Supplementary material 5 to: Focused review format prototype

Flemyng E, Mitchell D
https://doi.org/null

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Analyses

Analysis group 1: Increased versus stable dose of inhaled corticosteroids

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1.1 Treatment failure: need for systemic corticosteroids (all randomised participants)81774Odds Ratio (IV, Fixed, 95% CI)0.97 [0.76, 1.25]
1.2 Treatment failure: need for systemic corticosteroids (of those starting inhaler)7Odds Ratio (IV, Random, 95% CI)0.84 [0.54, 1.30]
1.3 Serious and non-serious adverse events4Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
1.3.1 Serious2394Odds Ratio (M-H, Fixed, 95% CI)1.69 [0.77, 3.71]
1.3.2 Non-serious2142Odds Ratio (M-H, Fixed, 95% CI)2.15 [0.68, 6.73]
1.4 Unscheduled physician visits3931Odds Ratio (M-H, Fixed, 95% CI)0.96 [0.66, 1.41]
1.5 Unscheduled acute care, emergency department visit or hospital admission4704Peto Odds Ratio (Peto, Fixed, 95% CI)0.50 [0.16, 1.56]
1.6 Duration of exacerbation1Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.7 Duration of exacerbation (days to symptom recovery)1Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.8 Duration of exacerbation (days to lung function recovery)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

Analysis group 2: Increased versus stable dose of inhaled corticosteroids (all randomised participants): Subgroup and sensitivity analyses

Analysis or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
2.1 Treatment failure (all randomised participants): Subgrouped by age81774Odds Ratio (IV, Fixed, 95% CI)0.97 [0.76, 1.25]
2.1.1 Adults41098Odds Ratio (IV, Fixed, 95% CI)0.86 [0.58, 1.26]
2.1.2 Children4676Odds Ratio (IV, Fixed, 95% CI)1.07 [0.77, 1.49]
2.2 Treatment failure (all randomised participants): Subgrouped by time to treatment initiation81774Odds Ratio (IV, Fixed, 95% CI)0.97 [0.76, 1.25]
2.2.1 Under 48 hours51056Odds Ratio (IV, Fixed, 95% CI)1.02 [0.76, 1.37]
2.2.2 At least 48 hours3718Odds Ratio (IV, Fixed, 95% CI)0.84 [0.51, 1.39]
2.3 Treatment failure (all randomised participants): Subgrouped by maintenance inhaled corticosteroid dose71746Odds Ratio (IV, Fixed, 95% CI)0.96 [0.75, 1.24]
2.3.1 Low2397Odds Ratio (IV, Fixed, 95% CI)1.30 [0.83, 2.02]
2.3.2 High2541Odds Ratio (IV, Fixed, 95% CI)0.91 [0.58, 1.42]
2.3.3 Medium3808Odds Ratio (IV, Fixed, 95% CI)0.76 [0.50, 1.17]
2.4 Treatment failure (all randomised participants): Subgrouped by inhaled corticosteroid dose during exacerbation71746Odds Ratio (IV, Fixed, 95% CI)0.96 [0.75, 1.24]
2.4.1 Low3451Odds Ratio (IV, Fixed, 95% CI)1.24 [0.72, 2.13]
2.4.2 High41295Odds Ratio (IV, Fixed, 95% CI)0.89 [0.67, 1.19]
2.4.3 Medium00Odds Ratio (IV, Fixed, 95% CI)Not estimable
2.5 Treatment failure (all randomised participants): subgrouped by inhaled corticosteroid fold increase81774Odds Ratio (IV, Fixed, 95% CI)0.97 [0.76, 1.25]
2.5.1 Double61120Odds Ratio (IV, Fixed, 95% CI)0.98 [0.72, 1.35]
2.5.2 More than double2654Odds Ratio (IV, Fixed, 95% CI)0.96 [0.63, 1.45]
2.6 Treatment failure (all randomised participants): Sensitivity analysis of parallel-group studies only61728Odds Ratio (IV, Fixed, 95% CI)0.96 [0.74, 1.24]
2.7 Treatment failure (all randomised participants): Sensitivity analysis to remove studies with results at high risk of bias51438Odds Ratio (IV, Fixed, 95% CI)0.93 [0.71, 1.21]
2.8 Treatment failure (all randomised participants): Sensitivity analysis of independent funded studies only61456Odds Ratio (IV, Fixed, 95% CI)0.93 [0.71, 1.21]

