The Efficacy and Safety of Adding Methotrexate to Etanercept in Psoriasis
Condition: Psoriasis
MeSH terms: Psoriasis
Intervention: Methotrexate; Etanercept; Placebo
Intervention description: Methotrexate tablets over-encapsulated for blinding; 1 mL for subcutaneous injection; Matching placebo to methotrexate capsules
Intervention MeSH terms: Etanercept; Methotrexate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 478.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Etanercept; Methotrexate; Psoriasis

Summary:

      The purpose of this study is to evaluate the efficacy of adding methotrexate to etanercept
      compared with etanercept monotherapy as measured by the percentage of participants achieving
      a 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at Week
      24.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Is capable of understanding and giving written, voluntary informed consent before
             study screening

          -  Male or female ≥18 years of age at time of screening

          -  Has had stable moderate to severe plaque psoriasis for at least 6 months (eg, no
             morphology changes or significant flares of disease activity)

          -  Has involved body surface area (BSA) ≥ 10% and Psoriasis Area and Severity Index
             (PASI) ≥ 10 at screening and at baseline

          -  Is a candidate for systemic therapy or phototherapy in the opinion of the investigator

          -  Has a negative test for hepatitis B surface antigen and hepatitis C antibody

          -  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. Patients 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.

          -  Has a negative serum pregnancy test within 28 days before initiating Investigational
             Product (IP) and negative urine pregnancy test at baseline for females (except those
             at least 3 years post menopausal or surgically sterile)

          -  Females are 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)

          -  Males are 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)

          -  Men with a pregnant female partner are willing to use effective methods (decided upon
             with the investigator) to ensure that an unborn child is not exposed to IP via semen

          -  Patient or designee must have the ability to inject etanercept subcutaneously

        Exclusion Criteria:

        Skin-disease related

          -  Has active guttate, erythrodermic, or pustular psoriasis at the time of the screening
             visit.

          -  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

          -  Has significant concurrent medical conditions, including:

          -  Type 1 diabetes

          -  Poorly controlled type 2 diabetes (hemoglobin A1c > 8.5)

          -  Symptomatic heart failure (New York Heart Association [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 human immunodeficiency virus (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 patient

          -  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

          -  Is pregnant or breast feeding

          -  Has any condition that could, in the opinion of the investigator, compromise the
             patient'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

          -  Has a family history of heritable liver disease (eg, hemachromatosis, Wilson's
             disease)

          -  Has a history of or evidence at screening or baseline of alcohol abuse, alcoholic
             liver disease, or other clinically significant liver disease

          -  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)

          -  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

          -  Has a history of significant methotrexate toxicity including pneumonitis or
             significant cytopenias

        Laboratory abnormalities

          -  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 /mm^3

          -  White blood cell count < 3,500 cells/mm^3

          -  Absolute neutrophil count < 1500/mm^3

          -  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 patient from completing the study or will interfere with the
             interpretation of the study results

        Washouts and disallowed medications

          -  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)

          -  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

          -  Has used methotrexate within 28 days of IP initiation. Patients 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 patient)

          -  Has used biologic therapies (other than interleukin (IL)12/IL23 inhibitors or
             anti-timor necrosis factor (TNF) agents) within 3 months of IP initiation

          -  Has used an IL12/23 inhibitor within 6 months of IP initiation (eg, CNTO 1275, ABT
             874)

          -  Has used one or more anti-TNF agents (eg, etanercept, adalimumab, infliximab) within 3
             months of IP initiation. Patients 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 patient).

          -  Has previously used efalizumab (Raptiva®).

          -  Other investigational procedures are excluded.

          -  currently 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 is receiving other investigational agent(s).