Double-blind, Randomized, Placebo-controlled Phase 3 Study of Etanercept in the Treatment of Psoriatic Arthritis and Psoriasis

Double-Blind, Randomized, Placebo-Controlled Study of Etanercept (ENBREL) in the Treatment of Psoriatic Arthritis (PsA) and Psoriasis

This was a phase 3, double-blind, placebo-controlled, randomized, multicenter study in subjects with psoriatic arthritis (PsA) and psoriasis comprising 3 periods: a 24-week double-blind period, a ≤ 24-week maintenance period, and a 48-week open-label period. During the double-blind period, subjects were randomized equally to 1 of 2 regimens: etanercept 25 mg twice weekly (BIW) or placebo, administered subcutaneously (SC). After the week 24 visit, subjects continued on blind-labeled therapy in a maintenance period until all subjects completed the double-blind period. After the maintenance period, all subjects received open-label etanercept 25 mg BIW.

Previously presented data from 2 double-blind, placebo-controlled trials (Protocols 016.0612 [Investigator IND] and 016.0030 [Immunex IND]) led to the approval of etanercept for reducing clinical signs and symptoms of PsA. One-year radiographic data from Protocol 20021630 led to an additional approval of etanercept for inhibiting structural progression in PsA.

Data are used for the following purposes:

• To summarize the clinical efficacy and safety results previously described in the 6-month clinical study report and the radiographic results previously described in the 1-year clinical study report.
• To show the effect of etanercept on physical function in subjects with PsA and psoriasis, as measured by 2 patient-reported outcome measures (disability index of the Stanford Health Assessment Questionnaire [HAQ] and Medical Outcomes Study Short-form Health Survey [SF-36]). • To present the radiographic results at 2 years from baseline and the final clinical efficacy and safety results during the open-label period of the study.

Inclusion Criteria: Subjects had to satisfy the following criteria before randomization into the study:

• Active PsA at the time of screening, including ≥ 3 swollen joints and ≥ 3 tender/painful joints. • Had ≥ 1 of the following subtypes of PsA: distal interphalangeal (DIP) involvement; polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis); arthritis mutilans; asymmetric peripheral arthritis; or ankylosing spondylitis-like.
• Arthritis had demonstrated an inadequate response to nonsteroidal antiinflammatory drug (NSAID) therapy.
• Subjects had plaque psoriasis with qualifying target lesion. Target lesion was to be ≥ 2 cm in diameter and could not be on the scalp, axilla, or groin. Psoriasis was to be stable (ie, not accelerating).
• Between 18 and 70 years of age.
• Subjects remaining on concomitant MTX (≤ 25 mg/week) had inadequate disease control in the opinion of the investigator and had been on a stable dose of MTX for 2 months before start of investigational product. Subjects were required to maintain a stable dose of MTX throughout the study.
• Negative serum pregnancy test within 14 days before the first dose of investigational product in all women (except those surgically sterile or ≥ 5 years postmenopausal).
• Heterosexually active men and women of childbearing potential agreed to use a medically accepted form of contraception throughout the study, including the exclusionary medicine washout period and follow-up period.
• Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 2 times laboratory's upper limit of normal; hemoglobin ≥ 8.5 g/dL; platelet count ≥ 125,000/mm3; white blood cell count ≥ 3,500 cells/mm3; and serum creatinine ≤ 2 mg/dL.
• Negative HIV test. Negative test for hepatitis B surface antigen and hepatitis C.
• Able to reconstitute and self-inject investigational product or have a designee who could do so.
• Capable of understanding and giving written, voluntary informed consent.

Exclusion Criteria:

• Guttate or pustular psoriasis.

• Evidence of skin conditions (eg, eczema) other than psoriasis that would interfere with evaluations of the effect of study medication on psoriasis.

• Active severe infection within 1 month of investigational product administration.

• Subjects must be off antibiotics for 1 week before investigational product administration.

• Previous receipt of etanercept, known antibody to TNF, or experimental metalloproteinase inhibitors (past or current use of minocycline and doxycycline was acceptable).

• Receipt of investigational drugs or biologics within 4 weeks of the screening visit.

• Receipt of anti-CD4 or diptheria IL-2 fusion protein within the previous 6 months, with a subsequent abnormal absolute T cell count.

• Psoralen ultraviolet A phototherapy (PUVA) within 4 weeks of investigational product initiation. Ultraviolet B (UVB) phototherapy within 2 weeks of investigational product initiation.

• Receipt of disease-modifying anti-rheumatic drugs (DMARDs) other than MTX (eg, hydroxycholorquine, oral or injectable gold, cyclophosphamide, cyclosporine, azathioprine, D-penicillamine, or sulfasalazine) or intra-articular corticosteroids within 4 weeks before the first dose of investigational product.

• Dose of NSAID greater than the maximum recommended dose in the product information. NSAID dose had to be stable for ≥ 4 weeks before screening evaluation.

• Concomitant corticosteroids > 10 mg/day of prednisone (or its equivalent). Corticosteroid dose had to be stable for ≥ 4 weeks before screening evaluation.

• Topical steroids, oral retinoids, topical vitamin A or D analog preparations or anthralin within 14 days of baseline. (Exception: Topical therapies were permitted on scalp, axillae, and groin but had to be stable throughout trial.)

• Pregnancy or lactation in women.

• Significant concurrent medical diseases including:

  • Diabetes mellitus requiring insulin
  • Uncompensated congestive heart failure
  • Myocardial infarction within 12 months of screening visit
  • Unstable or stable angina pectoris
  • Uncontrolled hypertension
  • Severe pulmonary disease (requiring medical or oxygen therapy)
  • History of cancer (other than resected cutaneous basal or squamous cell carcinoma or in situ cervical cancer) within 5 years of screening visit
  • HIV positive, hepatitis B surface antigen, or hepatitis C positive
  • Rheumatoid arthritis, systemic lupus, scleroderma, or polymyositis
  • Any condition judged by the subject's physician that would cause this study to be detrimental to the subject

• Current or history of psychiatric disease that would interfere with ability to comply with the study protocol or give informed consent.

• History of alcohol or drug abuse that would interfere with ability to comply with the study protocol.