Figures
- Fig. 1—
Randomisation schedule. Subjects were randomly allocated to one of four treatments and reviewed at 14 and 28 days. Treatment ceased at 28 days. Serious adverse effects: theophylline plus inhaled beclometasone, n = 0; theophylline, n = 2 (viral meningitis and chest pain secondary to reflux oesophagitis); inhaled beclometasone, n = 0.
- Fig. 2—
Change in a) peak expiratory flow (PEF), b) forced expiratory volume in one second (FEV1) and c) Asthma Control Questionnaire (ACQ) scores from randomisation to 28 days of treatment (paired t-test). Error bars represent 95% confidence intervals. p-values were derived from comparison of groups with inhaled beclometasone change using ANCOVA. BD: bronchodilator; ICS: inhaled corticosteroids; Theo: theophylline; Theo+ICS: theophylline and inhaled beclometasone combination. #: p = 0.008; ¶: p = 0.135; +: p = 0.069; §: p = 0.158; ƒ: p = 0.033; ##: p = 0.016.
- Fig. 3—
Change in histone deacetylase activity (HDAC) from randomisation to 28 days of treatment. Individual plots of HDAC activity are shown. Error bars represent 95% confidence intervals. ICS: inhaled corticosteroids; Theo: theophylline; Theo+ICS: theophylline and inhaled beclometasone combination.
Tables
- Table 1—
Baseline demographics
Characteristic Inhaled beclometasone Theophylline + inhaled beclometasone Theophylline Subjects n 23 22 23 Age yrs 42 (36–53) 44 (31–52) 46 (38–50) Female % of total 61 55 65 BMI kg·m−2 25.5 (18.4–34.2) 26.0 (17.3–36.1) 26.6 (18.6–37.1) Smoking pack·yrs−1 24 (15–30) 25 (11–40) 30 (15–35) Duration of asthma yrs 16 (8–31) 15 (9–21) 16 (9–30) ICS use at screening Total % 65 68 74 Dose beclometasone equivalent μg 800 (400–800) 800 (400–950) 400 (400–900) LABA use at screening % 26 36 35 Specific IgE antibody positive % 61 50 52 Total IgE level IU·mL−1 87 (34–396) 91 (31–383) 40 (9–346) Spirometry pre-BD FEV1 % pred 75 (72–89) 78 (65–84) 73 (64–84) Reversibility FEV1 % improvement 16 (13–20) 15 (14–18) 18 (14–24) ACQ score# 1.8±0.9 1.8±0.7 2.1±0.5 Data presented as median (interquartile range) and mean±sd, unless stated otherwise. BMI: body mass index; ICS: inhaled corticosteroids; LABA: long-acting β2-agonist; Ig: immunoglobulin; BD: bronchodilator; FEV1: forced expiratory volume in one second; ACQ: Asthma Control Questionnaire. #: range 0–6 with higher scores indicating worse asthma control.
- Table 2—
Baseline sputum counts and histone deacetylase activity(HDAC)
Characteristic Inhaled beclometasone# Theophylline + inhaled beclometasone¶ Theophylline§ Sputum total cell count 106 4.3 (2.6–7.3) 5.1 (3.1–9.4) 6.0 (2.4–16.1) Eosinophils % 0.9 (0.3–1.6) 0.8 (0.4–1.8) 1.3 (0.5–2.3) Absolute count 104 cells 2.1 (0.8–5.8) 3.7 (1.9–19.5) 6.3 (1.7–28.4) Neutrophils % 25.5 (9.6–44.6) 23.5 (8.6–42.3) 16.6 (8.4–40.3) Absolute count 104 cells 122.7 (25–188) 83.0 (35–302) 80.0 (25–323) Macrophages % 52.8 (32.0–64.4) 45.1 (38.1–60.8) 52.1 (39.1–64.3) Absolute count 104 cells 184.2 (96–437) 271.8 (165–452) 78.0 (147–729) Lymphocytes % 1.3 (0.6–2.6) 1.6 (1.0–2.7) 1.0 (0.5–2.5) Absolute count 104 cells 4.9 (2.3–11.2) 12.4 (3.2–20.7) 7.1 (1.5–22.6) Bronchial epithelial cells % 10.5 (8.3–15.4) 16.4 (8.0–28.9) 12.3 (6.1–27.2) Absolute count 104 cells 40.7 (20.5–99.4) 119.1 (63.8–157.6) 83.7 (22.1–168.2) HDAC activityƒ AFU 106 cells 2.25 (0.54–3.95) 3.75 (0.34–7.16) 3.62 (0.61–6.64) Data presented as median (interquartile range). AFU: arbitrary fluorescence units. #: n = 10; ¶: n = 12; §: n = 14; ƒ: mean (95% confidence interval).
