Clinical Trials Register

Summary
EudraCT Number:	2012-002716-10
Sponsor's Protocol Code Number:	165-001
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-11-08
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

UK - MHRA

A.2

EudraCT number

2012-002716-10

A.3

Full title of the trial

An international prospective, double-blind, placebo-controlled phase III RCT in which patients with moderate to severe psoriasis vulgaris are treated with s.c. methotrexate using an optimized treatment schedule

A.3.1

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

Clinical trial for optimization of tretament schedule for methrotexate in patients with moderate to severe psoriasis vulgaris

A.3.2

Name or abbreviated title of the trial where available

METOP

A.4.1

Sponsor's protocol code number

165-001

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	Prof. Dr. Kristian Reich
B.1.3.4	Country	Germany
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	medac GmbH
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	SCIderm GmbH
B.5.2	Functional name of contact point	Project Management
B.5.3	Address:
B.5.3.1	Street Address	Drehbahn 1-3
B.5.3.2	Town/ city	Hamburg
B.5.3.3	Post code	20354
B.5.3.4	Country	Germany
B.5.4	Telephone number	+4940554401123
B.5.5	Fax number	+4940554401291
B.5.6	E-mail	contact@sciderm.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	Yes
D.2.1.1.1	Trade name	metex® 50mg/ml solution for injection
D.2.1.1.2	Name of the Marketing Authorisation holder	medac 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.3.4	Pharmaceutical form	Solution for injection/infusion in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
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	Solution for injection/infusion in pre-filled syringe
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Psoriasis vulgaris

E.1.1.1

Medical condition in easily understood language

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10050576
E.1.2	Term	Psoriasis vulgaris
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 primary objective is to evaluate the efficacy of subcutaneous application of MTX in patients with moderate to severe psoriasis compared to placebo as determined by the number of patients reaching the primary endpoint PASI 75 after a 16 week treatment phase in the two study arms.

E.2.2

Secondary objectives of the trial

The following endpoints, which evaluate the efficacy, tolerability and safety are assessed:

•PASI75 after 52 weeks treatment
•PASI50 and 90 after 16 and 52 weeks treatment
•PASI75 after 32 weeks treatment in placebo arm (cross-over)
•NAPSI, BSA, PGA, , PsA and questionnaires such as PSAT metex® , EQ-5D and DLQI after 16 and 52 weeks treatment
•Safety and tolerability assessed by AE/SAE, laboratory values and local tolerability at the injection site
•Changes of levels of molecular biologic analysis (UBC and B2M as housekeeping gens; TNF-α, IL-17, IL-4, IFN-gamma) and immunohistochemistry analysis (CD3, CD1a, Ki67) at baseline and after 16 weeks (at 3 sites for approx. 30 patients); for explorative scientific purpose only

The data up to week 16 will be analyzed regarding the difference between verum and placebo treatment. The data from week 16 to week 52 will be analyzed regarding long term treatment effects in a descriptive manner only.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Skin biopsy (optional), requires a separate signature in a separate informed consent for skin bopsies. Approximately 30 patients from 2-3 German centers are foreseen to take part in this study. This sub-study has explorative purpose only. The statistical analysis will only be descriptive. It is required as part of this protocol that the investigator presents this option to all patients in the respective selected centers. If the patient consents to participate in this part of the study, at Visit 1 (week 0, baseline) and Visit 5 (week 16) skin biopsies will be taken from lesional (respectively formerly affected skin) skin by two connecting 3 mm punches that will be closed afterwards with one suture.

These samples will be used for analyzing the following parameters / marker:
•Molecular biologic analyses: Quant. RT-PCR, Kryo-samples: UBC and B2M as housekeeping gens; TNF-alpha, IL-17, IL-4, IFN-gamma
•Immunhistochemistry analyses: Paraffin-samples: CD3, CD1a, Ki67

The investigations are exploratory and are not intended to be used for regulatory judgments pertaining to the safety or efficacy of the investigational drug. However, these data may be considered for voluntary submission, consistent with applicable regulatory guidance on this topic, in order to develop the knowledge base necessary to establish the validity of new biomarkers.
Exploratory research studies are planned as a part of this study with the objectives of identifying inherited factors which may (1) be related to psoriasis, (2) predict response to treatment with methotrexate, or (3) predict predisposition to side effects. The intent is to develop a better understanding of psoriasis and how patients respond to methotrexate.

