Clinical Trials Register

Summary
EudraCT Number:	2012-002863-88
Sponsor's Protocol Code Number:	LP0041-64
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-11-12
Trial results	View 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

2012-002863-88

A.3

Full title of the trial

A Simultaneous Treatment Regimen Compared to a Sequential Treatment Regimen with Ingenol Mebutate Gel 0.015% and 0.05% of Two Areas with Actinic Keratosis on Face/Scalp and Trunk/Extremities

Comparación de un régimen de Tratamiento simultáneo respecto a un régimen de tratamiento secuencial con Ingenol Mebutato Gel 0,015% y 0,05% de dos áreas con keratosis actínica en cara/cuero cabelludo y tronco/extremidades

A.3.1

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

A Simultaneous Treatment Regimen Compared to a Sequential Treatment Regimen with Ingenol Mebutate Gel 0.015% and 0.05% of Two Areas with Actinic Keratosis on Face/Scalp and Trunk/Extremities

A.4.1

Sponsor's protocol code number

LP0041-64

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	LEO PHARMA A/S
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	LEO PHARMA A/S
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	LEO PHARMA France
B.5.2	Functional name of contact point	Florence Preaud
B.5.3	Address:
B.5.3.1	Street Address	2, Rue René Caudron
B.5.3.2	Town/ city	Voisins-Le-Bretonneux
B.5.3.3	Post code	78960
B.5.3.4	Country	France
B.5.4	Telephone number	33130144000
B.5.5	Fax number	33130144059
B.5.6	E-mail	florence.preaud@leo-pharma.com

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	Picato®
D.2.1.1.2	Name of the Marketing Authorisation holder	LEO PHARMA A/S
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Ingenol mebutate gel
D.3.4	Pharmaceutical form	Gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Topical use (Noncurrent) Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ingenol Mebutate
D.3.9.1	CAS number	75567-37-2
D.3.9.3	Other descriptive name	INGENOL MEBUTATE
D.3.9.4	EV Substance Code	SUB32495
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.015
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	Picato®
D.2.1.1.2	Name of the Marketing Authorisation holder	LEO Pharma A/S
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Ingenol mebutate gel
D.3.4	Pharmaceutical form	Gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Topical use (Noncurrent) Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ingenol Mebutate Gel
D.3.9.1	CAS number	75567-37-2
D.3.9.3	Other descriptive name	INGENOL MEBUTATE
D.3.9.4	EV Substance Code	SUB32495
D.3.10	Strength
D.3.10.1	Concentration unit	% percent
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.05
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Actinic Keratosis

Keratosis actínica

E.1.1.1

Medical condition in easily understood language

Actinic Keratosis

Keratosis actínica

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10000614
E.1.2	Term	Actinic keratosis
E.1.2	System Organ Class	10040785 - Skin and subcutaneous tissue 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 evaluate the safety of a simultaneous treatment regimen compared to a sequential treatment regimen when two separate areas with AKs (one located on face or scalp and the other located on trunk or extremities) are treated with ingenol mebutate gel.

The primary response criterion is the composite Local Skin Reaction (LSR) score 3 days after treatment start of each selected treatment area.

Evaluar la seguridad de una pauta de tratamiento simultáneo en comparación con una pauta de tratamiento secuencial cuando se tratan dos zonas independientes con QA (una en la cara o en el cuero cabelludo y la otra en el tronco o en las extremidades) con gel de ingenol mebuta-to.
El criterio principal de respuesta es la puntuación total de la reacción cutánea local (RCL) 3 días después del inicio del tratamiento en la zona de tratamiento seleccionada.

E.2.2

Secondary objectives of the trial

To determine the efficacy and treatment satisfaction of a simultaneous treatment regimen compared to a sequential treatment regimen when two separate areas with AKs (one located on face or scalp and the other located on trunk or extremities) are treated with ingenol mebutate gel.

