Clinical Trials Register

Summary
EudraCT Number:	2013-002861-20
Sponsor's Protocol Code Number:	2012-01
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2013-10-23
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

Bulgarian Drug Agency

A.2

EudraCT number

2013-002861-20

A.3

Full title of the trial

A multi-centre, randomised, double-blind, parallel-group phase III study to investigate the efficacy, safety, and tolerability of a generic calcipotriol-betamethasone ointment formulation compared to Daivobet® and vehicle in the treatment of adult patients with chronic stable plaque psoriasis

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

Trial on Efficacy, Safety and Tolerability of Calcipotriol-Betamethasone Sandoz

A.4.1

Sponsor's protocol code number

2012-01

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	Lek Pharmaceuticals d.d.
B.1.3.4	Country	Slovenia
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	Lek Pharmaceuticals d.d.
B.4.2	Country	Slovenia
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Lek Pharmaceuticals d.d.
B.5.2	Functional name of contact point	Nina Habjanič
B.5.3	Address:
B.5.3.1	Street Address	Verovskova 57
B.5.3.2	Town/ city	Ljubljana
B.5.3.3	Post code	1526
B.5.3.4	Country	Slovenia
B.5.4	Telephone number	+38615802111
B.5.5	Fax number	+38615683517
B.5.6	E-mail	nina.habjanic@sandoz.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	Calcipotriol-Betamethasone Sandoz
D.3.2	Product code	Calcipotriol-Betamethasone Sandoz
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	CALCIPOTRIOL MONOHYDRATE
D.3.9.1	CAS number	112965-21-6
D.3.9.2	Current sponsor code	CALCIPOTRIOL MONOHYDRATE
D.3.9.3	Other descriptive name	CALCIPOTRIOL MONOHYDRATE
D.3.9.4	EV Substance Code	SUB26081
D.3.10	Strength
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BETAMETHASONE DIPROPIONATE
D.3.9.1	CAS number	5593-20-4
D.3.9.2	Current sponsor code	BETAMETHASONE DIPROPIONATE
D.3.9.3	Other descriptive name	BETAMETHASONE DIPROPIONATE
D.3.9.4	EV Substance Code	SUB00783MIG
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	0.5
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	Daivobet®
D.2.1.1.2	Name of the Marketing Authorisation holder	Leo Pharma A/S, Denmark
D.2.1.2	Country which granted the Marketing Authorisation	Denmark
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	Daivobet®
D.3.2	Product code	Daivobet®
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	CALCIPOTRIOL MONOHYDRATE
D.3.9.1	CAS number	112965-21-6
D.3.9.2	Current sponsor code	CALCIPOTRIOL MONOHYDRATE
D.3.9.3	Other descriptive name	CALCIPOTRIOL MONOHYDRATE
D.3.9.4	EV Substance Code	SUB26081
D.3.10	Strength
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BETAMETHASONE DIPROPIONATE
D.3.9.1	CAS number	5593-20-4
D.3.9.2	Current sponsor code	BETAMETHASONE DIPROPIONATE
D.3.9.3	Other descriptive name	BETAMETHASONE DIPROPIONATE
D.3.9.4	EV Substance Code	SUB00783MIG
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	0.5
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.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	Ointment
D.8.4	Route of administration of the placebo	Cutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic stable plaque psoriasis.

E.1.1.1

Medical condition in easily understood language

Chronic stable plaque psoriasis.

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10071117
E.1.2	Term	Plaque psoriasis
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

To demonstrate that topical treatment with the generic calcipotriol-betamethasone ointment formulation is therapeutically equivalent to the originator product Daivobet® ointment in the treatment of chronic stable plaque psoriasis as determined by the percentage reduction in modified Psoriasis Area and Severity Index (PASI).

E.2.2

Secondary objectives of the trial

- to demonstrate that topical treatment with the generic calcipotriol-betamethasone ointment formulation is superior to vehicle (company’s ointment formulation) in the treatment of chronic stable plaque psoriasis as determined by the percentage reduction in modified Psoriasis Area and Severity Index (PASI).
- to assess the efficacy of the generic calcipotriol-betamethasone ointment formulation in comparison to the originator product Daivobet® and vehicle (company’s ointment formulation) in the treatment of chronic stable plaque psoriasis in terms of improvement in:
- Investigator's Psoriasis Global Assessment (IPGA) score;
- Body Surface Area (BSA) affected by psoriasis;
- Patient’s Psoriasis Global Assessment (PPGA) score.
- to assess the safety and local tolerance of the generic calcipotriol-betamethasone ointment formulation in comparison to the originator product Daivobet® and vehicle (company’s ointment formulation).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1] Male or female patients ≥18 years of age.
[2] Clinical diagnosis of chronic stable (at least 6 months) plaque psoriasis amenable to topical treatment and involving arms and/or legs and/or trunk (but excluding face, scalp, genitals and intertriginous areas).
[3] Psoriasis affecting less than 30% of the body surface area (BSA).
[4] A modified PASI score of ≥5 to ≤15 at baseline (Visit 2).
[5] Female patients of childbearing potential must have a negative pregnancy test prior to randomisation and must agree to use an appropriate method of contraception during the study.
[6] Patients willing and able (e.g. mental and physical condition) to participate in all aspects of the study, including use of medication, completion of subjective evaluations, attending scheduled visits, and compliance with protocol requirements as evidenced by providing signed written informed consent.
[7] An albumin-corrected serum calcium level below the upper reference range limit.