- Table 3—
Changes in lung function and biomarkers following treatment compared with response to treatment with inhaled beclometasone alone
Change (relative to inhaled beclometasone) Theophylline + inhaled beclometasone# Theophylline¶ Pre-BD FEV1 mL Day 14 133 (-27–293) 52 (-109–214) Day 28 165 (-13–342) 128 (-51–307) Pre-BD PEF L·min−1 Day 14 25 (-1–51) 6 (-20–33) Day 28 40 (11–69)* 22 (-7–51) Pre-BD FVC mL Day 14 132 (-23–286) 15 (-141–171) Day 28 254 (63–445)* 176 (-16–368) ACQ score -0.47 (-0.91– -0.04)* -0.55 (-0.99– -0.11)* Sputum total cell count cells × 106 -2.0 (-6.3–1.7) -1.7 (–6.2–2.1) Sputum eosinophil % 0.0 (-1.1–0·6) -0.6 (-1.7–0.3) Absolute 104 -1.62 (-9.58–1.82) -5.53 (-17.87–1.68) Sputum neutrophil % 0.3 (-12.3–17.7) -2.5 (-22.5–12.8) Absolute 104 46.8 (-65.1–236.2) -16.0 (-199.5–116.1) Sputum macrophage % 0.5 (-11.8–11.3) -2.5 (-21.0–15.3) Absolute 104 -52.7 (-251.4–118.7) -0.9 (-250.0–186.3) Sputum lymphocyte % -0.8 (-1.4– -0.1)* -0.6 (-1.3–0.2) Absolute 104 -10.99 (-18.15– -1.65)* -3.98 (-10.30–1.36) Sputum bronchial epithelial cells % 1.2 (-5.8–7.4) -1.0 (-11.3–5.7) Absolute 104 -20.9 (-85.1–50.5) -12.9 (-100.8–57.3) Sputum IL-8 pg·mL−1 -562.5 (-2131.0–131.4) -1201.3 (-2409.6– -76.6)* Sputum MPO ng·mL−1 -126.6 (-433.9–58.1) -215.0 (-556.0– -36.7) * HDAC activity AFU 106 cells -3.5 (-23.7–5.0) -2.2 (-23.4–3.5) Data are presented as n (95% confidence interval). Lung function data and Asthma Control Questionnaire (ACQ) score differences are the difference of adjusted means with adjustment for baseline measurement (ANCOVA). Changes in ACQ score, sputum cell counts, supernatant mediator levels and histone deacetylase activity (HDAC) refer to change from randomisation visit to day 28. BD: bronchodilator; FEV1: forced expiratory volume in one second; PEF: peak expiratory flow; FVC: forced vital capacity; IL: interleukin; MPO: myeloperoxidase; AFU: arbitrary fluorescence units. #: n = 7; ¶: n = 7. *: p<0.05.
Supplementary table
Table S1: Changes in exploratory endpoints following treatment (compared to response to treatment with inhaled beclometasone alone) adjusted for multiple comparisons P value of less than 0.00125 is deemed significant (Bonferroni correction)
Files in this Data Supplement:
- Supplementary table - Table S1: Changes in exploratory endpoints following treatment (compared to response to treatment with inhaled beclometasone alone) adjusted for multiple comparisons P value of less than 0.00125 is deemed significant (Bonferroni correction)
