Introduction
Methods
Search strategies
Inclusion and exclusion criteria
Study selection
Data extraction and quality assessment
Statistical analysis
Results
Study characteristics
Source | Study Design | Participants characteristics | Population | Intervention (Drug, Dose, Frequency) | Control | Concomitant treatments | Duration | Follow-up | Outcomes* |
---|---|---|---|---|---|---|---|---|---|
Barnes 2012 [11] | Multi-center, parallel-group, RCT | Steroid-free, moderate persistent asthma | 132 | OC000459, 200 mg, Twice daily | Placebo | SABA | 4 weeks | 10 weeks | ①⑤⑥⑦⑨⑪⑫⑯⑲ |
Pettipher 2014 [12] | Multi-center, parallel-group, RCT | Mild-to-moderate persistent steroid-free asthma | 482 | OC000459, 25 mg, Once daily | Placebo | SABA | 12 weeks | 20–22 weeks | ①⑤⑪⑯⑰⑱ |
OC000459, 200 mg, Once daily | |||||||||
OC000459, 100 mg, Twice daily | |||||||||
Singh 2013 [13] | Multi-center, two-period, cross-over, RCT | Steroid-naïve mild allergic asthma | 21 | OC000459, 200 mg, Twice daily | Placebo | SABA | 16 days | 35–41 days | ①③⑫⑭⑮⑯ |
Hall (trial 1) 2015 [14] | Multi-center, parallel-group, RCT | Symptomatic, mild-to-moderate, steroid-naïve asthma | 317 | BI 671800, 50 mg, Twice daily | Placebo | SABA | 6 weeks | 10 weeks | ③⑯⑰⑱⑲ |
BI 671800, 200 mg, Twice daily | |||||||||
BI 671800, 400 mg, Twice daily | |||||||||
Hall (trial 2) 2015 [14] | Symptomatic, mild-to-moderate asthmatic patients on ICS | 176 | BI 671800, 400 mg, Twice daily | Placebo | SABA, ICS | 10–12 weeks | ③⑯⑰⑱⑲ | ||
Bateman 2017 [16] | Multi-center, parallel-group, RCT | Allergic asthma inadequately controlled with low-dose ICS | 901 | Fevipiprant, 1 mg/3 mg/ 10 mg or 2 mg, Once daily or twice daily | placebo | SABA or ICS | 12 weeks | 22–24 weeks and 2 days | ⑪⑭⑯⑰⑱⑲ |
Fevipiprant, 30 mg/50 mg/ 75 mg or 25 mg, Once daily or twice daily | |||||||||
Fevipiprant, 150 mg/300 mg or 75 mg/ 150 mg, Once daily or twice daily | |||||||||
Fevipiprant, 450 mg, Once daily | |||||||||
Busse 2013 [17] | Multi-center, parallel-group, RCT | Inadequately controlled, moderate-to-severe asthma | 396 | AMG 853, 5 mg, Twice daily | Placebo | SABA, ICS | 12 weeks | 18 weeks | ①②③④⑤⑥⑧⑨⑩⑪⑫⑭⑯⑰⑱⑲ |
AMG 853, 25 mg, Twice daily | |||||||||
AMG 853, 100 mg, Twice daily | |||||||||
AMG 853, 200 mg, Twice daily | |||||||||
Erpenbeck 2016 [18] | Multi-center, parallel-group, RCT | mild-to-moderate persistent allergic asthma | 170 | Fevipiprant, 500 mg, Twice daily | Placebo | SABA | 4 weeks | 8 weeks | ⑧⑩⑯⑰ |
