Etanercept for Wegener's Granulomatosis
Etanercept for Wegener's Granulomatosis
This study will determine if the drug etanercept, also called Enbrel, is effective in
 producing and maintaining remission (reduction of disease symptoms) of Wegener's
 granulomatosis (WG). Etanercept blocks the action of tumor necrosis factor-alpha, a substance
 that may be involved in inflammatory conditions such as WG. Eight clinical centers around the
 United States will enroll 181 people who have WG. Patients will have an equal chance to
 receive either etanercept or placebo (inactive treatment). We will treat patients with
 standard medications for WG in addition to either etanercept or placebo. We will treat all
 patients with tapering doses of corticosteroids.

 After the patients' disease is controlled (in remission), we will reduce the dosages of the
 standard medications to lower the risk of side effects associated with these drugs. During
 the study, we will collect and save blood and tissues samples from patients and use the
 samples to address other medical questions, such as the cause of WG and factors that lead to
 disease progression.
The Wegener's Granulomatosis Etanercept Trial (WGET) is a randomized, placebo-controlled
 clinical trial. A primary objective of the trial is to evaluate the safety and efficacy of
 etanercept (Enbrel; Immunex Corporation, Seattle, WA) for the induction and maintenance of
 disease remissions for people with Wegener's granulomatosis (WG) when used in conjunction
 with standard medications. A secondary objective is to develop a specimen bank of serum,
 plasma, whole blood, and tissue biopsy samples that may be used to address basic questions
 regarding the etiology, pathophysiology, and monitoring of WG.

 The trial is a phase II/III randomized, double-masked, multicenter trial with a parallel
 treatment design. We will assign patients randomly to either etanercept or placebo in an
 assignment ratio of 1:1. In addition to either etanercept or placebo, we will treat all
 patients with standard drug regimens for WG according to the severity of their disease. We
 will treat those with limited WG with methotrexate and corticosteroids, and those with severe
 WG with cyclophosphamide and corticosteroids. After the patients' disease is controlled with
 therapy (i.e., the standard treatment regimen plus either etanercept or placebo), we will
 taper the standard medications according to regimens designed to ensure patient safety,
 diminish morbidity associated with the standard medications, and test the efficacy of
 etanercept in sustaining disease remissions.

 The principal outcome measure in this trial is the number of patients in the two treatment
 arms who achieve sustained remissions measured by the Birmingham Vasculitis Activity Score
 for WG (BVAS). The sample size is 181 patients recruited at eight clinical centers in the
 United States. We will stratify randomization by clinic and disease severity (limited versus
 severe). Every patient enrolled will have a BVAS of at least three, insuring unequivocally
 active disease.

 We will follow all randomized patients, regardless of whether or not they remain on their
 assigned treatments, until the common closing date of the trial, defined as 12 months after
 enrollment of the last patient. We will perform the primary analyses on an intention-to-treat
 basis.
Inclusion Criteria:

 -  Minimum weight of 40 kg.

 -  Diagnosis of WG, excluding infections, malignancies, systemic autoimmune disorders,
 and other forms of vasculitis that may mimic WG.

 -  At least two of the five modified American College of Rheumatology (ACR) criteria for
 a diagnosis of WG. The modified ACR criteria are: (1) nasal or oral inflammation,
 defined as the development of painful or painless oral ulcers or purulent or bloody
 nasal discharge; (2) abnormal chest radiograph, defined as the presence of nodules,
 fixed infiltrates, or cavities; (3) active urinary sediment, defined as microscopic
 hematuria (> 5 red blood cells per high-power field) or red blood cell casts; (4)
 granulomatous inflammation on biopsy, defined as histologic changes showing
 granulomatous inflammation within the wall of an artery or in the perivascular or
 extravascular area (artery or arteriole); and (5) positive serum ELISA for ANCAs
 (anti-neutrophil cytoplasmic antibodies) directed at PR-3.

 -  Birmingham Vasculitis Activity Score (BVAS) score 3 or greater within 28 days of
 randomization. This may include either the presence of one or more major items (3
 points each) or the presence of three or more minor items (1 point each).

 -  Willingness and ability, with the assistance of a caregiver if necessary, to comply
 with treatment and followup procedures.

 -  Willingness of men and women of childbearing potential to practice an adequate method
 of birth control during the study and for 3 months afterwards.

 -  Willingness to limit alcohol consumption to one alcoholic drink per week while taking
 methotrexate.

 -  Willingness to refrain from breast-feeding during the study and for 3 months
 afterwards.

 -  Collection of all baseline data within 14 days prior to randomization.

 -  Signed consent statement.

 Exclusion Criteria:

 -  Presence of an active systemic infection.

 -  White blood cell count less than 4,000/mm cubed or a platelet count less than
 120,000/mm cubed.

 -  Creatinine greater than 2.0 mg/dL secondary to non-WG causes (e.g., hypertensive
 nephropathy) for a patient with limited disease.

 -  Known acute or chronic liver disease.

 -  History of multiple sclerosis or other neurological symptoms suggesting a
 demyelinating syndrome.

 -  Current evidence of malignancy or malignancy diagnosed within 5 years of study entry.
 Patients with squamous or basal cell carcinomas of the skin may be enrolled if they
 have received curative surgical treatment.

 -  Positive serum pregnancy test for women of childbearing potential.

 -  Previous treatment with specific therapies directed against tumor necrosis factor,
 e.g., etanercept or infliximab.