Figures and tables

Analysis 1.1: Treatment failure: need for systemic corticosteroids (all randomised participants)

Study or Subgroup FitzGerald 2004 Garrett 1998 Harrison 2004 Jackson 2018 Martinez 2011 Oborne 2009 Rice-McDonald 2005 Wainwright 2009 Total (95% CI) Total events: Heterogeneity: Chi² = 6.65, df = 7 (P = 0.47); I² = 0% Test for overall effect: Z = 0.21 (P = 0.83) Test for subgroup differences: Not applicable Increased dose of inhaled corticosteroids Events 12 2 22 38 22 18 6 41 161 Total 142 14 192 127 71 197 9 127 879 Stable dose of inhaled corticosteroids Events 9 0 24 30 20 29 6 47 165 Total 148 14 198 127 72 203 9 124 895 Weight 7.9% 0.7% 16.8% 20.5% 12.3% 16.4% 1.7% 23.7% 100.0% Odds Ratio IV, Fixed, 95% CI 1.43 [0.58 , 3.50] 5.80 [0.25 , 132.56] 0.94 [0.51 , 1.74] 1.38 [0.79 , 2.41] 1.17 [0.57 , 2.40] 0.60 [0.32 , 1.13] 1.00 [0.14 , 7.10] 0.78 [0.46 , 1.31] 0.97 [0.76 , 1.25] Odds Ratio IV, Fixed, 95% CI 0.01 0.1 1 10 100 Favours increased corticosteroids Favours stable corticosteroids

Analysis 1.2: Treatment failure: need for systemic corticosteroids (of those starting inhaler)

Study or Subgroup FitzGerald 2004 Garrett 1998 Harrison 2004 Martinez 2011 Oborne 2009 Rice-McDonald 2005 Wainwright 2009 Total (95% CI) Heterogeneity: Tau² = 0.14; Chi² = 10.37, df = 6 (P = 0.11); I² = 42% Test for overall effect: Z = 0.80 (P = 0.42) Test for subgroup differences: Not applicable log[Odds Ratio] 0.4935 1.7238 -0.34 0.1547 -1.2993 0 -0.2377 SE 0.4963 1.5858 0.3499 0.3676 0.4597 0.5726 0.2936 Weight 13.0% 1.9% 19.2% 18.4% 14.3% 10.8% 22.4% 100.0% Odds Ratio IV, Random, 95% CI 1.64 [0.62 , 4.33] 5.61 [0.25 , 125.45] 0.71 [0.36 , 1.41] 1.17 [0.57 , 2.40] 0.27 [0.11 , 0.67] 1.00 [0.33 , 3.07] 0.79 [0.44 , 1.40] 0.84 [0.54 , 1.30] Odds Ratio IV, Random, 95% CI 0.01 0.1 1 10 100 Favours increased corticosteroids Favours stable corticosteroids

Analysis 1.3: Serious and non-serious adverse events

Study or Subgroup 1.3.1 Serious Martinez 2011 Wainwright 2009 Subtotal (95% CI) Total events: Heterogeneity: Chi² = 0.14, df = 1 (P = 0.71); I² = 0% Test for overall effect: Z = 1.30 (P = 0.19) 1.3.2 Non-serious Foresi 2000 Oborne 2009 Subtotal (95% CI) Total events: Heterogeneity: Chi² = 0.01, df = 1 (P = 0.91); I² = 0% Test for overall effect: Z = 1.31 (P = 0.19) Test for subgroup differences: Chi² = 0.12, df = 1 (P = 0.73), I² = 0% Increased dose of inhaled corticosteroids Events 1 17 18 2 9 11 Total 71 127 198 17 56 73 Stable dose of inhaled corticosteroids Events 1 10 11 2 3 5 Total 72 124 196 31 38 69 Weight 10.0% 90.0% 100.0% 29.4% 70.6% 100.0% Odds Ratio M-H, Fixed, 95% CI 1.01 [0.06 , 16.54] 1.76 [0.77 , 4.02] 1.69 [0.77 , 3.71] 1.93 [0.25 , 15.12] 2.23 [0.56 , 8.86] 2.15 [0.68 , 6.73] Odds Ratio M-H, Fixed, 95% CI 0.05 0.2 1 5 20 Favours increasd inhaled corticosteroids Favours stable corticosteroids