Fowler 2017 [19] | Single-center, parallel-group, RCT | Well controlled mild asthma | 84 | BI 1021958, 5/20/60/200 mg or 40/150/400 mg, Twice daily or once daily | Placebo | SABA | 15 days | 15 days | ⑯⑰⑱⑲ |
Gonem 2016 [20] | Single-center, parallel-group, RCT | Persistent, moderate-to-severe eosinophilic asthma | 61 | Fevipiprant, 225 mg, Twice daily | Placebo | SABA, ICS, LABA, or oral prednisone | 12 weeks | 20 weeks | ①②⑧⑨⑫⑬⑭⑯⑰ |
Kuna (trial 1) 2016 [21] | Multi-center, parallel-group, RCT | Stable asthma withdrawn from ICS | 113 | AZD1981, 1000 mg, Twice daily | Placebo | SABA | 4 weeks | 8 weeks | ①②⑤⑦⑥⑩⑫⑬⑭⑯⑰⑱⑲ |
Kuna (trial 2) 2016 [21] | Multi-center, parallel-group, RCT | Uncontrolled moderate-to-severe asthma despite moderate-to-high dose of ICS | 368 | AZD1981, 50 mg, Twice daily | Placebo | SABA, ICS | 4 weeks | 8 weeks | ①⑦⑯⑰⑱⑲ |
AZD1981, 400 mg, Twice daily | |||||||||
AZD1981, 1000 mg, Twice daily | |||||||||
Wenzel 2014 [22] | Multi-center, parallel-group, RCT | Steroid-free, mild atopic asthma | 184 | ARRY-502, 200 mg, Twice daily | Placebo | SABA | 4 weeks | 6 weeks | ①⑧⑨⑪⑯⑲ |
Bateman 2018 [23] | Multi-center, parallel-group, RCT | Persistent allergic asthma | 1144 | AZD1981, 80/200 mg, once daily, or 10/40/100 mg, twice daily | Placebo | ICS, LABA, SABA | 12 weeks | 15 weeks | ①⑧⑪⑯⑰⑱ |
Diamant 2014 [24] | Multi-center, two-period, cross-over, RCT | Stable, allergic asthma | 14 | Setipiprant, 1000 mg, Twice daily | Placebo | SABA | 5 days | 37 days | ⑬⑭⑮ |
Miller 2017 [25] | Multi-center, three-period, cross-over, RCT | Mild-to-moderate symptomatic asthma | 108 | BI 671800, 400 mg, Once daily (a.m) | Placebo | SABA, ICS | 12 weeks | 16–18 weeks | ③⑧⑯⑰⑱⑲ |
Source | No. | Age (years)* | Female (%) | BMI (kg/m2)* | Smoking (Pack-year) | Pre-bronchodilator FEV1% predicted* | FeNO (ppb)* | Positive atopic status (%) | Diagnosis or duration of asthma (years)* |
---|---|---|---|---|---|---|---|---|---|
Barnes 2012 [11] | 65 | 43.4 (18–55)** | 41.53 | NM | ≤10 | NM | NM | 100 | 6.5 (6.29) |
Pettipher 2014 [12] | 125 | 40.4 (11.4) | 70 | NM | < 10 | 71.5 (6.1) | NM | NM | NM |
123 | 39.7 (10.2) | 81 | NM | < 10 | 71.0 (6.2) | NM | NM | NM | |
117 | 38.9 (11.4) | 76 | NM | < 10 | 71.5 (6.9) | NM | NM | NM | |
Singh 2013 [13] | 21 | 31.1 (7.1) | 14.3 | NM | < 10 | 87.4 (12.0) | 32.7 (21.8) | 100 | NM |
Hall (trial 1) 2015 [14] | 77 | 39.1 (11.5) | 53.2 | 27.0 (4.6) | < 10 | 71.4 (7.3) | NM | 75.3 | NM |
83 | 35.1 (11.1) | 50.6 | 25.9 (4.3) | < 10 | 73.3 (7.3) | NM | 78.3 | NM | |
79 | 37.5 (12.2) | 54.4 | 26.5 (4.7) | < 10 | 73.6 (6.9) | NM | 84.8 | NM | |