E.4

Principal exclusion criteria

- History of hypersensitivity or intolerance to any active substance or any of the excipients of the study medication
- History of hypersensitivity to Adrenocorticotropic hormone (ACTH), Synacthen® or Synacthen® Depot
- Current diagnosis of unstable forms of psoriasis in the area(s) to be treated with study medication, including guttate, erythrodermic, exfoliative, or pustular psoriasis
- Other inflammatory skin disease in the area(s) to be treated with study medication that may confound the evaluation of plaque psoriasis
- Presence of pigmentation, extensive scarring, pigmented lesions, or sunburn in the area(s) to be treated with study medication which could interfere with efficacy evaluation
- History of psoriasis unresponsive to topical treatments
- Viral lesions of the skin
- Fungal or bacterial skin infections
- Parasitic infections
- Skin manifestations in relation to tuberculosis or syphilis
- Perioral dermatitis
- Atrophic skin, striae atrophicae
- Fragility of skin veins
- Ichthyosis
- Acne vulgaris, acne rosacea, rosacea
- Dermal ulcers, wounds
- Perianal and genital pruritus
- Allergic disorders or susceptibility for allergic reactions
- Active infectious diseases
- Peptic ulcer
- Refractory heart failure
- Any of the following conditions, whether known or suspected: endocrine disorders, Cushing’s syndrome, primary adrenocortical insufficiency, diabetes mellitus
- Current or past history or signs/symptoms suggestive of a clinically significant abnormality in calcium homeostasis with hypercalcaemia, vitamin D toxicity, severe renal impairment (CRCL <30 ml/min), or severe hepatic disorder (total bilirubin, AST, ALT, GGT, or AP >3 times the upper limit of normal)
- Use of topical anti-psoriatic therapy within 2 weeks prior to baseline (Visit 2) and during the study
- Use of systemic corticosteroids within 3 months prior to baseline (Visit 2) and during the study
- Use of other systemic anti-psoriatic therapy, systemic antibiotics, or systemic anti-inflammatory agents within 1 month prior to baseline (Visit 2) and during the study
- Use of immunosuppressive drugs or oral retinoids within 2 months prior to baseline (Visit 2) and during the study
- Chemotherapy or radiation therapy within 3 months prior to baseline (Visit 2) and during the study
- Use of systemic anti-psoriatic biologic therapy within 6 months prior to baseline (Visit 2) and during the study
- Psoralen + UVA (PUVA) therapy or UVB therapy within 1 month prior to baseline (Visit 2) and during the study
- Use of calcium supplements during the study
- More than 400 IU/day of vitamin D or vitamin D analogues during the study
- Initiation of or changes in non-anti-psoriatic concomitant medication(s) that could affect psoriasis during the study
- Initiation of or changes to concomitant medication that could affect calcium metabolism during the study
- Change in sleep pattern within 1 month prior to baseline (Visit 2) and during the study
- Initiation of or changes in oestrogen therapy (including contraceptives), antidepressant medications and any other medication known to affect cortisol levels or HPA axis integrity within 1 month prior to baseline (Visit 2) and during the study
- Use of CYP P450 3A4 inducers within 1 month prior to baseline (Visit 2) and during the study
- Use of systemic CYP P450 3A4 inhibitors (e.g. ketoconazole, itraconazole, metronidazole) within 1 month prior to baseline (Visit 2) and during the study
- Use of topical CYP P450 3A4 inhibitors (e.g. ketoconazole) within 2 weeks prior to baseline (Visit 2) and during the study
- Use of tanning booth, sun lamps, or non-prescription UV light sources within 2 weeks prior to baseline (Visit 2) and during the study
- Use of topical skin products other than the assigned treatment (including moisturisers, new brands of make-up, creams, ointments, lotions, and powders) during the study
- Phototherapy within 2 weeks prior to baseline (Visit 2) and during the study
- Pregnancy or breast-feeding
- Women of childbearing potential unable or unwilling to undergo pregnancy tests and practice adequate contraceptive measures. Reliable methods for women are hormonal contraceptives, surgical intervention (e.g. tubal ligation), intrauterine device (IUD) and sexual abstinence
- Any other condition of the patient (e.g., serious or unstable medical or psychological condition, acute psychosis) that in the opinion of the investigator may compromise evaluation of the study treatment or may jeopardize patient’s safety, compliance or adherence to protocol requirements
- Previous enrolment in this study or participation in any other drug investigational trial within the past 3 months prior to enrolment
- Alcohol /drug dependence or abuse (excluding tobacco abuse)
- Legal incapacity and/or other circumstances rendering the patient unable to understand the nature, scope and possible consequences of the study
- Unreliability or lack of cooperation

E.5 End points

E.5.1

Primary end point(s)

Mean percent change from baseline in modified PASI score at the end of
week 4.

E.5.1.1

Timepoint(s) of evaluation of this end point

After week 4 of the treatment.

E.5.2

Secondary end point(s)

- Mean percent change from baseline in modified PASI score at the end of week 1 and week 2.
- Proportion of patients with a reduction in modified PASI score of >75% between baseline and end of week 4 (responder).
- Proportion of patients with a reduction in modified PASI score of >50% between baseline and end of week 4.
- Mean percent change from baseline in IPGA at the end of week 1, week 2, and week 4.
- Mean percent change from baseline in PPGA at the end of week 1, week 2, and week 4.
- Proportion of patients with controlled disease (defined as "clear" or "almost clear") in IPGA at the end of week 4.
- Proportion of patients with controlled disease (defined as "clear" or "almost clear") in PPGA at the end of week 4.
- Mean percent change from baseline in BSA measurement at the end of week 1, week 2, and week 4.

E.5.2.1

Timepoint(s) of evaluation of this end point

After completion of study and closure of data base.

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

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:

411

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

411

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

200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

411

F.4.2.2

In the whole clinical trial

411

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)

No special treatment 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

2014-01-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-09-01

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