Analysis 1.4: Unscheduled physician visits

Study or Subgroup FitzGerald 2004 Harrison 2004 Wainwright 2009 Total (95% CI) Total events: Heterogeneity: Chi² = 1.65, df = 2 (P = 0.44); I² = 0% Test for overall effect: Z = 0.19 (P = 0.85) Test for subgroup differences: Not applicable Increased dose of inhaled corticosteroids Events 1 31 35 67 Total 142 192 127 461 Stable dose of inhaled corticosteroids Events 0 28 41 69 Total 148 198 124 470 Weight 0.9% 43.1% 56.0% 100.0% Odds Ratio M-H, Fixed, 95% CI 3.15 [0.13 , 77.93] 1.17 [0.67 , 2.04] 0.77 [0.45 , 1.32] 0.96 [0.66 , 1.41] Odds Ratio M-H, Fixed, 95% CI 0.02 0.1 1 10 50 Favours increased corticosteroids Favours stable corticosteroids Risk of Bias A + + + B + ? C ? + + D + + + E ? ? ? F + ? Risk of bias legend (A) Bias arising from the randomization process (B) Bias due to deviations from intended interventions (C) Bias due to missing outcome data (D) Bias in measurement of the outcome (E) Bias in selection of the reported result (F) Overall bias

Analysis 1.5: Unscheduled acute care, emergency department visit or hospital admission

Study or Subgroup Garrett 1998 Jackson 2018 Martinez 2011 Wainwright 2009 Total (95% CI) Total events: Heterogeneity: Chi² = 2.62, df = 1 (P = 0.11); I² = 62% Test for overall effect: Z = 1.20 (P = 0.23) Test for subgroup differences: Not applicable Increased dose of inhaled corticosteroids Events 0 0 0 4 4 Total 28 127 71 127 353 Stable dose of inhaled corticosteroids Events 0 4 0 4 8 Total 28 127 72 124 351 Weight 33.7% 66.3% 100.0% Peto Odds Ratio Peto, Fixed, 95% CI Not estimable 0.13 [0.02 , 0.95] Not estimable 0.98 [0.24 , 3.98] 0.50 [0.16 , 1.56] Peto Odds Ratio Peto, Fixed, 95% CI 0.01 0.1 1 10 100 Favours increased corticosteroids Favours stable corticosteroids

Analysis 1.6: Duration of exacerbation

Study or Subgroup Harrison 2004 Increased dose of inhaled corticosteroids Mean [days] 6.8 SD [days] 5.8209 Total 110 Stable dose of inhaled corticosteroids Mean [days] 6.1 SD [days] 6.9464 Total 97 Mean Difference IV, Fixed, 95% CI [days] 0.70 [-1.06 , 2.46] Mean Difference IV, Fixed, 95% CI [days] -100 -50 0 50 100 Favours increased corticosteroids Favours stable corticosteroids

Analysis 1.7: Duration of exacerbation (days to symptom recovery)

Study or Subgroup Harrison 2004 Increased dose of inhaled corticosteroids Mean [days] 6.8 SD [days] 5.8209 Total 110 Stable dose of inhaled corticosteroids Mean [days] 6.1 SD [days] 6.9464 Total 97 Mean Difference IV, Fixed, 95% CI [days] 0.70 [-1.06 , 2.46] Mean Difference IV, Fixed, 95% CI [days] -4 -2 0 2 4 Favours increased corticosteroids Favours stable corticosteroids