Hall (trial 2) 2015 [14] | 81 | 41.8 (12.7) | 61.7 | 27.6 (4.1) | < 10 | 72.6 (7.6) | NM | 82.7 | NM |
Bateman 2017 [16] | 201 | 45.2 (12.1) | 59.2 | 28.1 (5.7) | 0 | 64.4 (9.6) | NM | 100 | 20.5 (14.9) |
219 | 45.6 (12.1) | 54.34 | 26.9 (5.0) | 0 | 64.1 (10.1) | NM | 100 | 20.5 (14.9) | |
212 | 43.5 (12.3) | 60.85 | 27.4 (5.5) | 0 | 64.5 (9.7) | NM | 100 | 18.4 (14.0) | |
133 | 45.8 (12.5) | 54.89 | 27.8 (5.0) | 0 | 63.7 (10.5) | NM | 100 | 21.2 (15.0) | |
Busse 2013 [17] | 79 | 44.7 (11.5) | 65.8 | 29.6 (6.2) | < 10 | 68.2 (7.9) | 31.9 (21.4) | 93.7 | 28.0 (14.1) |
79 | 45.0 (11.3) | 58.2 | 32.0 (6.5) | < 10 | 67.1 (7.9) | 30.9 (30.5) | 91.1 | 24.8 (13.2) | |
79 | 44.6 (11.4) | 69.8 | 31.9 (8.0) | < 10 | 66.7 (8.5) | 28.3 (23.2) | 91.1 | 28.9 (14.5) | |
80 | 43.7 (11.4) | 40.0 | 31.4 (7.2) | < 10 | 66.1 (8.9) | 33.5 (31.6) | 95.0 | 27.3 (12.8) | |
Erpenbeck 2016 [18] | 82 | 41 (12.9) | 24 | 28.5 (5.81) | < 10 | 71.5 (7.11) | 32 (NM) | 100 | NM |
Fowler 2017 [19] | 63 | 33.1 (10.9) | NM | 24.2 (2.9) | < 10 | 85.2 (15.0) | NM | NM | NM |
Gonem 2016 [20] | 30 | 50 (17) | 40 | 31.0 (5.9) | NM | 72.5 (23.8) | 30 (24) | 87 | 32 (16) |
Kuna (trial 1) 2016 [21] | 57 | 38.4 (NM) | 16 | 26.3 (NM) | < 10 | 82.6 (NM) | NM | 100 | 13 (NM) |
Kuna (trial 2)2016 [21] | 95 | 43.3 (NM) | 28 | 26.9 (NM) | < 10 | 66.2 (NM) | NM | 72 | 11.1 (NM) |
90 | 43.0 (NM) | 21 | 27.0 (NM) | < 10 | 68.5 (NM) | NM | 77 | 12.1 (NM) | |
92 | 43.5 (NM) | 37 | 27.2 (NM) | < 10 | 69.0 (NM) | NM | 64 | 10 (NM) | |
Wenzel 2014 [22] | 93 | 35 (18–68)** | 49 | 26.0 (19.3–34.6)** | < 10 | 73.4 (60–84)*** | 47.5 (26–244)** | 100 | NM |
Bateman 2018 [23] | 976 | 41.0 (NM) | 49.5 | 27.5 (NM) | ≤10 | NM | NM | 100 | 18.2 (NM) |
Diamant 2014 [24] | 18 | 30.6 (21–46)** | 0 | 25.58 (NM) | < 10 | NM | 51.6 (38.5) | 100 | NM |
Miller 2017 [25] | 108 | 41.1 (12.4) | 53.7 | 28.8 (4.8) | < 10 | 72.8 (7.6) | NM | 63.9 | 28.2 (12.9) |
Quality assessment
Outcomes
FEV1
Forced vital capacity (FVC)
Peak expiratory flow (PEF)
Asthma control questionnaire (ACQ)
Asthma quality of life questionnaire (AQLQ)
Rescue use of SABA
Asthma exacerbations
Adverse events
Sputum and blood eosinophils
Source | Groups | Baseline | Treatment endpoint | Change after treatment | P value (Intervention vs Placebo) | Significant Difference |
---|---|---|---|---|---|---|
Sputum eosinophils (10
6
/g)
| ||||||
Singh 2013 [13] | Intervention | NM | 0.4## | NM | 0.002 | Yes |
Control | NM | 0.75## | NM | |||
