Clinical Trials Register

Summary
EudraCT Number:	2010-022244-20
Sponsor's Protocol Code Number:	H 569 000 – 1004
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2010-09-08
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

Germany - BfArM

A.2

EudraCT number

2010-022244-20

A.3

Full title of the trial

Double-blind, randomized, vehicle- and comparator-controlled, multicenter trial to evaluate the efficacy and safety of LAS41007 in the treatment of actinic keratosis

A.3.1

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

Trial to evaluate whether a 5 % diclofenac gel formula is effective and safe to use for treating actinic keratosis;
tested in comparison to a standard treatment (gel) and a 'placebo' gel; conducted by numerous practises / hosptitals, and in a fashion that neither doctor nor patient knows who receives the new treatment, the standard treatment, and the placebo treatment.

Studie zur Beurteilung der Wirksamkeit und Sicherheit einer 5 %igen Diclofenac Gel-Formulierung;
getested im Vergleich zu einer Standardtherapie (Gel) und einem "Placebo"-Gel; durchgeführt in zahlreichen Praxen / Kliniken und zwar so, dass weder Arzt noch Patient wissen, wer die neue Behandlung, die Standard-Behandlung und wer die Placebo-Behandlung erhält.

A.3.2

Name or abbreviated title of the trial where available

LAS41007 Phase III

A.4.1

Sponsor's protocol code number

H 569 000 – 1004

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01265602

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	Almirall S.A.
B.1.3.4	Country	Spain
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	Almirall S.A.
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	Almirall Hermal GmbH
B.5.2	Functional name of contact point	Clinical Project Leader
B.5.3	Address:
B.5.3.1	Street Address	Scholtzstraße 3
B.5.3.2	Town/ city	Reinbek
B.5.3.3	Post code	21465
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4940727 04528
B.5.5	Fax number	+4940727 04295
B.5.6	E-mail	sven.silberborth@almirall.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	No
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	LAS41007 (5% diclofenac gel)
D.3.2	Product code	LAS41007 (5% diclofenac 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)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DICLOFENAC SODIUM
D.3.9.1	CAS number	15307-79-6
D.3.9.3	Other descriptive name	DICLOFENAC SODIUM
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
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	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	Solaraze 3% gel
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratorios Almirall S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Solaraze® 3% 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)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DICLOFENAC SODIUM
D.3.9.1	CAS number	15307-79-6
D.3.9.3	Other descriptive name	DICLOFENAC SODIUM
D.3.10	Strength
D.3.10.1	Concentration unit	% (W/W) percent weight/weight
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	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	Gel
D.8.4	Route of administration of the placebo	Topical use (Noncurrent)

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients aged 18 and older suffering from actinic keratosis. Patients to be considered have at least 6 but no more than 16 clinically confirmed AK target lesions of mild to moderate intensity in up to 3 treatment areas (TAs) with a size of 25 cm2 per TA (i.e. total size of TA is up to 75 cm2) and additionally one representative AK lesion for histological diagnosis of AK, which must be located in the face including the forehead (excluding eyelids, lips and mucosa) and/or bald scalp.

E.1.1.1

Medical condition in easily understood language

Carcinoma in situ of the skin. Symptoms on skin: Rough, palpable, reddish. Occur on chronically sun-exposed skin, e.g. face, bald scalp, forearms.

Haut-Karzinom in situ. Symptome auf der Haut: rauh, tastbar, rötlich. Erscheinen auf chronisch der Sonne ausgesetzter Haut, z.B. Gesicht, kahler Kopf, Unterarme.

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	14.0
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

The primary objectives are to show:
• superiority of LAS41007 compared to vehicle
• superiority of LAS41007 compared to Solaraze®
in the treatment of clinically confirmed grade I and II AK, each assessed by histology to evaluate the histological clearance of one pre-selected target lesion at 60 days post-treatment (PT, V6).

E.2.2

Secondary objectives of the trial

The secondary objectives are to show:
• superiority of LAS41007 compared to vehicle
• improved clinical efficacy of LAS41007 compared to Solaraze®
in the treatment of clinically confirmed grade I and II AK with respect to clinical efficacy.

Clinical efficacy will be assessed by:
• AK lesion count (TLNS) to evaluate the complete clinical clearance (TLNS = 0) of all target lesions in the treatment area at 60 days PT (V6).
• Additional clinical efficacy parameters, e.g. rate of clinical clearance and rate of responders, reduction of total AK target lesion area per patient, improvement of target lesions.

Safety will be determined by incidence of adverse events, tolerability (overall and local), laboratory variables, vital signs and the patient's compliance.