Establecer la eficacia y la satisfacción con el tratamiento para un tratamiento simultáneo en comparación con una pauta de tratamiento secuencial cuando se tratan dos zonas independientes con QA (una en la cara o en el cuero cabelludo y la otra en el tronco o en las extremidades) con gel de ingenol mebutato.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Following verbal and written information about the trial, subject must provide informed consent documented by signing the Informed Consent Form (ICF) prior to any trial-related procedures.
2. Subjects with 4 to 8 clinically typical, visible and discrete AKs within a contiguous 25 cm2 treatment area on face or scalp.
3. Subjects with 4 to 8 clinically typical, visible and discrete AKs within a contiguous 25 cm2 treatment area on trunk or extremities.
4. Subject at least 18 years of age.
5. Female subjects must be of either:
a. Non-childbearing potential, i.e. post-menopausal or have a confirmed clinical history of sterility (e.g. the subject is without a uterus) or,
b. Childbearing potential, provided there is a confirmed negative urine pregnancy test prior to trial treatment, to rule out pregnancy.
6. Female subjects of childbearing potential must be willing to use effective contraception at trial entry and until completion.
Effective contraception is defined as follows:
- Oral/implant/injectable/transdermal/oestrogenic vaginal ring contraceptives, intrauterine device, condom with spermicide, diaphragm with spermicide.
- Abstinence or partner?s vasectomy are acceptable if the female agrees to implement one of the other acceptable methods of birth control if her partner changes.

1. Después de que se proporcione información verbal y escrita sobre el estudio, el paciente debe otorgar el consentimiento informado mediante la firma del documento de consentimiento informado (DCI), antes de que se realice cualquier procedimiento relacionado con el estudio.
2. Pacientes que presenten entre 4 y 8 QA clínicamente significativas, visibles e independientes en una zona contigua de tratamiento de 25 cm2 en la cara o en el cuero cabelludo.
3. Pacientes que presenten entre 4 y 8 QA clínicamente significativas, visibles e independientes en una zona contigua de tratamiento de 25 cm2 en el tronco o en las extremidades.
4. Pacientes de al menos 18 años.
5. En el caso de pacientes mujeres:
a. No deben tener capacidad reproductora, p. ej., deben ser postmenopáusicas o debe confirmarse su esterilidad clínicamente (p. ej., la paciente no tiene útero) o,
b. Si tienen capacidad reproductora, debe haberse obtenido un resultado negativo confirmado en una prueba de embarazo en orina antes del tratamiento del estudio, para descartar el embarazo.
6. Las pacientes con capacidad reproductora deben estar dispuestas a utilizar un método anticonceptivo eficaz desde el momento de su admisión en el estudio y hasta el final del mismo. Un método anticonceptivo eficaz se define como:
- Anticonceptivo oral/implante/inyectable/ transdérmico/anillo vaginal estrogénico, dispositivo intrauterino, preservativo con espermicida, diafragma con espermicida.
- Se aceptan la abstinencia sexual o la vasectomía de la pareja de la paciente, si la paciente se compromete a aplicar cualquiera de los otros métodos anticonceptivos aceptables si se produce algún cambio.

E.4

Principal exclusion criteria

1. Location of the selected treatment areas:
? on the periorbital skin,
? within 5 cm of an incompletely healed wound,
? within 10 cm of a suspected basal cell carcinoma (BCC) or squamous cell carcinoma (SCC).
2. Prior treatment with ingenol mebutate gel on face/scalp and on trunk/extremities.
3. Lesions in the selected treatment areas that have:
? atypical clinical appearance (e.g., hypertrophic, hyperkeratotic or cutaneous horns) and/or,
? recalcitrant disease (e.g., did not respond to cryotherapy on two previous occasions).
4. History or evidence of skin conditions other than the trial indication that would interfere with the evaluation of the trial medication (e.g., eczema, unstable psoriasis, xeroderma pigmentosum).
5. Use of cosmetic or therapeutic products and procedures which could interfere with the assessments of the selected treatment areas.
6. Clinical diagnosis/history or evidence of any medical condition that would expose a subject to an undue risk of a significant AE or interfere with assessments of safety and efficacy during the course of the trial, as determined by the investigator?s clinical judgment.
7. Anticipated need for hospitalisation or out-patient surgery during the first 15 days after the first trial medication application. Note that cosmetic/therapeutic procedures are not excluded if they fall outside of the criteria detailed in Prohibited Therapies or Medications (see Exclusion Criteria Nos. 14-21).
8. Known sensitivity or allergy to any of the ingredients in ingenol mebutate gel.
9. Presence of sunburn within the selected treatment areas.
10. Current enrolment or participation in an investigational clinical trial within 30 days of entry into this trial.
11. Subjects previously randomised in the trial.
12. Female subjects who are breastfeeding.
13. In the opinion of the investigator, the subject is unlikely to comply with the Clinical Study Protocol (e.g. alcoholism, drug dependency or psychotic state).