Analysis 1.8: Duration of exacerbation (days to lung function recovery)

Study or Subgroup Harrison 2004 Increased dose of inhaled corticosteroids Mean [days] 6.8 SD [days] 5.8209 Total 110 Stable dose of inhaled corticosteroids Mean [days] 7 SD [days] 6.4502 Total 97 Mean Difference IV, Fixed, 95% CI [days] -0.20 [-1.88 , 1.48] Mean Difference IV, Fixed, 95% CI [days] -4 -2 0 2 4 Favours increased corticosteroids Favours stable corticosteroids

Analysis 2.1: Treatment failure (all randomised participants): Subgrouped by age

Study or Subgroup 2.1.1 Adults FitzGerald 2004 Harrison 2004 Oborne 2009 Rice-McDonald 2005 Subtotal (95% CI) Total events: Heterogeneity: Chi² = 2.56, df = 3 (P = 0.46); I² = 0% Test for overall effect: Z = 0.78 (P = 0.44) 2.1.2 Children Garrett 1998 Jackson 2018 Martinez 2011 Wainwright 2009 Subtotal (95% CI) Total events: Heterogeneity: Chi² = 3.39, df = 3 (P = 0.34); I² = 11% Test for overall effect: Z = 0.39 (P = 0.70) Total (95% CI) Total events: Heterogeneity: Chi² = 6.65, df = 7 (P = 0.47); I² = 0% Test for overall effect: Z = 0.21 (P = 0.83) Test for subgroup differences: Chi² = 0.71, df = 1 (P = 0.40), I² = 0% Increased dose of inhaled corticosteroids Events 12 22 18 6 58 2 38 22 41 103 161 Total 142 192 197 9 540 14 127 71 127 339 879 Stable dose of inhaled corticosteroids Events 9 24 29 6 68 0 30 20 47 97 165 Total 148 198 203 9 558 14 127 72 124 337 895 Weight 7.9% 16.8% 16.4% 1.7% 42.9% 0.7% 20.5% 12.3% 23.7% 57.1% 100.0% Odds Ratio IV, Fixed, 95% CI 1.43 [0.58 , 3.50] 0.94 [0.51 , 1.74] 0.60 [0.32 , 1.13] 1.00 [0.14 , 7.10] 0.86 [0.58 , 1.26] 5.80 [0.25 , 132.56] 1.38 [0.79 , 2.41] 1.17 [0.57 , 2.40] 0.78 [0.46 , 1.31] 1.07 [0.77 , 1.49] 0.97 [0.76 , 1.25] Odds Ratio IV, Fixed, 95% CI 0.01 0.1 1 10 100 Favours increased corticosteroids Favours stable corticosteroids

Analysis 2.2: Treatment failure (all randomised participants): Subgrouped by time to treatment initiation

Study or Subgroup 2.2.1 Under 48 hours Harrison 2004 Jackson 2018 Martinez 2011 Rice-McDonald 2005 Wainwright 2009 Subtotal (95% CI) Total events: Heterogeneity: Chi² = 2.35, df = 4 (P = 0.67); I² = 0% Test for overall effect: Z = 0.14 (P = 0.89) 2.2.2 At least 48 hours FitzGerald 2004 Garrett 1998 Oborne 2009 Subtotal (95% CI) Total events: Heterogeneity: Chi² = 3.88, df = 2 (P = 0.14); I² = 48% Test for overall effect: Z = 0.67 (P = 0.50) Total (95% CI) Total events: Heterogeneity: Chi² = 6.65, df = 7 (P = 0.47); I² = 0% Test for overall effect: Z = 0.21 (P = 0.83) Test for subgroup differences: Chi² = 0.43, df = 1 (P = 0.51), I² = 0% Increased dose of inhaled corticosteroids Events 22 38 22 6 41 129 12 2 18 32 161 Total 192 127 71 9 127 526 142 14 197 353 879 Stable dose of inhaled corticosteroids Events 24 30 20 6 47 127 9 0 29 38 165 Total 198 127 72 9 124 530 148 14 203 365 895 Weight 16.8% 20.5% 12.3% 1.7% 23.7% 75.0% 7.9% 0.7% 16.4% 25.0% 100.0% Odds Ratio IV, Fixed, 95% CI 0.94 [0.51 , 1.74] 1.38 [0.79 , 2.41] 1.17 [0.57 , 2.40] 1.00 [0.14 , 7.10] 0.78 [0.46 , 1.31] 1.02 [0.76 , 1.37] 1.43 [0.58 , 3.50] 5.80 [0.25 , 132.56] 0.60 [0.32 , 1.13] 0.84 [0.51 , 1.39] 0.97 [0.76 , 1.25] Odds Ratio IV, Fixed, 95% CI 0.01 0.1 1 10 100 Favours increased corticosteroids Favours stable corticosteroids

