The Efficacy and Safety of Adding Methotrexate to Etanercept in Psoriasis

Inclusion Criteria:

• Subject is capable of understanding and giving written, voluntary informed consent before study screening
• Male or female ≥18 years of age at time of screening
• Subject has had stable moderate to severe plaque psoriasis for at least 6 months (eg, no morphology changes or significant flares of disease activity)
• Subject has involved BSA ≥ 10% and PASI ≥ 10 at screening and at baseline
• Subject is a candidate for systemic therapy or phototherapy in the opinion of the investigator
• Subject has a negative test for hepatitis B surface antigen and hepatitis C antibody
• Subject has a negative purified protein derivative test within 30 days prior to the first IP dose. Tuberculin skin tests should be considered positive when they have greater than or equal to 5 mm of induration at 48-72 hours after test is placed. Subjects with a positive tuberculin skin test (if less than or equal to 14 mm of induration) are allowed if they have a history of Bacillus Calmette-Guerin vaccination with a negative Quantiferon test in the past year, no symptoms per tuberculosis worksheet, and a negative chest X ray.
• Subject has a negative serum pregnancy test within 28 days before initiating IP and negative urine pregnancy test at baseline for female subjects (except those at least 3 years post menopausal or surgically sterile)
• Female subject is willing to use highly effective form of birth control (decided upon with the investigator) during the study and for 3 months after the end of treatment (except women at least 3 years post menopausal or surgically sterile)
• Male subject is willing to use highly effective form of birth control (decided upon with the investigator) during the study and for 5 months after the end of treatment (except for men who are surgically sterile or whose female partners are at least 3 years post menopausal, surgically sterile, or are using a highly effective form of birth control)
• Male subject with a pregnant female partner is willing to use effective methods (decided upon with the investigator) to ensure that an unborn child is not exposed to IP via semen
• Subject or designee must have the ability to inject etanercept subcutaneously

Exclusion Criteria:

Skin-disease related

• Subject has active guttate, erythrodermic, or pustular psoriasis at the time of the screening visit.
• Subject has evidence of skin conditions at the time of the screening visit (eg, eczema) that would interfere with evaluations of the effect of IP on psoriasis.

Medical conditions

• Subject has significant concurrent medical conditions, including:
• Type 1 diabetes
• Poorly controlled type 2 diabetes (hemoglobin A1c > 8.5)
• Symptomatic heart failure (NYHA class II, III, or IV)
• Myocardial infarction within the last year
• Current or history of unstable angina pectoris within the last year
• Uncontrolled hypertension as defined by a resting blood pressure ≥ 160/95 mmHg prior to randomization (confirmed by a repeat assessment)
• Severe chronic pulmonary disease (eg, requiring oxygen therapy)
• No major chronic inflammatory disease or connective tissue disease other than psoriasis and/or psoriatic arthritis
• Multiple sclerosis or any other demyelinating disease
• Active malignancy, including evidence of cutaneous basal or squamous cell carcinoma or melanoma, or history of cancer (other than fully resected and surgically cured cutaneous basal cell and squamous cell carcinoma) within 5 years before the first IP dose. If malignancy occurred more than 5 years ago, documentation of disease-free state since treatment is required.
• Known immunodeficiency syndromes including HIV
• Uncontrolled, clinically significant history of renal disease
• Alcoholic hepatitis
• Any condition that, in the opinion of the investigator, might cause this study to be detrimental to the subject
• Subject has any active CTC grade 2 or higher infection (including chronic or localized infections) within 30 days prior to screening, at screening, or during screening period prior to first investigational product (IP) dose
• Subject is pregnant or breast feeding
• Subject has any condition that could, in the opinion of the investigator, compromise the subject's ability to give written consent and/or comply with the study procedures, such as a history of substance abuse or a psychiatric condition Methotrexate contraindications or precautions
• Subject has a family history of heritable liver disease (eg, hemachromatosis, Wilson's disease)
• Subject has a history of or evidence at screening or baseline of alcohol abuse, alcoholic liver disease, or other clinically significant liver disease
• Subject is unwilling or unable to limit alcohol consumption during the 24-week trial period (allowable limits are: not more than 4 drinks a week, not more than 2 drinks in a single day. 1 drink = 1 (5 oz) glass of wine = 1.5 oz liquor = 12 oz of beer or hard cider)
• Subject has an estimated total cumulative methotrexate exposure (by medical history) exceeding 1000 mg, unless a subsequent liver biopsy has demonstrated no grade IIIb or greater injury
• Subject has a history of significant methotrexate toxicity including pneumonitis or significant cytopenias

Laboratory abnormalities

• Subject has laboratory abnormalities at screening, including:
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > the upper limit of normal (if screen fail for abnormal AST/ALT, 1 repeat measurement is allowed)
• Serum total bilirubin ≥ 1.5 mg/dL
• Abnormal serum albumin (< 3.5 g/dL)
• Hemoglobin < 11 g/dL
• Platelet count < 125,000 /mm3
• White blood cell count < 3,500 cells/mm3
• Absolute neutrophil count < 1500/mm3
• Estimated creatinine clearance < 50 mL/min (Cockroft-Gault formula, calculated value to be provided to sites)
• Any other laboratory abnormality, which, in the opinion of the investigator, will prevent the subject from completing the study or will interfere with the interpretation of the study results

Washouts and disallowed medications

• Subject has used any of the following therapies within 14 days of IP initiation:
• Ultraviolet light B therapy
• Topical cyclosporine or calcineurin inhibitors
• Topical vitamin A or D analog preparations
• Class III through VII topical steroids (exception: permitted on the scalp, axillae, and groin)
• Subject has used any of the following therapies within 28 days of IP initiation:
• Intravenous or oral calcineurin inhibitors
• Ultraviolet light A therapy
• Psoralen and ultraviolet light A therapy
• Oral retinoids
• Class I or II topical steroids
• Anthralin
• Any other systemic psoriasis therapy (eg, cyclosporine), including oral or parenteral corticosteroids
• Cyclophosphamide
• Sulfasalazine
• Subject has used methotrexate within 28 days of IP initiation. Subjects with prior use of methotrexate must be excluded if subject discontinued because of a clinically significant adverse event (eg, severe skin reactions, methotrexate-induced lung disease, or any other adverse event that the investigator feels might cause this study to be detrimental to the subject)
• Subject has used biologic therapies (other than interleukin (IL)12/IL23 inhibitors or anti-TNF agents) within 3 months of IP initiation
• Subject has used an IL12/23 inhibitor within 6 months of IP initiation (eg, CNTO 1275, ABT 874)
• Subject has used one or more anti-TNF agents (eg, etanercept, adalimumab, infliximab) within 3 months of IP initiation. Subjects with prior use of an anti-TNF agent must be excluded if the subject discontinued for lack of efficacy or a clinically significant adverse event (eg, serious infection, neurologic event, malignancy, hematologic event, or any other adverse event that the investigator feels might cause this study to be detrimental to the subject).
• Subject has previously used efalizumab (Raptiva®).
• Other investigational procedures are excluded.
• Subject currently is enrolled in or has not yet completed at least 30 days or 5 half-lives (if applicable; whichever is longer) since ending other investigational device or drug study(s), or subject is receiving other investigational agent(s).