Mechanism of Action Study for Psoriasis

Study Overview
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Brief Summary
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The objective of this study is to compare the mechanism of action between adalimumab and methotrexate in subjects with psoriasis.

Detailed Description
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Both methotrexate and adalimumab are FDA-approved drugs for the treatment of moderate to severe psoriasis. The two treatments, methotrexate and adalimumab, both show efficacy for psoriasis, however their profiles differ. In the CHAMPION Study, more adalimumab-treated, moderate to severe psoriasis patients achieved a PASI 75 after 16 weeks compared to those treated with methotrexate (80% vs. 36%). The reason for this difference is poorly understood. No direct comparative mechanism of action studies in psoriasis patients between methotrexate and adalimumab (or any tumor necrosis factor blocker) has been reported. With etanercept, another tumor necrosis factor blocker, the in vivo mechanism has been studied with some scientific rigor. These studies demonstrate that etanercept down regulates multiple pro-inflammatory pathways (as shown in Table 1 of the protocol). To date, there are no similar studies with adalimumab or methotrexate. In order to understand the molecular and cellular basis for the differential clinical efficacy of adalimumab and methotrexate, it is essential to compare their mechanisms of action in psoriatic plaques. Biopsies will be performed, and we will study biomarkers in this proposal with immunohistochemistry, real-time polymerase chain reaction, and gene arrays.

Official Title
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An Investigator-Initiated, Assessor Blinded, Randomized Study Comparing the Mechanism of Action of Adalimumab to Methotrexate in Subjects With Moderate to Severe Chronic Plaque Psoriasis.