Analysis 2.3: Treatment failure (all randomised participants): Subgrouped by maintenance inhaled corticosteroid dose

Study or Subgroup 2.3.1 Low Jackson 2018 Martinez 2011 Subtotal (95% CI) Total events: Heterogeneity: Chi² = 0.13, df = 1 (P = 0.72); I² = 0% Test for overall effect: Z = 1.15 (P = 0.25) 2.3.2 High FitzGerald 2004 Wainwright 2009 Subtotal (95% CI) Total events: Heterogeneity: Chi² = 1.29, df = 1 (P = 0.26); I² = 23% Test for overall effect: Z = 0.42 (P = 0.68) 2.3.3 Medium Harrison 2004 Oborne 2009 Rice-McDonald 2005 Subtotal (95% CI) Total events: Heterogeneity: Chi² = 1.05, df = 2 (P = 0.59); I² = 0% Test for overall effect: Z = 1.23 (P = 0.22) Total (95% CI) Total events: Heterogeneity: Chi² = 5.40, df = 6 (P = 0.49); I² = 0% Test for overall effect: Z = 0.30 (P = 0.76) Test for subgroup differences: Chi² = 2.92, df = 2 (P = 0.23), I² = 31.5% Increased dose of inhaled corticosteroids Events 38 22 60 12 41 53 22 18 6 46 159 Total 127 71 198 142 127 269 192 197 9 398 865 Stable dose of inhaled corticosteroids Events 30 20 50 9 47 56 24 29 6 59 165 Total 127 72 199 148 124 272 198 203 9 410 881 Weight 20.6% 12.4% 33.0% 8.0% 23.8% 31.8% 17.0% 16.5% 1.7% 35.2% 100.0% Odds Ratio IV, Fixed, 95% CI 1.38 [0.79 , 2.41] 1.17 [0.57 , 2.40] 1.30 [0.83 , 2.02] 1.43 [0.58 , 3.50] 0.78 [0.46 , 1.31] 0.91 [0.58 , 1.42] 0.94 [0.51 , 1.74] 0.60 [0.32 , 1.13] 1.00 [0.14 , 7.10] 0.76 [0.50 , 1.17] 0.96 [0.75 , 1.24] Odds Ratio IV, Fixed, 95% CI 0.01 0.1 1 10 100 Favours increased corticosteroids Favours stable corticosteroids

Analysis 2.4: Treatment failure (all randomised participants): Subgrouped by inhaled corticosteroid dose during exacerbation

