A placebo-controlled multicenter study of auranofin in the treatment of patients with corticosteroid-dependent asthma,☆☆,,★★

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Abstract

BACKGROUND: Previous clinical studies have demonstrated that injectable gold salts and the oral gold compound, auranofin, possess significant steroid-sparing effects in the treatment of asthma. OBJECTIVES: The objectives of this investigation were to determine whether auranofin could reduce oral corticosteroid requirements and to evaluate the safety of auranofin in the treatment of chronic corticosteroid-dependent asthma. METHODS: Patients with asthma were eligible if they required at least 10 mg of prednisone per day for control and prevention of asthma exacerbations. Two hundred seventy-nine patients with chronic corticosteroid-dependent asthma (requiring ≥ 10 mg/day) were randomized to receive auranofin, 3 mg twice daily, or placebo during an 8-month clinical trial, which was divided into three phases including: a 4-week baseline period (phase I), a 6-month double-blind treatment and steroid reduction period (phase II), and a 4-week posttreatment observation period during which steroid and auranofin doses or placebo doses were maintained at levels achieved by the end of phase II (phase III). The primary efficacy variable was “therapeutic success” or reduction of daily corticosteroid use by 50% or more. RESULTS: The proportion of patients in the auranofin group achieving therapeutic success (41%) was significantly higher than that in the placebo group (27%) (p = 0.01). This effect was greatest in patients requiring 10 to 19 mg of oral prednisone per day at baseline (p < 0.001). In all treated patients, including those who did and did not complete the trial, significant reduction (≥50% of baseline) in oral corticosteroid dosage was achieved in the auranofin group (60%) compared with the placebo group (32%) (p < 0.001). There were no significant differences between treatment groups in symptoms, concomitant medication use, or lung function. Mean serum total IgE levels decreased significantly from baseline in the auranofin group (-44.63 IU/ml) compared with the placebo group (p = 0.001). Gastrointestinal and cutaneous adverse events were greater in the auranofin group. CONCLUSIONS: Auranofin demonstrated a steroid-sparing effect without concomitant worsening of symptoms or lung function and appeared to be more effective in patients dependent on 10 to 19 mg of prednisone per day. Therefore this study has demonstrated that auranofin is useful as a steroid-sparing agent in the treatment of chronic corticosteroid-dependent asthma. (J ALLERGY CLIN IMMUNOL 1996;98:317-24.)

Section snippets

Patient selection

Patient eligibility was determined by the following inclusion criteria: (1) a diagnosis of asthma as defined by the American Thoracic Society15 and a 15% increase in FEV1 after treatment with an inhaled β2-agonist, (2) a history of perennial asthma with symptoms of equivalent severity throughout the year, (3) optimal concomitant therapy with β2-agonists and/or methylxanthines, and (4) dependency on oral corticosteroid dosages of at least 10 mg of prednisone or 8 mg of methylprednisolone per day

RESULTS

Of 334 patients screened, 140 were randomized to the auranofin group and 139 to the placebo group. Four patients in the auranofin group were excluded from the intent-to-treat efficacy analyses because of noncompliance in the initial 2 weeks of phase I. Therefore 136 patients were analyzed in the auranofin group. Eighty-two patients treated with auranofin and 75 patients treated with placebo completed the study. Forty-eight subjects withdrew because of adverse experiences: 47 because of protocol

DISCUSSION

Evaluation of the steroid-sparing effects of a novel drug in the treatment of steroid-dependent asthma has been approached from two perspectives: (1) drug evaluation while patients continue to receive a maintenance or minimally effective dose of oral corticosteroids3 or (2) deliberate reduction of maintenance corticosteroid dosages after patients have been stabilized while receiving the steroid-sparing drug.2 Improvement in symptoms and lung function have been the primary efficacy end points

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From aUniversity of Cincinnati College of Medicine, Department of Medicine, Division of Immunology; bSmithKline Beecham, King of Prussia, Pa.; and cAbbott Laboratories, Abbott Park.

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Supported by a grant from the SmithKline Beecham Pharmaceuticals, King of Prussia, Pa.

Reprint requests: I. Leonard Bernstein, MD, University of Cincinnati College of Medicine, 231 Bethesda Ave., M.L. 563 Cincinnati, OH 45267.

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