The effect of low-dose corticosteroids and theophylline on the risk of acute exacerbations of COPD: the TASCS randomised controlled trial

Abstract

Background: The highest burden of chronic obstructive pulmonary disease (COPD) occurs in low- and middle-income countries. Low-cost oral medications, if effective, could enable affordable, accessible COPD treatment.

Methods: In this randomised, three-arm, double-blind, double-dummy, placebo-controlled study conducted in 37 centres in China, symptomatic patients with moderate to very severe COPD were randomised 1:1:1 to placebo twice daily plus placebo once daily, low-dose theophylline 100 mg twice daily plus placebo once daily or low-dose theophylline 100 mg twice daily plus low-dose oral prednisone 5 mg once daily for 48 weeks. The primary end-point was annualised exacerbation rate.

Results: 1670 subjects were randomised and 1242 completed the study (1142 with acceptable data at week 48). Subjects (75.7% male) had a mean age of 64.4 years, with mean±sd baseline post-bronchodilator forced expiratory volume in 1 s (FEV1) 1.1±0.4 L (42.2% predicted) and St George's Respiratory Questionnaire (SGRQ) score 45.8±20.1. There were negligible differences between annualised exacerbation rates across the three treatments: 0.89 (95% CI 0.78-1.02) on theophylline plus prednisone, 0.86 (95% CI 0.75-0.99) on theophylline plus placebo and 1.00 (95% CI 0.87-1.14) on placebo. The rate ratio for theophylline plus prednisone versus pooled theophylline plus placebo and placebo was 0.96 (95% CI 0.83-1.12), for theophylline plus placebo versus placebo was 0.87 (95% CI 0.73-1.03; p=0.101) and for theophylline plus prednisone versus placebo was 0.90 (95% CI 0.76-1.06; p=0.201). Secondary outcomes of hospitalisations, FEV1, SGRQ and COPD Assessment Test score showed no statistically significant difference between treatment arms. Serious adverse events other than exacerbations were <2% and did not differ between treatment arms.

Conclusions: Low-dose theophylline alone or in combination with prednisone did not reduce exacerbation rates or clinically important secondary end-points compared with placebo.

Trial registration: ClinicalTrials.gov NCT02261727.

Conflict of interest statement

Conflict of interest: C.R. Jenkins reports personal fees from Boehringer Ingelheim and Chiesi, grants, personal fees and nonfinancial support from GlaxoSmithKline, personal fees and nonfinancial support from AstraZeneca, Novartis and Sanofi Genzyme, outside the submitted work. Conflict of interest: F-Q. Wen has nothing to disclose. Conflict of interest: A. Martin has nothing to disclose. Conflict of interest: P.J. Barnes reports grants and personal fees for consultancy and advisory board work from AstraZeneca, grants and personal fees for advisory board work and lectures from Boehringer Ingelheim, personal fees for advisory board work and lectures from Novartis and Teva, personal fees for advisory board work from Pieris and Epi-Endo, outside the submitted work. Conflict of interest: B. Celli reports grants and research facilities from AstraZeneca, personal fees for consultancy and scientific committee work from GlaxoSmithKline, personal fees for consultancy from Boehringer Ingelheim, Sanofi-Aventis, Menarini, Chiesi and Pulmonx, outside the submitted work. Conflict of interest: N-S. Zhong has nothing to disclose. Conflict of interest: J-P. Zheng has nothing to disclose. Conflict of interest: A. Scaria has nothing to disclose. Conflict of interest: G-L. Di Tanna is a former employee of Amgen. Conflict of interest: T. Bradbury reports receiving a top-up scholarship funded by GlaxoSmithKline, outside the submitted work. Conflict of interest: N. Berend reports grants from the National Health and Medical Research Council, Australia, State Key Laboratory of Respiratory Disease and Guangzhou Institute of Respiratory Disease China, and West China Hospital, Chengdu, China, during the conduct of the study; and a salary from GlaxoSmithKline, outside the submitted work.

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