WGET 2005.

Study characteristics
Methods	Study design: double‐blinded parallel RCT Location: USA: Michigan, San Francisco, Rochester, Maltimore, Durham, Cleveland, Boston, New York Setting: clinical centres Number of centres: 8 Time frame of the study: June 2000 through September 2003 Duration of follow‐up mean: 27 months
Participants	Inclusion criteria: Body weight ≥ 40 kg GPA diagnosis: at least two of the five criteria of modified Americal College of Rheumatology (ACR) a criteria for the classification of GPA (nasal or oral inflammation; abnormal chest radiograph; active urine sediment; granulomatous inflammation and/or necrotizing vasculitis on tissue biopsy; positive enzyme immunoassay for antibodies to serine proteinase 3). BVAS/WG of 3 or more within 28 days before the baseline assessment Completion of all baseline procedures within 14 days before enrolment to trial Readiness to limit alcohol intake to one drink/week while on methotrexate Females of childbearing potential practicing an acceptable method of birth control during a clinical trial and no breastfeeding Exclusion criteria: Active systemic infection White blood cell count < 4000/mm3 Platelet count < 120000/mm3 Creatinine > 2 mg/dL not associated with GPA for a patient with limited GPA Hepatic dysfunction of severity which may interfere with trial participation A history of cancer within the last 5 years except fully excised basal cell or squamous cell carcinomas of the skin, or cervical carcinoma in situ which has been treated or excised in a curative procedure. Pregnancy History of a demyelinating neurological syndrome Previous therapy with anti‐tumour necrosis factor specific therapies Total number of participants: 181 participants randomised. Etanercept group: 89 Placebo group: 91 Characteristics: Mean (SD) age: Etanercept: 52.4 ± 13.9; Placebo: 47.5 ± 16.5 Mean age at onset of symptoms: Etanercept: 52.4 ± 13.9; Placebo: 47.5 ± 16.5 Female sex: Etanercept: 33 (37.1%); Placebo: 39 (42.9%) BMI value: not reported Mean (SD) CrCI value: Etanercept: 1.85 ± 2.05; Placebo: 1.62 ± 1.76 Disease duration (time since diagnosis, median (IQR)): Etanercept: for new diagnosis: 0.79 months IQR: 0.36–1.38; for previous diagnosis: 36 months IQR:19–61; Placebo: for new diagnosis: 0.66 months IQR: 0.36–1.12; for previous diagnosis: 25 months IQR: 10–50. Race/ethnic group (%) Etanercept: white, non‐Hispanic 91%; black, non‐Hispanic 2.3%; Hispanic 4.5%; other 2.2%; Placebo: white, non‐Hispanic 93.4%); black, non‐Hispanic 1.1%; Hispanic 3.3%; other 2.2% Disease diagnosed at enrolment to the study (%): Etanercept: 34.8%; Placebo: 53.9% Disease assessment index BVAS/WG (mean(SD)): Etanercept: 6.5 ± 3.0; Placebo: 7.5 ± 3.7 Disease assessment VDI: mean ± SD: Etanercept: 1.6 ± 1.9; Placebo: 1 ± 1.4 Disease assessment index Global assessment (Physicians’ global assessment), mean±SD: Etanercept: 5.3 ± 2.3; Placebo: 5.8 ± 2.3 Disease assessment index baseline Global assessment (Patients’ global assessment), mean ±SD: Etanercept: 6.5 ± 2.8; Placebo: 6.4 ± 2.7 Quality of life mean ± SD: SF‐36 physical score: Etanercept: 34.4 ± 9.7; Placebo: 32.6 ± 9.6; SF‐36 mental score: Etanercept: 45.4 ± 12.2; Placebo: 42.9 ± 10.9 Disease severity (limited /severe) [%]: Etanercept: 30.3%; Placebo: 27.5% Organ involvement (%): Etanercept: systemic (65.2%); skin (15.7%); mucous membranes/eyes (24.7%); ears, nose, throat (69.7%); cardiovascular (0%); gastrointestinal (0%); pulmonary (51.7%); renal (52.8%); nervous (6.7%); other (44.9%); Placebo: systemic (78%); skin (24.2%); mucous membranes/eyes (27.5%); ears, nose, throat (83.5%); cardiovascular (2.2%); gastrointestinal (2.2%); pulmonary (68.1%); renal (55%); nervous (12.1%); other (35.2%) Prior treatment: not reported ANCA laboratory results: ever positive by IF (%): Etanercept 85.4%; Placebo: 89.0%: C‐ANCA (% of total ANCA positive by IF) Etanercept: 85.3%; Placebo: 89.7%; P‐ANCA (% of total ANCA positive by IF) Etanercept: 14.7%; Placebo: 10.3%; ANCA ever positive by EIA (%): Positive for PR3‐ANCA Etanercept: 70.8%; Placebo:74.7%; Positive for MPO‐ANCA Etanercept: 16.9%; Placebo: 6.6%
Interventions	All participants were followed for 12 months after randomization of the last participant. Etanercept group: 25 mg twice a week, subcutaneous; for 25 months (median value) Placebo group: lyophilised powder containing 40 mg of mannitol, 10 mg of sucrose, and 1,2 mg of tris(hydroxymethyl)methylamine twice a week, subcutaneous; for 19 months (median value) Concominant treatment for both groups: ‐ Patients with severe GPA received cyclophosphamide + glucocorticoids at the time of enrolment. Those with limited GPA receive methotrexate and glucocorticoids. After control of the patients’ disease, the standard medications are tapered according to regimens consistent with patient safety to reduce the risk of medication‐associated morbidity and to test the benefit of etanercept in sustaining disease remissions. ‐ All patients received prophylaxis against pneumocystis infection and osteoporosis.
