Clinical Trials Register

Summary
EudraCT Number:	2018-002532-24
Sponsor's Protocol Code Number:	0155/2018
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:	2018-10-17
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

2018-002532-24

A.3

Full title of the trial

A phase III, multicentre, randomised, double-blind, parallel-group trial to evaluate the efficacy and safety of a generic gel (calcipotriol + betamethasone 50 μg/g + 0.5 mg/g gel) compared to originator gel (Daivobet® gel) and vehicle in the treatment of mild to moderate plaque-type psoriasis

A.3.1

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

A study to demonstrate that topical treatment with the generic calcipotriol- betamethasone gel is therapeutically equivalent to the originator Daivobet® gel in the treatment of chronic stable, mild to moderate plaque-type psoriasis

A.4.1

Sponsor's protocol code number

0155/2018

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	HELM AG
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	Helm AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Helm AG
B.5.2	Functional name of contact point	Medical Affairs Manager
B.5.3	Address:
B.5.3.1	Street Address	Nordkanalstr. 28
B.5.3.2	Town/ city	Hamburg
B.5.3.3	Post code	20097
B.5.3.4	Country	Germany
B.5.4	Telephone number	00494023750
B.5.5	Fax number	0049402375290484
B.5.6	E-mail	SBX-HAG-MedicalAffairs@helmag.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 50 μg/g_Betamethasone 0.5 mg/g
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.3.8	INN - Proposed INN	Calcipotriol monohydrate
D.3.9.1	CAS number	112965-21-6
D.3.9.3	Other descriptive name	CALCIPOTRIOL MONOHYDRATE
D.3.9.4	EV Substance Code	SUB26081
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	0.05
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.3.9.3	Other descriptive name	BETAMETHASONE DIPROPIONATE (PH. EUR.)
D.3.9.4	EV Substance Code	SUB45443
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
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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.3.8	INN - Proposed INN	Calcipotriol monohydrate
D.3.9.1	CAS number	112965-21-6
D.3.9.3	Other descriptive name	CALCIPOTRIOL MONOHYDRATE
D.3.9.4	EV Substance Code	SUB26081
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	0.05
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.3.9.3	Other descriptive name	BETAMETHASONE DIPROPIONATE (PH. EUR.)
D.3.9.4	EV Substance Code	SUB45443
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	Gel
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

mild to moderate plaque-type psoriasis

E.1.1.1

Medical condition in easily understood language

mild to moderate 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	20.0
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 gel is therapeutically equivalent to the originator Daivobet® gel in the treatment of chronic stable, mild to moderate plaque-type psoriasis as determined by the percentage reduction in psoriasis area and severity index (PASI).

E.2.2

Secondary objectives of the trial

To demonstrate the superiority of the generic gel to its vehicle

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent, personally signed and dated by the subject, is obtained prior to any trial-related activities
2. Male or female subjects 18 years of age or older
3. Clinical diagnosis of stable plaque psoriasis of at least 6 months duration (stable meaning neither spontaneously improving nor rapidly deteriorating plaque psoriasis)
4. Subjects with mild to moderate chronic plaque psoriasis (Psoriasis vulgaris) defined by:
• up to 20% BSA affected with plaques (corresponding to a total area of approximately 4000 cm2)
• PASI ≥5.0 to ≤15.0
• category “mild”, “moderate” or “moderate to severe” on IGA scoring
at the screening and baseline visits and who are suitable for topical treatment
5. Female volunteers of childbearing potential must either be surgically sterile (hysterectomy or tubal ligation) or agree to use a reliable method of contraception with a failure rate of less than 1 % per year when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intra-uterine devices [IUDs], sexual abstinence in accordance to the preferred life style or vasectomized partner during the 8-week treatment period
*Note: Providing that partner is the sole sexual partner of the female trial participant and has received medical assessment of the surgical success.
6. Ability to understand and comply with study procedures and restrictions.