1. Localización de las áreas de tratamiento seleccionadas:
? en la piel periorbitaria,
? a una distancia máxima de 5 cm de una herida cicatrizada de forma incompleta,
? a una distancia máxima de 10 cm de un posible carcinoma basocelular (CBC) o carcinoma epidermoide (CE).
2. Tratamiento previo con gel de ingenol mebutato en la cara/cuero cabelludo y en el tronco/extremidades.
3. Lesiones en las zonas de tratamiento seleccionadas que tengan:
? apariencia clínica atípica (p. ej., hipertrofia, hiperqueratosis o cuernos cutáneos) y/o,
? enfermedad resistente al tratamiento (p. ej., no respondieron a crioterapia en dos ocasiones anteriores).
4. Antecedentes o indicios de enfermedades cutáneas diferentes a la indicación del estudio que puedan interferir en la evaluación de la medicación del estudio (p. ej., eccema, soriasis inestable, xerodermia pigmentosa).
5. Uso de productos cosméticos o terapéuticos y procedimientos que pudieran interferir en las evaluaciones de las áreas de tratamiento seleccionadas.
6. Antecedentes/diagnóstico clínico o signos de cualquier afección médica que pueda exponer al paciente a un riesgo excesivo de un AA significativo o interferir en las evaluaciones de la seguridad y eficacia durante el transcurso del estudio, según el juicio clínico del investigador.
7. Necesidad prevista de hospitalización o cirugía ambulatoria durante los primeros 15 días tras la primera aplicación la medicación del estudio. Obsérvese que los procedimientos terapéuticos/cosméticos no se excluirán si quedan fuera de los criterios que se detallan en el apartado Medicamentos o tratamientos prohibidos (véanse los criterios de exclusión n.º 14-21).
8. Sensibilidad conocida o alergia a cualquiera de los componentes del gel de ingenol mebutato.
9. Presencia de quemaduras solares en las zonas de tratamiento seleccionadas.
10. Inclusión o participación en un estudio clínico de investigación en los 30 días previos a la admisión en este estudio.
11. Pacientes aleatorizados con anterioridad en el estudio.
12. Pacientes en periodo de lactancia.
13. A juicio del investigador, es improbable que el paciente cumpla el protocolo del estudio clínico (p. ej., alcoholismo, drogodependencia o estado psicótico).

E.5 End points

E.5.1

Primary end point(s)

Composite LSR score 3 days after treatment start of each selected treatment area

Puntuación total de las RCL 3 días después del inicio del tratamiento en cada zona de tratamiento seleccionada.

E.5.1.1

Timepoint(s) of evaluation of this end point

3 days

3 días

E.5.2

Secondary end point(s)

? TSQM after a treatment cycle of 8 weeks,
? Complete clearance of AKs in each separate treatment area 8 weeks after treatment,
? Partial clearance of AKs in each separate treatment area 8 weeks after treatment, defined as 75% or greater reduction in AKs from start of treatment to 8 weeks after treatment,
? Percent reduction in number of AKs in each separate treatment area 8 weeks after treatment.

? TSQM después de un ciclo de tratamiento de 8 semanas,
? Remisión completa de la QA en cada zona de tratamiento independiente 8 semanas después del tratamiento,
? Remisión parcial de la QA en cada zona de tratamiento independiente 8 semanas después del tratamiento, definida como una reducción del 75 % o más desde el inicio del tratamiento hasta 8 semanas después del tratamiento,
? Porcentaje de reducción del número de lesiones de QA en cada zona de tratamiento independiente 8 semanas después del tratamiento,

E.5.2.1

Timepoint(s) of evaluation of this end point

8 weeks

8 semanas

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

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Tratamiento simultaneo comparado con tratamiento secuencial con Ingenol Mebutate gel

Simultaneous Treatment Compared to a Sequential Treatment with Ingenol Mebutate Gel 0.015% and 0.05%

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

LVLS

Última visita del último paciente

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial 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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

120

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

Yes

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

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

200

F.4.2.2

In the whole clinical trial

200

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)

Treatment after the subject has ended the participation in the trial will be let up to Investigator judgement.

Al final de la participación en el ensayo, el investigador establecerá, a su juicio, el tratamiento para el paciente

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

2013-01-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-01-11

P. End of Trial
P.	End of Trial Status	Completed

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