Study or Subgroup 2.4.1 Low FitzGerald 2004 Martinez 2011 Rice-McDonald 2005 Subtotal (95% CI) Total events: Heterogeneity: Chi² = 0.17, df = 2 (P = 0.92); I² = 0% Test for overall effect: Z = 0.78 (P = 0.43) 2.4.2 High Harrison 2004 Jackson 2018 Oborne 2009 Wainwright 2009 Subtotal (95% CI) Total events: Heterogeneity: Chi² = 4.13, df = 3 (P = 0.25); I² = 27% Test for overall effect: Z = 0.76 (P = 0.45) 2.4.3 Medium Subtotal (95% CI) Total events: Heterogeneity: Not applicable Test for overall effect: Not applicable Total (95% CI) Total events: Heterogeneity: Chi² = 5.40, df = 6 (P = 0.49); I² = 0% Test for overall effect: Z = 0.30 (P = 0.76) Test for subgroup differences: Chi² = 1.10, df = 1 (P = 0.30), I² = 8.7% Increased dose of inhaled corticosteroids Events 12 22 6 40 22 38 18 41 119 0 159 Total 142 71 9 222 192 127 197 127 643 0 865 Stable dose of inhaled corticosteroids Events 9 20 6 35 24 30 29 47 130 0 165 Total 148 72 9 229 198 127 203 124 652 0 881 Weight 8.0% 12.4% 1.7% 22.1% 17.0% 20.6% 16.5% 23.8% 77.9% 100.0% Odds Ratio IV, Fixed, 95% CI 1.43 [0.58 , 3.50] 1.17 [0.57 , 2.40] 1.00 [0.14 , 7.10] 1.24 [0.72 , 2.13] 0.94 [0.51 , 1.74] 1.38 [0.79 , 2.41] 0.60 [0.32 , 1.13] 0.78 [0.46 , 1.31] 0.89 [0.67 , 1.19] Not estimable 0.96 [0.75 , 1.24] Odds Ratio IV, Fixed, 95% CI 0.01 0.1 1 10 100 Favours increased corticosteroids Favours stable corticosteroids

Analysis 2.5: Treatment failure (all randomised participants): subgrouped by inhaled corticosteroid fold increase

Study or Subgroup 2.5.1 Double FitzGerald 2004 Garrett 1998 Harrison 2004 Martinez 2011 Rice-McDonald 2005 Wainwright 2009 Subtotal (95% CI) Total events: Heterogeneity: Chi² = 2.89, df = 5 (P = 0.72); I² = 0% Test for overall effect: Z = 0.10 (P = 0.92) 2.5.2 More than double Jackson 2018 Oborne 2009 Subtotal (95% CI) Total events: Heterogeneity: Chi² = 3.75, df = 1 (P = 0.05); I² = 73% Test for overall effect: Z = 0.22 (P = 0.83) Total (95% CI) Total events: Heterogeneity: Chi² = 6.65, df = 7 (P = 0.47); I² = 0% Test for overall effect: Z = 0.21 (P = 0.83) Test for subgroup differences: Chi² = 0.01, df = 1 (P = 0.91), I² = 0% Increased dose of inhaled corticosteroids Events 12 2 22 22 6 41 105 38 18 56 161 Total 142 14 192 71 9 127 555 127 197 324 879 Stable dose of inhaled corticosteroids Events 9 0 24 20 6 47 106 30 29 59 165 Total 148 14 198 72 9 124 565 127 203 330 895 Weight 7.9% 0.7% 16.8% 12.3% 1.7% 23.7% 63.1% 20.5% 16.4% 36.9% 100.0% Odds Ratio IV, Fixed, 95% CI 1.43 [0.58 , 3.50] 5.80 [0.25 , 132.56] 0.94 [0.51 , 1.74] 1.17 [0.57 , 2.40] 1.00 [0.14 , 7.10] 0.78 [0.46 , 1.31] 0.98 [0.72 , 1.35] 1.38 [0.79 , 2.41] 0.60 [0.32 , 1.13] 0.96 [0.63 , 1.45] 0.97 [0.76 , 1.25] Odds Ratio IV, Fixed, 95% CI 0.01 0.1 1 10 100 Favours increased corticosteroids Favours stable corticosteroids

Analysis 2.6: Treatment failure (all randomised participants): Sensitivity analysis of parallel-group studies only

