The Efficacy and Safety of Adding Methotrexate to Etanercept in Psoriasis

Phase 3

Completed

Conditions: Psoriasis

Interventions: Drug: Methotrexate
Drug: Placebo
Drug: Etanercept

Registration Number: NCT01001208

Lead Sponsor: Amgen

Brief 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 478

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Etanercept Plus Placebo	Placebo	Participants received 50 mg etanercept twice weekly (BIW) for the first 12 weeks and then 50 mg etanercept once weekly (QW) for the second 12 weeks. Participants also received oral placebo that was the same number of capsules per week as the methotrexate dosing regimen.
Etanercept Plus Methotrexate	Methotrexate	Participants received 50 mg etanercept twice weekly (BIW) for the first 12 weeks and then 50 mg etanercept once weekly (QW) for the second 12 weeks. Participants also received active methotrexate titrated as follows: 7.5 mg per week (3 capsules) for weeks 1 and 2, 10 mg per week (4 capsules) for weeks 3 and 4, and then up to 15 mg per week (6 capsules) or the maximum tolerated dose for the remainder of the 24-week treatment period.
Etanercept Plus Methotrexate	Etanercept	Participants received 50 mg etanercept twice weekly (BIW) for the first 12 weeks and then 50 mg etanercept once weekly (QW) for the second 12 weeks. Participants also received active methotrexate titrated as follows: 7.5 mg per week (3 capsules) for weeks 1 and 2, 10 mg per week (4 capsules) for weeks 3 and 4, and then up to 15 mg per week (6 capsules) or the maximum tolerated dose for the remainder of the 24-week treatment period.
Etanercept Plus Placebo	Etanercept	Participants received 50 mg etanercept twice weekly (BIW) for the first 12 weeks and then 50 mg etanercept once weekly (QW) for the second 12 weeks. Participants also received oral placebo that was the same number of capsules per week as the methotrexate dosing regimen.

Primary Outcome Measures

Name	Time	Method
PASI 75 Response at Week 24	Baseline and 24 Weeks	Percentage of participants achieving at least a 75% decrease (improvement) from Baseline in the Psoriasis Area and Severity Index (PASI) at Week 24. PASI Score incorporates measures of erythema, desquamation, infiltration, and affected body surface area. Involvement and severity of psoriasis was scored by a blinded assessor using a scale of 0 to 72, where 0 = no psoriasis and 72 = severe disease.

Secondary Outcome Measures

Name	Time	Method
PASI 90 Response at Week 24	Baseline and 24 Weeks	Percentage of participants achieving at least a 90% decrese (improvement) from Baseline in the Psoriasis Area and Severity Index (PASI) at Week 24. PASI Score incorporates measures of erythema, desquamation, infiltration, and affected body surface area. Involvement and severity of psoriasis was scored by a blinded assessor using a scale of 0 to 72, where 0 = no psoriasis and 72 = severe disease.
PASI 50 Response at Week 24	Baseline and 24 Weeks	Percentage of participants achieving at least a 50% decrease (improvement) from Baseline in the Psoriasis Area and Severity Index (PASI) at Week 24. PASI Score incorporates measures of erythema, desquamation, infiltration, and affected body surface area. Involvement and severity of psoriasis was scored by a blinded assessor using a scale of 0 to 72, where 0 = no psoriasis and 72 = severe disease.
PASI 90 Response at Week 12	Baseline and 12 Weeks	Percentage of participants achieving at least a 90% decrease (improvement) from Baseline in the Psoriasis Area and Severity Index (PASI) at Week 12. PASI Score incorporates measures of erythema, desquamation, infiltration, and affected body surface area. Involvement and severity of psoriasis was scored by a blinded assessor using a scale of 0 to 72, where 0 = no psoriasis and 72 = severe disease.
Static Physician Global Assessment (sPGA) Response at Week 24	Week 24	Percentage of participants achieving a clear (0) or almost clear (1) status on the Static Physician Global Assessment (sPGA) at Week 24. This index evaluates the physician's global assessment of the participant's psoriasis based on severity of induration, scaling, and erythema. The assessment was scored by a blinded assessor on a scale of 0 to 5, where 0 = clear, with no evidence of plaque elevation, erythema, or scale, and 5 = severe induration, erythema, and scaling.
PASI 50 Response at Week 12	Baseline and 12 Weeks	Percentage of participants achieving at least a 50% decrease (improvement) from Baseline in the Psoriasis Area and Severity Index (PASI) at Week 12. PASI Score incorporates measures of erythema, desquamation, infiltration, and affected body surface area. Involvement and severity of psoriasis was scored by a blinded assessor using a scale of 0 to 72, where 0 = no psoriasis and 72 = severe disease.
PASI 75 Response at Week 12	Baseline and 12 Weeks	Percentage of participants achieving at least a 75% decrease (i.e. improvement) from Baseline in the Psoriasis Area and Severity Index (PASI) at Week 12. PASI Score incorporates measures of erythema, desquamation, infiltration, and affected body surface area. Involvement and severity of psoriasis was scored by a blinded assessor using a scale of 0 to 72, where 0 = no psoriasis and 72 = severe disease.
Static Physician Global Assessment (sPGA) Response at Week 12	Week 12	Percentage of participants achieving a clear (0) or almost clear (1) status on the Static Physician Global Assessment (sPGA) at Week 12. This index evaluates the physician's global assessment of the participant's psoriasis based on severity of induration, scaling, and erythema. The assessment was scored by a blinded assessor on a scale of 0 to 5, where 0 = clear, with no evidence of plaque elevation, erythema, or scale, and 5 = severe induration, erythema, and scaling.
Change From Baseline in the Percentage of Body Surface Area Involved With Psoriasis at Week 12	Baseline and 12 Weeks	A measurement of psoriasis involvement, given as the physician's assessment of the percentage of the participant's total body surface area (BSA) involved with psoriasis. The BSA numerical score was completed by a blinded assessor. A decrease from Baseline indicates improvement. Change from Baseline was calculated as Baseline score - Week 12 score; a positive change from Baseline therefore indicates improvement.
Change Form Baseline in Percentage of Body Surface Area Involved With Psoriasis at Week 24	Baseline and 24 Weeks	A measurement of psoriasis involvement, given as the physician's assessment of the percentage of the participant's total body surface area (BSA) involved with psoriasis. The BSA numerical score was completed by a blinded assessor. A decrease from Baseline indicates improvement. Change from Baseline was calculated as Baseline score - Week 24 score; a positive change from Baseline therefore indicates improvement.