| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Psoriasis and Psoriatic Arthritis | |
| MedDRA Classification |
| 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 proposed study is a single center, open label study of 15 patients with PsA and cutaneous Ps treated with a 3-month course of Etanercept (Enbrel).
The aims of this study are to assess the effect of TNF inhibition with Etanercept on:
The clinical features of PsA disease activity
The clinical features of Ps disease activity
Synovial immunohistologic changes
Cutaneous immunohistologic changes
Change of MRI features from baseline of the affected knee joint
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| E.2.2 | Secondary objectives of the trial | |
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria | Patients must give written informed consent, given prior to any study-related procedure not part of the patient’s normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to his or her future medical care.
Patients between the ages 18 and 80 years, with a joint disease onset after 16 years old
Female patients must be neither pregnant nor breast-feeding, and must lack childbearing potential, as defined by either
being post-menopausal or surgically sterile, or
using an accepted form of contraception.
Confirmation that the patient is not pregnant must be established by a negative serum or urinary hCG test within 7 days prior to study day 1. A pregnancy test is not required if the patient is post-menopausal or surgically sterile.
Patients with PsA of > 3 months duration defined by the following criteria:
Peripheral arthritis alone or in combination with sacroiliitis
Active arthritis with >3 swollen joints and >3 tender joints considered capable of responding to drug therapy. At least one of the inflamed joints should be a knee joint.
An evaluable psoriatic skin lesion, diagnosed by a consultant rheumatologist or dermatologist.
Negative serum test for rheumatoid factor.
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| E.4 | Principal exclusion criteria | Patients who have received systemic treatment with biologics, including cytokines/anti-cytokines within three months prior to study day 1.
Patients who have participated in any other investigational study (and received active compound) or received an experimental therapeutic procedure considered by the investigator to interfere with the study within three months prior to study day 1.
Patient with inadequate bone marrow reserve, defined as:
·leukocytes ≤ 3.5 x 109/L,
·thrombocytes ≤ 100 x 109/L, and
·haemoglobin ≤ 5.5 mmol/L (8.9 g/dL).
Patients treated with prednisone >10 mg/day or a treatment change in the prednisone regime during the 28 days prior to Study Day 1.
Positive antibodies against double stranded DNA.
Patients taking more than one NSAID or a treatment change in the NSAID regime during the 28 days prior to Study Day 1.
Patients previously treated with chlorambucil or cyclophosphamide.
Patients treated with DMARDS during the 28 days prior to Study Day 1 or cyclosporin within 8 weeks of Study Day 1 or leflunomide within 8 weeks of Study Day 1 (Patients taking leflunomide must undergo a cholestyramine washout consisting of Cholestyramine 8 Grams three times per day, or activated powdered charcoal four times a day, for eleven days followed by a two week waiting period prior to the screening visit, or complete an 8 week washout prior to the screening visit).
Patients with inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase ≥ 1.5 times the upper limit of the normal values.
Inadequate renal function, defined by serum creatinine > 150 micromol/L.
Planned major surgery (eg. joint replacement) within the duration of the treatment period of the study.
History of cancer in the preceding 5 years (except adequately treated basal cell carcinoma of the skin and carcinoma in situ of the skin).
Have history of active Tuberculosis, or currently active Tuberculosis or currently undergoing treatment for Tuberculosis.
Active severe infection (or non-severe infections at the discretion of the Investigator).
Opportunistic infection in the preceding 3 months.
Clinically significant serious abnormalities on electrocardiography or chest X?ray.
Other serious concomitant disorders incompatible with the study (at the discretion of the Investigator).
Have history of drug (including narcotics) abuse, or current active problems with alcohol abuse.
For Articular Component:
Patients with seropositive, symmetric polyarthritis.
Patients treated with intra-articular injections with corticosteroids within 28 days prior to Study Day 1.
Patients with Arthritis Mutilans.
Patients who are wheelchair bound or bedridden.
For Cutaneous Component:
Patients with guttate, erythrodermic or pustular psoriasis as sole or predominant form of psoriasis.
Evidence of skin conditions other than psoriasis (e.g. eczema).
Topical therapies and oral retinoids within 14 days of study day 1.
Phototherapy within 28 days of study day 1.
Clinically significant psoriasis flare during screening or at the time of enrollment
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| E.5 End points |
| E.5.1 | Primary end point(s) | The primary response endpoint is the detection of an efficacy signal expressed as a change from baseline. Responses will be established on the basis of the clinical, immunohistologic and MRI changes at week 12 from baseline.
For the articular component a clinical response will be evaluated using:
Physician’s global assessment of disease activity (improvement: decrease by at least 1 unit; worsening increase by at least 1 unit)
Patient’s global self-assessment of disease activity (improvement: decrease by at least 1 unit; worsening: increase by at least 1 unit)
Tender joints score (improvement; decrease by at least 30%; worsening: increase by at least 30%)
Swollen joints score (improvement: decrease by at least 30%; worsening: increase by at least 30%)
ACR 20, 50 and 70 response criteria will be applied and the evolution of individual PsARC/ACR parameters will be followed over the duration of the study.
The response to treatment of the cutaneous components of disease will be based on the change of the Psoriatic Area and Severity Index (PASI) at Week 12 from baseline. To have a PASI response, patients must improve at least by 75% in their PASI score between baseline and the end of treatment (Week 12).
The evolution of individual PASI parameters will be followed over the duration of the study. Finally, a target lesion will be photographed at baseline and compared with findings at 12 weeks.
With the exception of target lesion photography, all of the above assessments will be obtained at each patient visit (screening 0, 2, 8 and 12 weeks). In addition, blood will be obtained at each visit for FBC, ESR and CRP.
Synovial immunohistologic change
Using a standard mini-arthroscopic procedure, synovial tissue will be obtained from an inflamed knee joint at 0 and at 12 weeks. Tissue will be embedded in OCT for standard immunohistochemical staining to include cell surface markers (CD3, CD4, CD8, CD68), cytokines (IL-1, TNF) and markers of angiogenesis (Factor VIII, VEGF and its receptors, angiopoietins, avß3). Staining will be quantified and compared at each time point using quantitative methods and/or image analysis. All of the synovial immunohistologic analysis will be performed at the end of the study.
Skin immunohistologic change
In patients with evaluable skin lesions, a 6mm punch, lesion biopsy will be obtained at 0 and 12 weeks. Half of the biopsy will be embedded in OCT for immunohistologic staining as outlined above. All of the skin immunohistologic analysis will be performed at the end of the study.
MRI of the affected knee joint
While plain x-rays of affected joints will be obtained at baseline it is not expected that x-rays will show any major change during the short period of follow up. The MRI findings in PsA are more dramatic sometimes showing substantial bone oedema and periosteal / entheseal change. It is likely that MRI findings are also considerably more sensitive to change. Gadolinium–enhanced MRI will be obtained in all subjects at baseline and at 12 weeks.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Information not present in EudraCT |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
| E.7.1.1 | First administration to humans | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
| E.7.3 | Therapeutic confirmatory (Phase III) | Information not present in EudraCT |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.3 | The trial involves single site in the Member State concerned | Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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 | | The end of the trial is the last follow-up visit for safety of the last patient. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
