Clinical Trials Register

Summary
EudraCT Number:	2006-002410-35
Sponsor's Protocol Code Number:	10 0330 02 - 0486
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2007-02-01
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

2006-002410-35

A.3

Full title of the trial

Double-blind, double-dummy, randomized, placebo-controlled, five-armed, multi-centre phase II/III study to evaluate the efficacy and safety of different concentrations of isotretinoin versus doxycycline in the treatment of rosacea, subtype II and III

A.3.2

Name or abbreviated title of the trial where available

AURORA

A.4.1

Sponsor's protocol code number

10 0330 02 - 0486

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Almirall Hermal GmbH
B.1.3.4	Country	Germany
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	Aknenormin 10 mg Weichkapseln
D.2.1.1.2	Name of the Marketing Authorisation holder	Almirall Hermal GmbH
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	Isotretinoin
D.3.2	Product code	10033002
D.3.4	Pharmaceutical form	Capsule, soft
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Isotretinoin
D.3.9.1	CAS number	4759-48-2
D.3.9.2	Current sponsor code	10033002
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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)	Information not present in EudraCT
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	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	Information not present in EudraCT
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	Information not present in EudraCT
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	Doxyderma 50
D.2.1.1.2	Name of the Marketing Authorisation holder	Dermapharm GmbH
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	Doxycyclin
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
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	Doxycyclin
D.3.9.1	CAS number	564-25-0
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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)	Information not present in EudraCT
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	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	Information not present in EudraCT
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	Information not present in EudraCT
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	Capsule, soft
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients aded 18 and older suffering from papulopustular rosacea (subtype II) or moderate phymateous rosacea (moderate subtype III) with a minimum grade 4 in the 'Global physicians's assessment score - Rosacea' (= Half of the face centrofacial and frontal covered with small papules. Some pustules or prominent papules/noduli, edema and strong erythema, telangiectasia) and a minimum of 8 inflammatory lesions.

MedDRA Classification

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 the study is to show that at least one of the three different chosen concentrations of isotretinoin is non-inferior to doxycycline and superior to placebo.

As primary objective the reduction in the total sum of facial papules and pustules/nodudi after a 12 week treatment will be compared between the treatment groups.

E.2.2

Secondary objectives of the trial

As secondary objectives the following efficacy variables will be compared between the treatment groups:
- changes in the static “Global physician’s assessment score – Rosacea”
- changes in the severity scores for erythema, edema, telangiectasia, seborrhoea, and rhinophyma
- investigator’s overall improvement rating
- patient’s overall improvement rating
- changes in the quality of life measured by patient reported outcomes
- achievement of patient’s treatment preferences

As secondary objectives the following safety variables will be compared between the treatment groups:
- changes in laboratory values
- overall tolerability based on number and severity of study medication-related AEs/SAEs
As a further secondary objectives the following safety variables will be compared between the isotretinoin treatment groups:
- changes in the severity scores for mucocutaneous side effects (xerosis cutis, burning and itching, cheilitis, and eye dryness)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

· the written informed consent form has been signed and dated
· papulopustular rosacea (rosacea subtype II) or moderate phymatous rosacea (moderate rosacea subtype III)
· a minimum grade 4 in the “Global physician’s assessment score – Rosacea”
· at least 8 inflammatory lesions
· existence of rosacea for at least three months prior to inclusion
· age 18 years or older
· body weight between 50 kg and 130 kg
· high probability of a good compliance and orderly completion of the study
FOR FERTILE WOMEN ONLY
· medically controlled, negative pregnancy test within the first 3 days of the actual menstrual cycle in all women except those who were surgically sterile or at least one year postmenopausal.

E.4

Principal exclusion criteria

· advanced phymatous rosacea, where phyma in particular rhinophyma is indicated for surgical therapy at the discretion of the investigator
· exclusively ocular rosacea
· nodular rosacea
· erythematotelangiectatic rosacea
· severe facial skin dryness or xerosis
· known keratoconjunctivitis sicca
· known Sjögren’s syndrome
· the topical use of any medication that may influence rosacea (e.g. metronidazole, azelaic acid, adapalene or antibiotics) within the last 2 weeks proir to treatment start
· the systemic use of metronidazole within the last 6 weeks prior to study start
· systemic antibiotic treatment within the last 6 weeks prior to treatment start – particularly tetracycline
· need for concomitant antibiotic treatment (except study indication)
· corticoid treatment within the last month prior to treatment start (exception: inhalation with corticosteroids in subjects with asthma will be allowed at a dose not exceeding 1 mg/day; the dosage should remain consistent throughout the entire study period)
· need for corticoid treatment (exception: see above)
· isotretinoin treatment within the last 6 months prior to treatment start
· use of drugs that can increase sensitivity towards light, e.g. Saint-John’s-wort (hypericum preparations)
· use of drugs or food supplements containing Vitamin A or ß-carotin
· known or suspected depression or psychosis, either present or in medical history
· known or suspected mental or neurological disorders (e.g. dementia, Alzheimer’s disease, Parkinson’s disease)
· history of malignoma
· known or suspected gastric or intestine ulcera
· known or suspected pancreatitis
· known or suspected oesophagitis
· known or suspected HIV
· known or suspected hypervitaminosis A
· acute nausea and/or diarrhoea
· liver enzymes (AST, ALT, and γ-GT) higher than 2 fold upper limits of normal (ULN)*
· triglycerides higher than 1.5 fold upper limits of normal (ULN)*
· cholesterol higher than 1.5 fold upper limits of normal (ULN)*
· pregnant or breast-feeding women
· participation in another clinical trial within 30 days directly preceding the administration of the study drug
· simultaneous participation in another clinical trial
· any suspicion of drug and/or alcohol abuse
· clinical history suggestive of intolerance or allergy to one of the products
· any chronic disease that may affect the absorption, metabolism or elimination of the investigational product
* = based on screening blood sampling

FOR FERTILE WOMEN ONLY
· fertile women without hormonal contraception during the last menstrual cycle prior to study start and/or not willing to accept the continuation of this hormonal contraception (combination oral contraceptive, hormonal patch, hormonal implants, hormonal injections, IUD – hormonal intra uterine device) during the entire study and for at least 35 days after end of treatment
· fertile women not willing to accept two established and reliable methods of contraception including one barrier method during the entire study and for at least 35 days after end of treatment

E.5 End points

E.5.1

Primary end point(s)

The reduction in the total sum of facial papules and pustules/noduli is the primary efficacy variable. The reduction will be measured as difference in the total sum from baseline to end of treatment after 12 weeks.

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

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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)

Yes

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.8.3

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

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

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

Yes

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

Information not present in EudraCT

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

550

F.4.2

For a multinational trial

F.4.2.1

In the EEA

550

F.4.2.2

In the whole clinical trial

550

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)

After study completion patients will be asked to participate voluntarily in a post-study observation in order to obtail information about remission periods. This post-study observation will be described in a separate obsevation plan.

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

2006-12-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-12-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2008-07-31

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