Functional name of contact point	JOSÉ MARIA RAMON TORRELL
B.5.3	Address:
B.5.3.1	Street Address	FEIXA LLARGA S/N
B.5.3.2	Town/ city	L'HOSPITALET DE LLOBREGAT
B.5.3.3	Post code	08907
B.5.3.4	Country	Spain
B.5.4	Telephone number	34932607557
B.5.5	Fax number	34932607849
B.5.6	E-mail	jmramon@bellvitgehospital.cat

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	Spain
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	VARENICLINE
D.3.2	Product code	SUB25195
D.3.4	Pharmaceutical form	Tablet
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	249296-44-4
D.3.9.4	EV Substance Code	SUB25195
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.5 to 2.0
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	NICOTINELL
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	NICOTINE
D.3.2	Product code	SUB14645MIG
D.3.4	Pharmaceutical form	Transdermal patch
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Transdermal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	54-11-5
D.3.9.3	Other descriptive name	NICOTINE
D.3.9.4	EV Substance Code	SUB14645MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	21 to 14
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: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	Spain
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	VARENICLINE
D.3.2	Product code	SUB25195
D.3.4	Pharmaceutical form	Tablet
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	249296-44-4
D.3.9.4	EV Substance Code	SUB25195
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	0.5 to 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.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	Transdermal patch
D.8.4	Route of administration of the placebo	Transdermal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

NICOTINE DEPENDENCE.

DEPENDENCIA NICOTINA.

E.1.1.1

Medical condition in easily understood language

NICOTINE DEPENDENCE

DEPENDENCIA NICOTINA

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10032707
E.1.2	Term	Other specified drug dependence, continuous use
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.0
E.1.2	Level	LLT
E.1.2	Classification code	10012336
E.1.2	Term	Dependence addictive
E.1.2	System Organ Class	10037175 - Psychiatric disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine the efficacy of combined therapy (VRN+nicotine patches) versus monotherapy (VRN+placebo patches) in smoking cessation assessed as continuous abstinence rate (CAR) from week 2 to week 12

Determinar la eficacia de la terapia combinada (VRN+parches de nicotina) versus monoterapia (VRN+parches de placebo) en la cesación tabáquica según la tasa de abstinencia continuada en las semanas 2 a 12 de tratamiento.

E.2.2

Secondary objectives of the trial

i) To determine safety of combined therapy (VRN+nicotine patches) versus monotherapy (VRN+placebo patches)
ii) To determine the withdrawal and craving relief according to combined therapy (VRN+nicotine patches) or monotherapy (VRN+placebo patches).
iii) To determine the efficacy of combined therapy (VRN+nicotine patches) versus monotherapy (VRN+placebo patches) assessed as continuous abstinence rate (CAR) at long time (52 weeks).
iv) To determine the efficacy of combined therapy (VRN+nicotine patches) versus monotherapy (VRN+placebo patches) according to 3OHcotinine/Cotinine ratio.

i) Determinar la seguridad de la terapia combinada (VRN+parches de nicotina) versus monoterapia (VR+parches placebo).
ii) Determinar el síndrome de abstinencia y craving según terapia combinada (VRN+parches de nicotina) o monoterapia (VR+parches placebo).
iii) Determinar la eficacia de la terapia combinada (VRN+parches de nicotina) versus monoterapia (VR+parches placebo) según la tasa de abstinencia continuada a largo plazo (semana 52).
iv)Determinar la eficacia de la terpai combinada (VRN+parches de nicotina) versus monoterapia (VR+parches placebo) según el ratio 3OHcotinine/Cotinine

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

i) Aged 18 to 65 years old
ii) Smoking 20 or more cigarettes per day, who wants to stop smoking (seeking treatment), and who has no period of smoking abstinence longer than 3 months in the past year.
iii)Be able to give informed consent to participate and to complete the study questionnaires.

i) Edad de 18 a 65 años
ii) Fumador de 20 o más cigarrillos/día que quiere dejar de fumar (motivo de demanda) y que no presente un período de abstinencia tabáquica mayor a 3 meses en el pasado año.
iii) Con capacidad para otorgar el consentimiento informado y completar los cuestionarios del estudio

E.4

Principal exclusion criteria

i) Previous use of nicotine transdermal patches or varenicline (VRN) in the last 6 months
ii) Cigar, pipe and oral tobacco users who do not smoke 20 or more cigarettes per day
iii) Those who meet the criteria contra-indicating nicotine patches or VRN use

i) Uso previo de Vareniclina o parches transdérmicos de nicotina en los últimos 6 meses
ii) Fumadores de cigarrillos, pipa o tabaco oral con un consumo menor de 20 cigarrillos/dia
iii) Cuando exista una contraindicación del los parches de nicotina o Vareniclina

E.5 End points

E.5.1

Primary end point(s)

To idetermine continuous abstinence rate (CAR) from week 2 to week 12 measured objectively by the CO exhaled

Determinar la tasa de abstinencia de la semana 2 a la semana 12 de tratamiento medida de forma objetiva según CO exhalado

E.5.1.1

Timepoint(s) of evaluation of this end point

Biweekly at visits or weeks 2 (w2), 3 (w4), 4 (w6), 5 (w8), 6 (w10) and 7 (w12).

Bisemanales en las visitas o semanas 2 (s2), 3 (s4), 4 (s6), 5 (s8), 6 (s10) and 7 (s12).

E.5.2

Secondary end point(s)

To determine efficacy, safety and cravings appearances of combined therapy (VRN+nicotine patches) versus monotherapy (VRN+placebo patches) mesured objectively by the BDI, SSI, SIS and HARS scales as well as self-reports, physical examination

Determinar la eficacia, seguridad y síndrome de abstinencia de la terapia combinada (VRN+parches de nicotina) o monoterapia (VR+parches placebo) medidas de forma objetiva según valoración de las escalas BDI, SSI, SIS y HARS, auto-reportada y examen físico.

E.5.2.1

Timepoint(s) of evaluation of this end point

At visits or weeks 1 (w1), 7 (w12), 8 (w24), and 11 (w52).

En las visitas o semanas 1 (s1), 7 (s12), 8 (s24), and 11 (s52).

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

Yes

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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

The total duration for one subject will be 52 weeks, including a twelve week treatment period and 40 weeks of follow-up.
The end of the study will be once the last patient will be followed 52 weeks after inclusion in the study.
If patient discontinue for any reason different from death or withdrawal of informed consent, the efficacy and safety data will be collected as soon as possible (within 3 months after discontinuation to avoid recall bias).

La duración total para cada uno de los pacientes será de 52 semanas (en las que se incluyen un período de tratamiento de 12 semanas y las 40 semanas restantes de seguimiento).
En el caso que un paciente abandone el estudio por una causa distinta a muerte o no cumplimiento del consentimiento informado, la seguridad y eficacia serán recogidos lo antes posible (dentro de los 3 primeros meses del abandono)

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:

322

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

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

322

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

Any

Ninguno

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	HOSPITAL UNIVERSITARI DE BELLVITGE
G.4.3.4	Network Country	Spain

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-11-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-11-24

P. End of Trial
P.	End of Trial Status	Ongoing

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