Conditions
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Psoriasis

Intervention / Treatment
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* Drug: Methotrexate
* Drug: Adalimumab (Humira)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults 18-85 years of age with moderate to severe psoriasis, in general good health as determined by the PI based upon the results of medical history, laboratory profile, and physical examination, and who are candidates for systemic or phototherapy Presence of a psoriatic plaque of >2cm in an area which can be biopsied repeatedly. Men must agree to avoid impregnating a woman while on this study. Women are eligible to participate in the study if they meet one of the following criteria: Women who are postmenopausal (>1 year), sterile, or hysterectomized Women of childbearing potential must undergo monthly pregnancy testing during the study and agree to use two of the following methods of contraception throughout and for 60 days after the last dose of study drug: Oral contraceptives Transdermal contraceptives Injectable or implantable methods Intrauterine devices Barrier methods (diaphragm or condom with spermicide) Abstinence and Tubal Ligation are also considered a form of Birth control Exclusion Criteria: Patients <18 or >85 years old Absence of a psoriatic plaque >2cm in diameter Active guttate, erythrodermic, or pustular psoriasis at the time of the screening visit Evidence of skin conditions at screening (e.g. eczema) that would interfere with evaluations of the effect of study medication Inability to understand the consent process Receipt of any investigational drugs, psoralen+ultraviolet A or oral systemic treatments within 4 weeks of study drug initiation Biologics within 3 months of study initiation Topical steroids, topical vitamin A or D analog preparations, Ultraviolet B therapy or anthralin within 2 weeks of study drug initiation. (Exception-stable regimen of class I-II topical steroids on scalp, axillae, and groin) Methotrexate within 6 weeks of study initiation History of treatment with adalimumab History of primary non-response to methotrexate, infliximab or etanercept History of discontinuation of methotrexate or tumor necrosis factor (TNF) blocker for a safety-related reason that makes it unwise to restart either type of drug Any internal malignancy within 5 years (excluding fully excised cutaneous basal cell or squamous cell carcinoma) Pregnancy, not practicing effective birth control, or inability to practice safe sex during the length of the study Lactation Subjects who have known hypersensitivity to adalimumab or methotrexate or any of its components or who is known to have antibodies to etanercept History of alcohol or drug abuse one year before and during the study Known HIV-positive status or any other immune-suppressing disease Presence of a grade 3 or 4 infection <30 days prior to the screening visit, between the screening visit and the first day of treatment on study, or any time during the study that in the opinion of the PI would preclude participation in the study Any grade 3 or 4 adverse event, or laboratory toxicity, at the time of the screening visit or at any time during the study, which in the opinion of the PI would, preclude participation in the study Serum creatinine >3.0 mg/dL (265 micromoles/L) Serum potassium <3.5 mmol/L or > 5.5 mmol/L Serum alanine aminotransferase or aspartate aminotransferase >3 times the upper limit of normal for the lab Platelet count <100,000/mm3 White blood cell count <3,000/mm3 Hgb, Hct, or red blood cell outside 30% of the upper or lower limits of normal for the Lab Receipt of live vaccines 1 month prior to or while on study History of tuberculosis, and/or a positive PPD skin test/chest x-ray at screening without appropriate treatment-treatment of latent tuberculosis (for those with positive PPD tests) must be initiated prior to therapy with adalimumab or methotrexate Chronic hepatitis B or C infection, history of multiple sclerosis, transverse myelitis, optic neuritis or epilepsy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Adalimumab<br>Dosing will be on day 1 and then weekly. For the injections, dosing will occur according to product recommendations. Patients will receive 80mg adalimumab (2 pre-filled syringes, each with 40mg) on day 1, and then 40mg on week 1 and then every 2 weeks (from week 1 through week 15). | Drug: Adalimumab (Humira)<br>* 2 cohorts (Randomized 1:1 adalimumab:methotrexate). Subjects will receive treatment on Day 1 (baseline visit) and then weekly or every 2 weeks for 16 weeks.<br>* Other names: Humira;|
| Active Comparator: Methotrexate (MTX)<br>Patients will be dosed according to the CHAMPION study in single weekly doses of methotrexate: 7.5mg at week 0, 10mg at week two, and 15mg at week 4 for all patients. For each subject if the PASI did not decrease by at least 50% from baseline (PASI-50) at week 8, dosing will be increased to 20mg per week; the dose will be maintained at 15mg per week if PASI-50 was achieved at week 8. If PASI-50 was not achieved at week 12, dosing will be increased to 25mg per week; the dose will be maintained at 20mg per week if the PASI-50 was achieved at week 12. All patients on methotrexate will also receive a dietary supplement of oral folate (5mg per week). Methotrexate-treated patients will then receive 16 weeks of adalimumab at the end of study. | Drug: Methotrexate<br>* 2 cohorts (Randomized 1:1 adalimumab:methotrexate). Subjects will receive treatment on Day 1 (baseline visit) and then weekly or every 2 weeks for 16 weeks. Methotrexate-treated patients will then receive 16 weeks of adalimumab at the end of study.<br>* Other names: Folic Acid;Drug: Adalimumab (Humira)<br>* 2 cohorts (Randomized 1:1 adalimumab:methotrexate). Subjects will receive treatment on Day 1 (baseline visit) and then weekly or every 2 weeks for 16 weeks.<br>* Other names: Humira;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biologic Activity Endpoints | Histologic and Immunohistochemistry endpoints; Relative messenger RNA gene expression (normalized to HARP); and Gene Arrays. | Weeks 0, 1, 2, 4 and 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Endpoints for Psoriasis: PASI 75 | PASI 75 is the percent of subjects who experience an improvement in PASI (Psoriasis Area and Severity Index) score of at least 75% from their baseline PASI score. | Weeks 0 and week 16 | 
| Clinical Endpoints for Psoriasis: Physician's Global Assessment (PGA) Clear or Almost Clear (PGA 0-1) |  | Week 0 and Week 16 | 
| Clinical Endpoints for Psoriasis: % Body Surface Area |  | Week 0 and week 16 | 
| Clinical Endpoints for Psoriasis: Target Lesion Score | The lesion score of a single psoriatic plaque selected at baseline. Total range is 0 - 12 with 0 being clear and 12 representing the most severe disease. The target lesion score is composed of scale, erythema, and induration, each parameter is scored 0 (clear) through 4 (very severe). Totals are summed for target lesion score. S+E+I = TLS | Week 0 and Week 16 | 
| Clinical Endpoints for Psoriasis: Photography Completed |  | Week 0 and Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tumor necrosis factor (TNF) inhibitor, tumor necrosis factor (TNF) blockade, Methotrexate, treatment, mechanism, psoriasis