Outcomes	Major outcome: Sustained disease remission: defined as a BVAS/WG of 0 for >= six months (three follow‐up visits, excluding the first follow‐up visit, because of its shorter interval) Minor outcomes: The number and rate of flares during the treatment phase: defined as an increase of >= one point in the BVAS/WG. Percentage of patients with a sustained low level of disease activity: defined by a BVAS/WG of less than 3 for at least six months. Remission: the percentage of patients with remission defined as a BVAS/WG score of 0. Cumulative area under the curve for the BVAS/WG. AEs related to Wegener’s granulomatosis or its treatment: defined as any untoward medical occurrences in patients who received etanercept, regardless of their presumed relationships to treatment, were graded according to the National Cancer Institute Toxicity Grading Scale. Quality of Life: defined as results from SF‐36 scale. Mortality. Time to mortality; but not reported. Number achieving BVAS ≤ 2; but not reported. Time from randomisation to first BVAS/WG=0; but not reported. Time from sustained remission to first disease flare; but not reported. Number of severe flares. Number of limited flares. End‐stage renal disease; but not reported. Physician’s global assessment of GPA activity. Patient’s global assessment of GPA activity. Birmingham Vasculitis Damage Index. Other outcomes: Change from baseline in Westergren erythrocyte sedimentation rate; but not reported. Change from baseline in serum C‐reactive protein; but not reported. Change from baseline in ANCA titers; but not reported. Completion of prednisone taper regimen; but not reported. Switch from cyclophosphamide to methotrexate at 3 to 6 months after randomisation; but not reported. Cumulative doses of cyclophosphamide and methotrexate; but not reported. Cumulative doses of prednisone; but not reported.
Notes	Discontinuation: 69 (38.12%) participants (34 participants from placebo group and 35 participant from etanercept group): 12 (6.63%) due to AEs, 4 (2.21%) died, 20 (11.94%) had treatment failure, 9 (4.97%) physician decision, 18 (9.94%) participant decision, 6 (3.31%) other reasons. Funded by: A contract (N01‐AR‐9‐2240) with the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; A grant (FD‐R‐001652‐01) from the Food and Drug Administration Office of Orphan Products General Clinical Research Center grants to Johns Hopkins University School of Medicine (M01‐RRO‐2719), Boston University (M01‐RRO‐00533), the University of Michigan (M01‐RRO‐0042), and Duke University (M01‐RR‐30) from the National Institutes of Health, National Center for Research Resources; Amgen.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Treatment assignments are generated in permuted blocks of varying lengths."
Allocation concealment (selection bias)	Low risk	Central allocation. "Patients are assigned to one of six experimental medication “bins”: A1, B2, C3, D4, E5, or F6" (information obtained from the author of the study)
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants receive medicinal dosage from the same bin. "The packaging of etanercept and placebo into identical vials". Blinding of study personnel ensured. "One potential source of unmasking among clinical personnel is the occurrence of injection site reactions. Injection site reactions have been reported in both the placebo‐ and etanercept‐assigned groups in other trials, albeit more commonly among etanercept‐assigned patients."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"The board is masked to the specific treatment assignment of each group. In the evaluation of all data regarding the harm and benefit, the board receives data relating to treatment group (i.e., either etanercept or placebo) labelled as either treatment “A” or “B.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis, however 7% of patients in control group were excluded from primary analysis because lost to follow‐up and 0% were excluded in etanercept group. Including those patients would not have clinically relevant impact on the intervention effect estimate for major outcome
Selective reporting (reporting bias)	High risk	One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis.
Other bias	Low risk	No other biases were identified.

AE – adverse event

ANCA – antineutrophil cytoplasmic antibody

anti‐MPO – anti‐myeloperoxidase

anti‐PR3 – Anti‐proteinase 3 ‐

BMI – body mass index

BREVAS‐ Belimumab in Remission of VASculitis

BVAS – Birmingham Vasculitis Activity Score

BVAS/WG – Birmingham Vasculitis Activity Score for granulomatosis with polyangiitis

CrCl – creatinine clearance

EGPA – eosinophilic granulomatosis with polyangiitis

EudraCT ‐ European Union Drug Regulating Authorities Clinical Trials Database

EULAR – European League against Rheumatism

GPA – granulomatosis with polyangiitis

HBcAb – hepatitis B core antibody

HBsAg – hepatitis B Surface antigen

HIV ‐ human immunodeficiency virus

ITT – intention to treat

IV – intravenous

MPA – microscopic polyangiitis

NR – not reported

QTc(F) – QT interval corrected using Fridericia formula

RCT – randomized controlled trial

SC – subcutaneous

SD – standard deviation

VDI – Vasculitis Damage Index

WGET ‐ Wegener's Granulomatosis Etanercept Trial