Kuna (trial 1) 2016 [21] | Intervention | 0.024 (0.00 to 0.53)§ | 0.004 (0.00 to 0.53)§ | NM | NM | No |
Control | 0.033 (0.00 to 1.21)§ | 0.014 (0.00 to 0.73)§ | NM | |||
Sputum eosinophils (%)
| ||||||
Barnes 2012 [11] | Intervention | 2.1 (NM)‡ | 0.7 (NM)‡ | 3.1 (1.1, 8.8)§§ | 0.37 | No |
Control | 1.8(NM)‡ | 1.2 (NM)‡ | 1.5 (0.4, 5.3)§§ | |||
Singh 2013 [13] | Intervention | 6.0 (1.5, 23.9)‡ | 18.1 (10.0, 33.2)‡ | NM | 0.002 | Yes |
Control | 6.0 (1.5, 23.9)‡ | 5.6 (2.7, 11.6)‡ | ||||
Busse 2013 [17] | Intervention | 2.0 (0 to 93)§ | NM | −3.5 (−93 to 5)§ | NM | No |
1.0 (0 to 69)§ | NM | −0.5 (−68 to 36)§ | NM | |||
1.0 (0 to 91)§ | NM | 0.0 (−72 to 6)§ | NM | |||
1.0 (0 to 80)§ | NM | 0.0 (−24 to 4)§ | NM | |||
Control | 0.0 (0 to 53)§ | NM | 2.0 (−2.3 to 84)§ | – | ||
Gonem 2016 [20] | Intervention | 5.4 (3.1, 9.6)‡ | 1.1 (0.7, 1.9)‡ | 0.22 (0.13, 0.39)§§ | 0.0014 | Yes |
Control | 4.6 (2.5–8.7)‡ | 3.9 (2.3–6.7)‡ | 0.78 (0.45, 1.33)§§ | |||
Blood eosinophils (10
9
/L)
| ||||||
Gonem 2016 [20] | Intervention | 0.29 (95.03)# | 0.29 (0.23–0.36)‡ | 1.01 (0.79, 1.28)§§ | 0.44 | No |
Control | 0.28 (80.63)# | 0.32 (0.25, 0.41)‡ | 1.13 (0.89, 1.43)§§ | |||
Kuna (trial 1) 2016 [21] | Intervention | NM | NM | NM | NM | No |
Control | NM | NM | NM | |||
Diamant 2014 [24] | Intervention | NM | NM | NM | NM | No |
Control | NM | NM | NM | |||
FeNO (ppb)
| ||||||
Singh 2013 [13] | Intervention | 33.9 (22.4)* | 26.3 (23.7)* | NM | NM | No |
Control | 39.3 (23.9)* | 23.3 (22.8)* | NM | |||
Bateman 2017 [16] | Intervention | NM | NM | NM | > 0.05 | No |
NM | NM | NM | > 0.05 | |||
NM | NM | NM | > 0.05 | |||
Control | NM | NM | NM | – | ||
Busse 2013 [17] | Intervention | 31.9 (21.4)* | NM | 0.221 | > 0.05 | No |
30.9 (30.5)* | NM | 2.368 | > 0.05 | |||
28.3 (23.2)* | NM | −0.080 | > 0.05 | |||
33.5 (31.6)* | NM | 1.333 | > 0.05 | |||
Control | 28.1 (22.0)* | NM | −7.000 | – | ||
Gonem 2016 [20] | Intervention | 37.72 (4.75)† | 34.88 (3.97)† | −5.82 (−13.79, 2.16)** | 0.49 | No |
Control | 43.67 (6.97)† | 38.48 (4.32)† | −2.21 (−10.90, 6.48)** | |||
Kuna (trial 1) 2016 [21] | Intervention | NM | NM | NM | NM | No |
Control | NM | NM | NM | |||
Diamant 2014 [24] | Intervention | 51.6 (38.5)* | NM | NM | NM | No |
Control | 71.0 (36.5)* | NM | NM | |||
Methacholine PC
20
(mg/mL)
| ||||||
Singh 2013 [13] | Intervention | 1.48 (3.2)* | 0.31* | NM | NM | No |
Control | 1.48 (3.2)* | 0.39* | ||||
Diamant 2014 [24] | Intervention | 0.91 (2.21)†† | 0.97 (1.98)†† | NM | 0.038 | Yes |
Control | 1.00 (2.19)†† | 0.49 (2.19)†† |