E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10050576 |
E.1.2 | Term | Psoriasis vulgaris |
E.1.2 | System Organ Class | 100000004858 |
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E.1.3 | Condition being studied is a rare disease | No |
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. |
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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 • RESTRICTED TO GERMAN SITES (Sub-Study): Changes of levels of molecular biologic analysis (UBC + 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.
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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, RESTRICTED TO GERMAN SITES), 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.
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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 |
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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
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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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.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
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. |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
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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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 14 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |