Table 2.
Summary of key phase III studies.
| Parameters | EVOLVE | EDIT, including extensions | EAGER |
|---|---|---|---|
| Study design | Randomized, double-blind, placebo-controlled trial* | Core study: Randomized, double-blind, placebo-controlled trial | Randomized, open-label, active-controlled, noninferiority trial |
| Treatment arms (28-days-on/28-days-off drug) | TIP: 112 mg bid (n = 46); placebo (n = 49) | TIP: 112 mg bid (n = 30); placebo (n = 32) |
TIP: 112 mg bid (n = 308); TIS: 300 mg/5 ml bid (n = 209) |
| Primary objective | To demonstrate the efficacy of a 28-day bid dosing regimen of TIP versus placebo, as measured by the relative change in FEV1% predicted from baseline to the end of cycle 1 dosing | To evaluate the efficacy of TIP manufactured by an improved process versus placebo, assessed by relative change in FEV1% predicted from baseline to day 29 | To evaluate the safety of bid dosing of TIP delivered with the T-326 inhaler, versus TOBI delivered with the PARI-LC® PLUS Jet nebulizer and DeVilbiss PulmoAide® compressor |
| Duration | 24 weeks (1 cycle TIP or placebo followed by 2 cycles open-label TIP) | Core study: 8 weeks (1 cycle TIP or placebo) Extensions: Each consisted of 3 additional cycles of TIP |
24 weeks (3 cycles TIP or TIS) |
| Patients | 95 patients aged 6–21 years | 62 patients aged 6–21 years | 517 patients aged ⩾6 years |
| Key efficacy endpoint | |||
| Primary | |||
| Change in FEV1% predicted (mean treatment difference) | Baseline to day 28–TIP versus placebo: 13.3% (95% CI: 5.3 to 21.3; p = 0.0016) | Baseline to day 29–TIP versus placebo: 5.9% (95% CI: –2.2 to 14.0; p = 0.148) | Baseline to day 28 of cycle 3–TIP versus TIS†: 1.1% relative change (least squares mean difference) |
| Secondary | |||
| Antibiotic (antipseudomonal) use | Antibiotic use–TIP versus placebo: 13.0% versus 18.4% | Antibiotic use–TIP versus placebo: 6.7% versus 12.5% | Antibiotic use–TIP versus TIS: 64.9% versus 54.5% |
| Pseudomonas aeruginosa sputum density log10 CFU/g | Nonmucoid–TIP versus placebo: −1.91 (SD: 2.54)
versus –0.15 (0.68); mucoid–TIP versus placebo: –2.61 (2.53) versus −0.43 (1.05) |
Sum of all biotypes–TIP versus placebo): −1.2 versus 0 (p = 0.002) | Nonmucoid–TIP versus TIS: −1.77 versus −0.73; mucoid–TIP versus TIS: −1.6 versus −0.92 |
| Safety | |||
| Overall AEs | TIP versus placebo: 23 (50.0%) versus 37 (75.5%) | TIP versus placebo: 8 (26.7%) versus 11 (34.4%) | TIP versus TIS†: 278 (90.3%) versus 176 (84.2%) |
| Cough | TIP versus placebo: 6 (13.0%) versus 13 (26.5%) | TIP versus placebo: 3 (10.0%) versus 0 | TIP versus TIS: 149 (48.4%) versus 65 (31.1%) |
| Pulmonary exacerbation | TIP versus placebo: Cycle 1: 5 (10.9%) versus 6 (12.2%) | TIP versus placebo: 1 (3.3%) versus 0 | TIP versus TIS: 104 (33.8%) versus 63 (30.1%) |
| Discontinuation | TIP versus placebo: 7 (15.2%) versus 9 (18.4%) | TIP versus placebo: 1 (3.3%) versus 1 (3.1%) | TIP versus TIS: 83 (26.9%) versus 38 (18.2%) |
| References | Konstan et al.44 | Galeva et al.45; data on file | Konstan et al.43 |
*
Cycle 1: double-blind, placebo-controlled; cycles 2 and 3: open-label. †The primary endpoint for the EAGER trial related to safety (efficacy was a secondary endpoint).
AE, adverse event; bid, twice daily; CFU/g, colony forming units per gram; FEV1, forced expiratory volume in 1 second; TIP, tobramycin inhalation powder; TIS, tobramycin inhalation solution; SD, standard deviation.