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.
Abstract
This large, rigorously conducted RCT showed that the combination of low-dose theophylline and prednisone did not affect exacerbation rate in patients with moderate to severe COPD in China https://bit.ly/2KSQ2BK
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.04564-2020
This article has supplementary material available from erj.ersjournals.com
This study is registered at ClinicalTrials.gov with identifier number NCT02261727. Individual de-identified participant data are available on application to the corresponding author. The protocol and statistical analysis plan are available on the Centre for Open Science website: https://osf.io/39qkm
Author contributions: C.R. Jenkins, N. Berend, P.J. Barnes and B. Celli contributed to the study concept and design, data interpretation, and final approval of the manuscript. A. Martin contributed to implementation of the study, data collection, cleaning, interpretation and final approval of the manuscript. A. Scaria, G-L. Di Tanna and T. Bradbury contributed to statistical analysis and interpretation, and final approval of the manuscript. F-Q. Wen, N-S. Zhong, J-P. Zheng and A. Martin contributed to the study execution, data interpretation, review and final approval of the manuscript. C.R. Jenkins wrote the primary manuscript, and all authors revised and contributed to its final review. C.R. Jenkins had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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.
Support statement: This work was supported by the National Health and Medical Research Council, Australia; State Key Laboratory of Respiratory Diseases and Guangzhou Institute of Respiratory Diseases, Guangzhou, China; and West China Hospital, Chengdu, China. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received September 1, 2020.
- Accepted November 21, 2020.
- Copyright ©ERS 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
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