The objective of the non-interventional phase is to determine the maintenance of sustained complete clinical clearance, recurrences, and the incidence of squamous cell carcinoma.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed and dated written informed consent,
2. Caucasian male and female patients,
3. Aged ≥ 18 years,
4. Women of childbearing potential are allowed to participate in this study, only if they use a highly effective method of contraception ,
5. Have at least 6 but no more than 16 clinically confirmed AK target lesions of mild to moderate (grade I to II, according to Olsen et al, 1991) intensity in the whole treatment area (TA) (and additionally one representative AK lesion for histological diagnosis of AK), which must be located in the face including the forehead (excluding eyelids, lips and mucosa) and/or bald scalp,
6. The AK target lesions must be discrete and quantifiable; the distance from one lesion to its neighbor lesion must be greater than 1.0 cm,
7. The diameter of each AK target lesion should be not less than 0.5 cm and not greater than 1.5 cm,
8. The target lesions must be located in up to 3 TAs with a size of 25 cm2 per TA (i.e. total area of TA is up to 75 cm2),
9. Patient consents to take punch biopsies in the TA.
Additionally, to be eligible for randomization, a patient must comply with the following criterion:
10. Diagnosis of AK histologically confirmed by result of punch biopsy taken at screening visit (classification according to Röwert-Huber, 2007).

E.4

Principal exclusion criteria

1. Have known hypersensitivity, intolerance or allergies against diclofenac sodium or other ingredients of the IMPs (hyaluronic acid, benzyl alcohol, poly ethyleneglycol monomethyl ether) and other non-steroidal anti-inflammatory agents,
2. Have a history of bronchospasm, asthma, urticaria, or rhinitis after the intake of acetylsalicylic acid or other non-steroidal anti-inflammatory drugs (NSAIDs),
3. Have a history of gastrointestinal bleeding or perforation associated with prior therapy with NSAIDs,
4. Have evidence of clinically significant or unstable medical conditions such as:
- metastatic tumor or tumor with high probability of metastatic spread,
- heart failure (NYHA class III or higher),
- immunosuppressive disorder (e.g. HIV, patients following organ transplantation)
- hematologic, hepatic, renal, neurologic or endocrine disorder,
- collagen-vascular disorder (e.g. cerebro-vascular disorder or other bleedings),
- gastrointestinal disorder (e.g. active ulcera or history of recurrent peptic ulcera or hemorrhage),
5. Have currently and within the past 3 months other malignant tumors of the skin in the treatment areas (e.g. malignant melanoma, basal cell carcinoma, squamous cell carcinoma),
8. Are known to be pregnant or lactating (currently or within the past 3 months),
10. Have received the following topical treatments for any indication in the target area (defined as the whole face, including the forehead and the bald scalp) within 6 weeks before treatment with IMP: topical retinoids, topical steroids, topical 5-fluorouracil preparations, topical immunomodulators, topical diclofenac,
11. Have received the following physical treatments in the TAs within the designated period before treatment with IMP: treatment (6 weeks), surgical excision - except biopsy for diagnostic confirmation (6 weeks), cryo-, thermo- or chemodestruction (6 weeks), photodynamic therapy (6 weeks), curettage (4 weeks),
16. Anticoagulative therapy, e.g. with cumarines (e.g. phenprocoumon - e.g. trade name Marcumar® - or heparines throughout the interventional phase of the study. Treatment with ASA at a dose not exceeding 100 mg/d and clopidogrel at a dose not exceeding 75 mg/d will be allowed,
17. Patients having any significant physical abnormalities (e.g. tattoos, dermatoses) in the potential treatment areas that may cause difficulty with examination or final evaluation

E.5 End points

E.5.1

Primary end point(s)

The histological clearance of the (second) pre-selected target lesion at 60 days PT (V6).

E.5.1.1

Timepoint(s) of evaluation of this end point

60 days post treatment

E.5.2

Secondary end point(s)

1. complete clinical clearance (target lesions); 2. responder rate (target lesions); 3. responder rate (cumulative lesions); 4. rate of clearance; 5. reduction of target lesion area per patient; 6. reduction of overall target lesion area; 6. AK severity scoring; 7. Inv. Global Improv. Index; 8. Patient Global Improv. Index; 9. Dermatol. Qual. of Life Quest.

E.5.2.1

Timepoint(s) of evaluation of this end point

nos. 1-3, 6: 60 days post treatment; nos. 4-6: from baseline to each study visit; no. 7: at each visit after baseline; no. 8: at End of Treatment visit & 60 days post treatment; 9. at baseline & 60 days post 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

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)

Yes

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

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

Interventional phase:
The interventional phase of the study will end with visit V6 of the last patient undergoing the trial.

Non-interventional phase:
The interventional phase will be followed by a non-interventional phase comprising two visits, scheduled 6 (FU M6) and 12 months (FU M12) after EoT (V5). Thus, the overall end of the study will be the visit FU M12 of the last patient.

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:

107

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

717

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

549

F.4.2

For a multinational trial

F.4.2.1

In the EEA

824

F.4.2.2

In the whole clinical trial

824

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)

not applicable (not different from the expected normal treatment of that condition)

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

2010-10-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2010-10-15

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2012-07-16

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