Clinical Trials Register

Summary
EudraCT Number:	2018-000545-39
Sponsor's Protocol Code Number:	DERMAQ-001
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:	2021-05-25
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-000545-39

A.3

Full title of the trial

A randomized half-side comparative study of Methyl aminolevulinate (MAL, Metvix®) Daylight photodynamic therapy (DL-PDT) with or without pre-treatment with calcitriol (Silkis®) for Actinic Keratosis (AK) of the upper extremities

Studio randomizzato, intra-paziente, di confronto tra terapia fotodinamica in daylight (DL-PDT) con metil aminolevulinato (Metvix®) con o senza pretrattamento con calcitriolo unguento (Silkis®) per le cheratosi attiniche multiple degli arti superiori

A.3.1

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

MAL DL-PDT and Calcitriol for AK treatment of the upper extremities

MAL DL-PDT e Calcitriolo per le AK degli arti superiori

A.3.2

Name or abbreviated title of the trial where available

MAL DL-PDT and Calcitriol for AK treatment of the upper extremities

MAL DL-PDT e Calcitriolo per le AK degli arti superiori

A.4.1

Sponsor's protocol code number

DERMAQ-001

A.5.4

Other Identifiers

Name:

Number:

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	ASL 1 AVEZZANO-SULMONA-L'AQUILA
B.1.3.4	Country	Italy
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	Galderma R&D
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ASL 1 Avezzano-Sulmona-L'Aquila
B.5.2	Functional name of contact point	UOSD Dermatologia Generale ed Oncol
B.5.3	Address:
B.5.3.1	Street Address	Via Lorenzo Natali 1
B.5.3.2	Town/ city	L'Aquila
B.5.3.3	Post code	67100
B.5.3.4	Country	Italy
B.5.4	Telephone number	0862368519
B.5.5	Fax number	0862368519
B.5.6	E-mail	mariaconcetta.fargnoli@univaq.it

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	SILKIS - 1 TUBO AL DA 30 G DI POMATA
D.2.1.1.2	Name of the Marketing Authorisation holder	GALDERMA ITALIA S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	SILKIS
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Ointment
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.3.8	INN - Proposed INN	00056400
D.3.9.1	CAS number	32222-06-3
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	(5Z, 7E)-9, 10-secocholesta-5, 7, 10(19)-triene-1a, 3ß, 25-triol (1a, 3ß, 5Z, 7E)-9, 10-secocholesta-5, 7 10(19)-triene-1, 3, 25-triol
D.3.9.4	EV Substance Code	SUB06047MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	METVIX - TUBO DA 2 DI CREMA 160 MG/G
D.2.1.1.2	Name of the Marketing Authorisation holder	GALDERMA ITALIA S.P.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	METVIX
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Cream
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.3.8	INN - Proposed INN	Metil 5-aminolevulinato
D.3.9.1	CAS number	3332-16-0
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	methyl 5-aminolevulinate hydrochloride, 5-aminolevulinic acid methyl ester hydrochloride, 5-amino-4-oxopentanoic acid methyl ester hydrochloride, methyl5-amino-4-oxopentanoate hydrochloride, methyl 5-amino -4-oxovaleroate hydrochloride, 5-amino-4-oxovaleric acid methyl ester hydrochloride
D.3.9.4	EV Substance Code	SUB21579
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	160
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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 are skin lesions that represent the first phase of cutaneous malignant tumour.

Le cheratosi attiniche sono lesioni della pelle che rappresentano la fase iniziale di un tumore maligno cutaneo.

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	21.0
E.1.2	Level	HLT
E.1.2	Classification code	10020648
E.1.2	Term	Hyperkeratoses
E.1.2	System Organ Class	100000004858

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The aim of this intra-patient, prospective study is to investigate the clearance rate of multiple AKs (grade I to III) on the upper extremities (dorsum of the hand or forearm) treated with 2 sessions of MAL DL-PDT (1 week apart) with or without pre-treatment with calcitriol 1x day for 15 days.