Sampling method:
Lab manuals will be provided with detailed information on sample collection, handling, and shipment. The sample collection date and exact time must be entered on the sample collection eCRF page. The biopsies will only be performed by respectively experienced investigators / dermatologists.

Packaging of samples:
Once the sample has been taken, it will be immediately placed in a receptor tube already marked for identification. Storage and shipping procedures will be described in a separate document.

E.3

Principal inclusion criteria

To be eligible for the study, patients must meet all of the following criteria:
1. Are 18 years of age or older at time of informed consent; may be men or women.
2. Are MTX naïve
3. Moderate to severe plaques psoriasis (according rule of ten (PASI ≥10 or BSA ≥
10 or DLQI ≥ 10) for at least 6 months with or without psoriatic arthritis (however,highly active psoriatic arthritis is excluded, defined by > 5 swollen tender joints or soles and CRP >2 x UNL) .
4. Women of childbearing potential and all men must be using a highly effective method of contraception (pearl index < 1%) as defined blow and must agree to continue to use such measures and not become pregnant or plan a pregnancy until 6 months after receiving the last injection of IMP. Highly effective method is defined as: Use of oral, injected or implanted hormonal methods, intrauterine device (IUD) or intrauterine system (IUS), barrier methods of contraception:condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
5. Able to adhere to the study visit schedule and other protocol requirements.
6. Capable of giving informed consent. The informed consent must be obtained prior
to any study related procedures.
7. Must avoid prolonged sun exposure and avoid use of tanning booths or other
ultraviolet light sources during study.
8. Must agree not to receive a live virus or live bacterial vaccination 4 weeks prior to
the first IMP s.c. administration, during the trial and up to 3 months after the last
injection.
9. Chest X-ray investigation within the last 6 months prior to first s.c. administration of
IMP and show no clinically relevant abnormalities

E.4

Principal exclusion criteria

Patients meeting any of the following criteria may not be enrolled in the study:
1.Currently have non-plaque forms of psoriasis (eg, erythrodermic, guttate, or pustular).
2.Have current drug-induced psoriasis (eg, a new onset of psoriasis or an exacerbation of psoriasis from beta blockers, (hydroxy-) chloroquine, or lithium).
3.Are pregnant, nursing, or planning pregnancy (both men and women) while enrolled in the study.
4.Have screening laboratory test results for the following parameters outside the stated ranges (please refer also to :
a.Hemoglobin < 10 g/dL
b.White blood cells < 3.0 x 109/L
c.Neutrophils < 1.5 x 109/L
d.Platelets < 100 x 109/L
e.Creatinine clearance (calculated according to Cockroft-Gault) < 50 mL/min)
f.AST, ALT, and γ-GT levels must be > 2 times the upper limit of normal range
g.Bilirubin > 5mg/dl (85,5 µmol/l)
h.Hypalbuminemia <3,5 g/dl
5.Have used any other IMP within the previous 4 weeks or 5 times the half-life of an investigational agent prior to the first s.c. administration of the IMP of this study, whichever is longer.
6.Not able or willing to wash out any prohibited medications as listed below [Medication / Therapy --> Washout requirements (all times with regard to first s.c. administration of the IMP)] :
6.1 Any biologics --> 5 times of half-life
6.2 Phototherapy or any systemic medications that could affect the psoriasis (including but not limited to oral or injectable corticosteroids, retinoids, 1,25 dihydroxy vitamin D3 and analogues, sulfasalazine, hydroxyurea, or fumaric acid derivates) -->Within 4 weeks
6.3 Any topical medications that could affect the psoriasis (e.g. corticosteroids, anthralin, calcipotriene, topical vitamin D derivates, retinoids, tazarotene) -->Within 2 weeks
6.4 Any systemic immunosuppressants (e.g. azathioprine, cyclosporine, 6-thioguanine, mercaptopurine, mycophenolate mofetil, hydroxyurea, and tacrolimus) --> Within 4 weeks
6.5 lithium, antimalarial agents --> To be stopped directly prior to first s.c. administration of IMP
6.6 Intramuscular gold --> Within 4 weeks