E.4

Principal exclusion criteria

1. Pregnant or breastfeeding women
2. Clinically relevant history or presence of any disease or any chronic medical condition which is not well controlled (e.g., disorders of calcium metabolism, hypertension, diabetes, etc.) or surgical history which may interfere with the conduct of the trial in the opinion of the investigator
3. Other active skin diseases (e.g., urticaria, atopic dermatitis, etc.), skin infections (bacterial, fungal, parasitic or viral) or skin conditions that might interfere in the opinion of the investigator with treatment and evaluation of psoriasis
4. Acute psoriasis guttata, psoriasis punctata as well as erythrodermic, exfoliative and pustular psoriasis
5. Findings determined in physical examination including vital signs, or clinical laboratory safety tests which are not deemed eligible in the opinion of the investigator
6. Calcium test at V1 (screening) exceeding the upper limit of reference range (including serum calcium, albumin, phosphate, parathyroid hormone)
7. History of an allergic reaction or significant sensitivity to constituents of IMP
8. Contraindications according to summary of product characteristics of the originator gel (Daivobet® gel): Viral (e.g., herpes or varicella) lesions of the skin, fungal or bacterial skin infections, parasitic infections, skin manifestations in relation to tuberculosis, perioral dermatitis, atrophic skin, striae atrophicae, fragility of skin veins, ichthyosis, acne vulgaris, acne rosacea, rosacea, ulcers and wounds in the areas to be treated
9. Use of topical therapies for the treatment of psoriasis including but not limited to: corticosteroids, vitamin D analogs, retinoids, urea, salicylic acid, coal tar and anthralin during the study or having discontinued less than 2 weeks prior to randomisation
10. Phototherapy for the treatment of psoriasis including but not limited to: UV-A, UV-B, sunbaths less than 4 weeks, and PUVA less than 8 weeks prior to randomisation
11. Systemic therapies for the treatment of psoriasis including but not limited to: cyclosporine, retinoids, methotrexate, tacrolimus, azathioprine, salazosulfapyridine, apremilast and glucocorticoids less than 4 weeks prior to randomisation
12. Use of biologic agents for the treatment of psoriasis as follows:
Anti-tumor necrosis factor (TNF) drugs:
Adalimumab, infliximab, brodalumab, ixekizumab, etanercept: 8 weeks
guselkumab, certolizumab pegol, golimumab: 12 weeks
Other biologics:
Ustekinumab, alefacept, secukinumab: 24 weeks
Rituximab: 12 months
13. Treatment with systemic or locally acting medications which might have countered or influenced the trial aim (medications which are known to provoke or aggravate psoriasis, e.g. antimalarial drugs, lithium) within 8 weeks before first treatment and/or during the trial. Beta-blockers or angiotensin converting enzyme (ACE) inhibitors are allowed if on a stable dose for 3 months before study medication initiation
14. Use of another investigational agent or participation in the treatment phase of a clinical trial within the last 4 weeks prior to first dose or 5 half-life periods
15. Taking of oral vitamin D supplement, except when the subject has been on a stable dose (up to 2,000 international unit [IU] per day allowed) for at least 56 days (8 weeks) before the day of randomisation and plan to continue the dose for the duration of the trial
16. Taking of medicines that affect calcium metabolism (e.g. any oral prescription Vitamin D derivatives, calcium preparations, bisphosphonate or thiazide diuretics), except for subjects who have been on a stable dose for a period of 84 days (12 weeks) prior to the day of randomisation and plan to continue the dose for the duration of the trial
17. History of alcohol or other substance abuse within the last year
18. In the opinion of the investigator performing the initial examination the subject should not participate in the trial, e.g. due to probable noncompliance or inability to understand the trial and give adequately informed consent
19. Close affiliation with the investigator (e.g., a close relative) or subject is an employee of sponsor, CRO or sites
20. Subject is institutionalised because of legal or regulatory order.

E.5 End points

E.5.1

Primary end point(s)

Mean % change from baseline in PASI (psoriasis area and severity index) at Week 4/Day 29

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 4/Day 29

E.5.2

Secondary end point(s)

Improvement (1 or more points change on a 6 point scale) in IGA (investigator’s global assessment) at Week 4/Day 29 - Mean % change from baseline in mPASI (modified psoriasis area and severity index, excluding head and neck) at Week 4/Day 29 and Week 8/Day 56 (will be calculated using values from PASI evaluation) - Mean % change from baseline in PSSI (psoriasis scalp severity index) at Week 4/Day 29 (will be assessed using the same component scoring criteria and the extent (%) as for PASI evaluation)

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 4/Day 29 and Week 8/Day 56

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

Yes

E.6.13.1

Other scope of the trial description

To demonstrate therapeutical equivalencce of generic gel to the originator Daivobet® gel
according tp primary endpoint
To demonstrate the superiority of the generic gel to its vehicle.

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.1.3

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

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

280

F.4.2.2

In the whole clinical trial

280

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)

None

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

2018-12-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-11-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-11-04

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