Lo scopo di questo studio, intra-paziente, prospettico è di paragonare il tasso di remissione delle cheratosi attiniche multiple (dal grado I al III) localizzate su due aree simmetriche degli arti superiori (dorso della mano o avambraccio) dopo trattamento con due diversi regimi terapeutici. Un’area verrà trattata con 2 sedute di terapia fotodinamica in daylight con metil aminolevulinato (MAL, Metvix®) a distanza di una settimana l’una dall’altra, precedute dall’uso di un unguento a base di calcitriolo (Silkis®), applicato 1 volta al giorno per 15 giorni; l’altra area verrà trattata con la stessa procedura di 2 sedute terapia fotodinamica Daylight e MAL, senza il pretrattamento con il calcitriolo.

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patient must provide informed consent documented by signing the ICF prior to any trial-related procedures, following verbal and written information about the trial.
- Subjects (male and female) at least 18 years of age.
- 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.
Only women of child bearing potential who are willing to adopt highly effective contraceptive measures, can be enrolled in the study.
According to CTFG recommendations highly effective birth control methods include:
- combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal and transdermal;
- progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable and implantable;
- intrauterine device (IUD);
- intrauterine hormone-releasing system (IUS);
- bilateral tubal occlusion;
- vasectomised partner;
- sexual abstinence.
- Subjects with clinically typical, visible and multiple AK lesions (grade I to III), at least 5 in 2 symmetrical areas of each upper extremity (dorsum of the hands or forearms).
- Subjects who are not eligible for the treatment of AK on the upper limbs with alternative therapies (e.g. cryotherapy, diclofenac in hyaluronic acid, ingenol mebutate).

- Dopo essere stati informati verbalmente e per iscritto sullo studio, il paziente deve fornire il consenso informato e firmarlo prima di ogni procedura relativa alla sperimentazione clinica.
- Soggetti (maschi e femmine) con almeno 18 anni di età.
- I soggetti di sesso femminile devono essere:
a. potenzialmente non fertili, cioè in menopausa o avere una storia clinica di sterilità confermata (per esempio il soggetto senza utero) oppure,
b. in età fertile, purché venga effettuato un test di gravidanza sulle urine prima del trattamento sperimentale con risultato confermato negativo, per escludere un’eventuale gravidanza. Solo i soggetti femminili che saranno disposti ad adottare misure contraccettive altamente efficaci, potranno essere arruolati nello studio. Secondo le CTGF recommendations i metodi altamente efficaci di controllo delle nascite includono:
- contraccezione ormonale combinata (contenente estrogeno e progesterone) associata all’inibizione dell’ovulazione: orale, intravaginale, transdermica;
- contraccezione ormonale solo con progesterone associata all’inibizione dell’ovulazione: orale, iniettabile, impiantabile;
- dispositivo intrauterino (IUD);
- sistema di rilascio ormonale intrauterino (IUS);
- occlusione bilaterale delle tube;
- vasectomia del partner;
- astinenza sessuale.
- Soggetti con lesioni di cheratosi attinica clinicamente tipiche, visibili e multiple (dal grado I al III), almeno 5 in due aree simmetriche su ogni arto superiore (dorso della mano o avambraccio).
- Soggetti che non sono eleggibili per il trattamento delle cheratosi attiniche sugli arti superiori con terapie alternative (per esempio crioterapia, diclofenac in acido ialuronico, ingenolo mebutato).

E.4

Principal exclusion criteria

- Patients undergoing any of the prohibited therapies within the times listed at point 5.6.
- Organ Transplant Recipient (OTR) patients.
- Lesions in the selected treatment areas that are suspected to be an invasive SCC and/or, recalcitrant disease (e.g., did not respond to cryotherapy on two previous occasions).
- 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, sunburns).
- Clinical diagnosis/history or evidence of any medical condition (e.g. hypercalcemia, abnormal calcium metabolism, systemic treatment of calcium homeostasis, mild to severe renal impairment or end-stage renal disease, liver dysfunction, cutaneous photosensitivity/porphyria, or known allergies to porphyrins, morpheaform basal cell carcinoma) that, as determined by the investigator’s clinical judgment (see SmPC of Silkis® and Metvix®), would be contraindicated for the study treatments, expose a subject to an undue risk of significant AEs, interfere with assessments of safety and efficacy during the course of the trial.
- Patients with known or suspected allergies or hypersensitivities to any component of Silkis®, Metvix® (for both see SmPC) and Cetaphil®.
- Female patients who are pregnant, nursing or planning a pregnancy during the study.
- 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).