Study or Subgroup FitzGerald 2004 Harrison 2004 Jackson 2018 Martinez 2011 Oborne 2009 Wainwright 2009 Total (95% CI) Total events: Heterogeneity: Chi² = 5.39, df = 5 (P = 0.37); I² = 7% Test for overall effect: Z = 0.30 (P = 0.76) Test for subgroup differences: Not applicable Increased dose of inhaled corticosteroids Events 12 22 38 22 18 41 153 Total 142 192 127 71 197 127 856 Stable dose of inhaled corticosteroids Events 9 24 30 20 29 47 159 Total 148 198 127 72 203 124 872 Weight 8.1% 17.2% 21.0% 12.6% 16.8% 24.2% 100.0% Odds Ratio IV, Fixed, 95% CI 1.43 [0.58 , 3.50] 0.94 [0.51 , 1.74] 1.38 [0.79 , 2.41] 1.17 [0.57 , 2.40] 0.60 [0.32 , 1.13] 0.78 [0.46 , 1.31] 0.96 [0.74 , 1.24] Odds Ratio IV, Fixed, 95% CI 0.01 0.1 1 10 100 Favours increased corticosteroids Favours stable corticosteroids

Analysis 2.7: Treatment failure (all randomised participants): Sensitivity analysis to remove studies with results at high risk of bias

Study or Subgroup Harrison 2004 Jackson 2018 Martinez 2011 Oborne 2009 Wainwright 2009 Total (95% CI) Total events: Heterogeneity: Chi² = 4.59, df = 4 (P = 0.33); I² = 13% Test for overall effect: Z = 0.55 (P = 0.58) Test for subgroup differences: Not applicable Increased dose of inhaled corticosteroids Events 22 38 22 18 41 141 Total 192 127 71 197 127 714 Stable dose of inhaled corticosteroids Events 24 30 20 29 47 150 Total 198 127 72 203 124 724 Weight 18.8% 22.8% 13.7% 18.3% 26.4% 100.0% Odds Ratio IV, Fixed, 95% CI 0.94 [0.51 , 1.74] 1.38 [0.79 , 2.41] 1.17 [0.57 , 2.40] 0.60 [0.32 , 1.13] 0.78 [0.46 , 1.31] 0.93 [0.71 , 1.21] Odds Ratio IV, Fixed, 95% CI 0.01 0.1 1 10 100 Favours increased corticosteroids Favours stable corticosteroids Risk of Bias A + ? + + + B + + + + ? C + + + + + D + + + + + E ? + ? ? ? F + + + + ? Risk of bias legend (A) Bias arising from the randomization process (B) Bias due to deviations from intended interventions (C) Bias due to missing outcome data (D) Bias in measurement of the outcome (E) Bias in selection of the reported result (F) Overall bias

Analysis 2.8: Treatment failure (all randomised participants): Sensitivity analysis of independent funded studies only

Study or Subgroup Harrison 2004 Jackson 2018 Martinez 2011 Oborne 2009 Rice-McDonald 2005 Wainwright 2009 Total (95% CI) Total events: Heterogeneity: Chi² = 4.59, df = 5 (P = 0.47); I² = 0% Test for overall effect: Z = 0.54 (P = 0.59) Test for subgroup differences: Not applicable Increased dose of inhaled corticosteroids Events 22 38 22 18 6 41 147 Total 192 127 71 197 9 127 723 Stable dose of inhaled corticosteroids Events 24 30 20 29 6 47 156 Total 198 127 72 203 9 124 733 Weight 18.4% 22.4% 13.5% 18.0% 1.8% 25.9% 100.0% Odds Ratio IV, Fixed, 95% CI 0.94 [0.51 , 1.74] 1.38 [0.79 , 2.41] 1.17 [0.57 , 2.40] 0.60 [0.32 , 1.13] 1.00 [0.14 , 7.10] 0.78 [0.46 , 1.31] 0.93 [0.71 , 1.21] Odds Ratio IV, Fixed, 95% CI 0.01 0.1 1 10 100 Favours increased corticosteroids Favours stable corticosteroids Risk of Bias A + ? + + + + B + + + + ? C + + + + + D + + + + + + E ? + ? ? ? ? F + + + + ? Risk of bias legend (A) Bias arising from the randomization process (B) Bias due to deviations from intended interventions (C) Bias due to missing outcome data (D) Bias in measurement of the outcome (E) Bias in selection of the reported result (F) Overall bias