Many patients with persistent asthma could not achieve the treatment goal for asthma with a single controller medication. The study aimed to assess the lung function and rescue medication usage in asthmatic patients receiving four different categories of drugs in combination with an inhaled corticosteroid. Recruited patients were randomized into four groups to receive Budesonide with Formoterol, Doxofylline, Montelukast and Tiotropium for a period of three months. Lung function i.e. Forced Expiratory Volume in one second (FEV1) and rescue medication usage was measured at baseline, day 15, 30, 45, 60 and 90. A total of 297 patients completed the study. At baseline, no significant difference (P>0.05) was observed in any of the outcome measures. Significant within‐group improvement in% FEV1 was observed in all the groups. At day 90, between‐group difference showed that improvement in% FEV1 was significantly (p<0.05) high for budesonide plus formoterol followed by budesonide plus montelukast, budesonide plus doxofylline and least for budesonide plus tiotropium. Similarly, within‐group and between‐group comparisons showed significant (p<0.05) reduction in rescue medication usage in all the groups. The intensity in decrease was more in budesonide plus formoterol group followed by budesonide plus montelukast, budesonide plus doxofylline and budesonide plus tiotropium groups. Based on our findings, among the second‐line treatment regimens, budesonide with either montelukast or doxofylline was found to be better than budesonide plus tiotropium in mild to moderate persistent asthmatic patients. Further studies with a longer duration are likely to be useful. This article is protected by copyright. All rights reserved.