- Pazienti che si sono sottoposti a una delle terapie proibite nei tempi riportati nella sezione Terapie e/o Farmaci Proibiti e nel paragrafo 5.6 del protocollo.
- Pazienti trapiantati d’organo.
- Lesioni sospette di essere un SCC invasivo e/o malattie recalcitranti (che non hanno risposto a crioterapia in due precedenti occasioni). nelle aree selezionate per il trattamento.
- Storia o evidenza di condizioni della pelle a parte quelle indicate per lo studio clinico che potrebbero interferire con la valutazione del trattamento farmacologico (ad es. eczema, psoriasi instabile, xeroderma pigmentoso, ustioni).
- Diagnosi clinica, storia o evidenza clinica di ogni condizione medica (ad es. ipercalcemia, alterato metabolismo del calcio, trattamento sistemico dell’omeostasi del calcio, insufficienza renale da moderata a severa o insufficienza renale in stadio terminale, disfunzione epatica, fotosensibilità cutanea/porfiria o allergie note alle porfirine, carcinoma basocellulare morfeiforme) che, secondo il giudizio clinico del medico sperimentatore, potrebbero essere controindicate per i trattamenti previsti dallo studio, esponendo il soggetto a un eccessivo rischio di eventi avversi significativi e interferendo con le valutazioni della safety e dell’efficacia durante il corso della sperimentazione (come riportato nelle RCP di Silkis® and Metvix®).
- Pazienti con note o sospette allergie o ipersensibilità ad ogni componente di
Silkis®, Metvix® (come riportato nelle rispettive RCP) e Cetaphil®.
- Soggetti femminili nel periodo di gravidanza o di allattamento o che pianificano una gravidanza durante lo studio.
- 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)

Complete lesion response rate of AKs defined as the percentage reduction of AK lesions from baseline to follow-up Visit (3 months after the first MAL DL-PDT session).

Tasso di risposta completa delle lesioni di cheratosi attinica definito come percentuale di riduzione delle lesioni di AK dalla Visita basale alla Visita di follow-up (3 mesi dopo la prima seduta di MAL DL-PDT).

E.5.1.1

Timepoint(s) of evaluation of this end point

3 months after the first MAL DL-PDT session (Visit 3, follow-up).

3 mesi dopo la prima seduta di MAL DL-PDT (Visita 3, di follow-up).

E.5.2

Secondary end point(s)

The per patient response rate of AKs defined as the mean percentage reduction of AKs from baseline to follow-up Visit (3 months after the first MAL DL-PDT session) in each patient; Assessment of patient's pain experienced during each MAL DL-PDT treatment session using 10-point scale VAS.

Tasso di risposta delle cheratosi attiniche per paziente definito come la percentuale media di riduzione delle AK in ogni paziente dalla Visita basale alla Visita di follow-up (3 mesi dopo la prima seduta di MAL DL-PDT). ; Valutazione del dolore avvertito dal paziente durante ogni seduta di trattamento con MAL DL-PDT tramite la scala VAS a 10 punti.

E.5.2.1

Timepoint(s) of evaluation of this end point

3 months after the first MAL DL-PDT session (Visit 3, follow-up). ; After each session of MAL DL-PDT (Visit 1 and 2).

3 mesi dopo la prima seduta di MAL DL-PDT (Visita 3, di follow-up).; Dopo ogni seduta di MAL DL-PDT (Visite 1 e 2).

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

INTRAPAZIENTE

INTRAPATIENT

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

2 sedute di MAL DL-PDT (a distanza di una settimana l'una dall'altra) senza pretrattamento con calci

2 sessions of MAL DL-PDT (1 week apart) without pre.treatment with calcitriol (Silkis®), but with p

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

Information not present in EudraCT

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.1.1.1

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:

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

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)

Return to normal clinical practice

Ritorno alla normale pratica clinica

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

2018-04-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-04-19

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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