Clinical Trials Register

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

Italy - Italian Medicines Agency

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

Un regime di trattamento simultaneo comparato ad un regime di trattamento sequenziale con Ingenolo mebutato Gel allo 0.015% e 0.05% di due aree con cheratosi attinica su Viso/Cuoio cappelluto e Tronco/Estremita'

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.3.4	Pharmaceutical form	Gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
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	.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.3.4	Pharmaceutical form	Gel
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
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	.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

Cheratosi Attinica

E.1.1.1

Medical condition in easily understood language

Actinic Keratosis

Cheratosi Attinica

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.

Valutare la sicurezza di un regime di trattamento simultaneo rispetto ad un regime di trattamento sequenziale nel trattamento di due aree distinte affette da cheratosi attinica (AK) (una situata sul viso o sul cuoio capelluto e l’altra sul tronco o sulle estremità) con gel a base di ingenolo mebutato.

Il criterio della risposta primaria è il punteggio di risposta cutanea locale (LSR composito) raggiunto 3 giorni dopo l’inizio del trattamento di ciascuna area di trattamento selezionata.

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.

Determinare l’efficacia e la soddisfazione relative ad un regime di trattamento simultaneo rispetto ad un regime di trattamento sequenziale nel trattamento di due aree distinte affette da cheratosi attinica (AK) (una situata sul viso o sul cuoio capelluto e l’altra situata sul tronco o sulle estremità) con gel a base di ingenolo 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. Dopo essere stati informati verbalmente e per iscritto sullo studio, i soggetti dovranno fornire il proprio consenso informato, documentato dalla firma del modulo per il consenso informato (ICF) prima dell’inizio delle procedure dello studio.
2. Soggetti con 4-8 lesioni di cheratosi attinica (AK) clinicamente tipiche e ben visibili situate entro un’area di trattamento contigua di 25 cm2 sul viso o sul cuoio capelluto.
3. Soggetti con 4-8 lesioni di cheratosi attinica (AK) clinicamente tipiche e ben visibili situate entro un’area di trattamento contigua di 25 cm2 sul tronco o sulle estremità.
4. Soggetti di almeno 18 anni di età.
5. I soggetti femminili devono essere:
a. non in età fertile, ossia in età post-menopausale o con una storia clinica confermata di sterilità (es. donne precedentemente sottoposte ad isterectomia); oppure
b. in età fertile, ma con test di gravidanza effettuato sull’urina con risultato negativo confermato eseguito prima del trattamento sperimentale per escludere una gravidanza.
6. I soggetti femminili in età fertile devono essere disposte ad utilizzare un contraccettivo efficace a partire dall’inizio dello studio e fino al termine dello stesso.
Per contraccettivo efficace si intende:
– contraccettivi orali, ad impianto, iniettabili, transdermici, anello vaginale a estrogeni, dispositivo intrauterino, preservativo con agente spermicida, diaframma con agente spermicida.
- L’astinenza o la vasectomia del partner sono accettabili se il soggetto femminile accetta di utilizzare uno degli altri metodi ammessi per il controllo delle nascite in caso di cambio di partner.

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. Ubicazione delle aree di trattamento selezionate:
• sulla cute periorbitale;
• a meno di 5 cm da una ferita non completamente guarita;
• a meno di 10 cm da un sospetto carcinoma delle cellule basali (BCC) o carcinoma a cellule squamose (SCC).
2. Precedente trattamento con gel a base di ingenolo mebutato sul viso/cuoio capelluto e sul tronco/estremità.
3. Lesioni nelle aree di trattamento selezionate che presentano:
• un aspetto clinico atipico (es. ipertrofia, ipercheratosi o corni cutanei) e/o,
• malattia recalcitrante (ad es. mancata risposta alla crioterapia in due occasioni precedenti).
4. Anamnesi o evidenza di patologie cutanee diverse da quelle trattate nello studio che potrebbero interferire sulla valutazione del farmaco sperimentale (come eczema, psoriasi instabile, xeroderma pigmentoso).
5. Uso di prodotti e procedure cosmetiche o terapeutiche che potrebbe interferire sulle valutazioni delle aree di trattamento selezionate.
6. Diagnosi clinica/anamnesi o evidenza di una qualsiasi condizione medica che potrebbe esporre il soggetto a un rischio troppo alto di eventi avversi significativi o interferire sulle valutazioni relative alla sicurezza e all’efficacia durante lo svolgimento dello studio, secondo il giudizio clinico dello sperimentatore.
7. Previsto bisogno di ricovero ospedaliero o di intervento chirurgico ambulatoriale durante i primi 15 giorni dopo l’applicazione del primo farmaco sperimentale. Si noti che non sono escluse le procedure cosmetiche o terapeutiche che non rientrano nei criteri illustrati nell'elenco delle Terapie o Farmaci Vietati (vedi Criteri di esclusione n° 14-21).
8. Sensibilità o allergia nota ad uno degli ingredienti del gel a base di ingenolo mebutato.
9. Presenza di scottature solari nelle aree di trattamento selezionate.
10. Arruolamento o partecipazione ad uno studio clinico sperimentale ad una distanza di meno di 30 giorni dall’ingresso nel presente studio.
11. Soggetti precedentemente randomizzati nello studio.
12. Soggetti femminili nel periodo dell’allattamento.
13. Quando, secondo lo sperimentatore, il soggetto sia ritenuto non idoneo a garantire l’osservanza del Protocollo dello studio clinico (ad es. per alcolismo, tossicodipendenza o stato psicotico).

E.5 End points

E.5.1

Primary end point(s)

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

Punteggio ottenuto all’LSR composito 3 giorni dopo l’inizio del trattamento di ciascuna area di trattamento selezionata.

E.5.1.1

Timepoint(s) of evaluation of this end point

3 days

3 giorni

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 dopo un ciclo di trattamento di 8 settimane;
• scomparsa totale delle lesioni di AK in ogni area di trattamento 8 settimane dopo il trattamento;
• scomparsa parziale delle lesioni di AK in ogni area di trattamento 8 settimane dopo il trattamento, intesa come riduzione pari ad almeno il 75% delle lesioni a partire dall’inizio del trattamento fino all’ottava settimana di trattamento;
• riduzione della percentuale di lesioni di AK in ogni area di trattamento 8 settimane dopo il trattamento.

E.5.2.1

Timepoint(s) of evaluation of this end point

8 weeks

8 settimane

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

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

Yes

E.8.1.7.1

Other trial design description

Trattamento simultaneo comparato a trattamento sequenziale con Ingenolo Mebutato gel 0,015% e 0,05%

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

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

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

Number of subjects for this age range:

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

F.3.3.2

Women of child-bearing potential using contraception

Yes

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.

Il trattamento dopo che il soggetto ha concluso la partecipazione allo studio sarà lasciato al giudizio dello sperimentatore.

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

2013-01-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-12-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-01-22

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