Patients who take prohibited medications that cannot be washed out within 4 weeks or at least 5 times of the half-life of the investigational agent prior to first s.c. administration of IMP should not be asked to participate in the trial.

7.Have a history of chronic or recurrent infectious disease or had a serious infection or have been hospitalized or received i.v. antibiotics for the treatment of an infection within 2 months prior to screening.
8. History of radiotherapy or planed concomitant radiotherapy
9. Ulcers of the oral cavity (e.g. ulcerative stomatitis) and/or known gastrointestinal
ulcer disease
10. A known B12/cobalamin deficiency
11. Known diagnosed ascites or pleural effusions
12.Have a history of latent or active TB ( prior to screening).
13.Have current signs or symptoms of severe, progressive, or uncontrolled renal (specifically with calculated creatinine clearance < 20), hepatic (especially with bilirubin > 5mg/dl (85,5 mol/l), hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease.
14.Have any known malignancy or have a history of malignancy (with the exception of basal cell carcinoma, squamous cell carcinoma in situ of the skin, or cervical carcinoma in situ that has been treated with no evidence of recurrence, or squamous cell carcinoma of the skin that has been treated with no evidence of recurrence within 5 years prior to the first administration of study agent).
15.Have shown a previous immediate hypersensitivity response, including anaphylaxis, to the folic acid
16.Are unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access to veins.
17.Are known to have had a substance abuse (drug or alcohol) problem within the previous 12 months.
18.Staff or relatives/partner of any clinical research site

E.5 End points

E.5.1

Primary end point(s)

PASI75 after 16 weeks

E.5.1.1

Timepoint(s) of evaluation of this end point

week 16

E.5.2

Secondary end point(s)

•PASI75 after 52 weeks treatment
•PASI50 and 90 after 16 and 52 weeks treatment
•PASI75 after 32 weeks treatment in placebo arm (cross-over)
•NAPSI, BSA, PGA, PsA and questionnaires such as PSAT metex®, EQ-5D and DLQI after 16 and 52 weeks treatment
•Safety and tolerability assessed by AE/SAE, laboratory values and local tolerability at the injection site from V1- V10
•Changes of levels of molecular biologic analysis (UBC and B2M as housekeeping gens; TNF-α, IL-17, IL-4, IFN-gamma) and immunohistochemistry analysis (CD3, CD1a, Ki67) at baseline and after 16 weeks (at 3 sites for approx. 30 patients); for explorative scientific purpose only

The data up to week 16 will be analyzed regarding the difference between verum and placebo treatment. The data from week 16 to week 52 will be analysed regarding long term treatment effects in a descriptive manner only.

E.5.2.1

Timepoint(s) of evaluation of this end point

refer to E.5.2

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

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

Others refers to the biopsy substudy described under 2.3.1. Scopes evaluated here are only for exploratory scientific purpose only and refer to immunohistochemistry and molecular biologic analysis.

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

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)

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

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:

140

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

150

F.4.2.2

In the whole clinical trial

150

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)

Patients who prematurely withdraw from the study will be treated to standard practice by their dermatologist or will be referred to a dermatologic practice for further treatment according to standard practice. Withdrawn patients with side effects will be treated according to standard practice by their general practitioner or will be referred to a specialist. In the case of AE, the investigator should ensure that the patient receives a suitable therapy appropriate to patient’s 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

2012-11-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-03-27

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-05-13

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