Table 3.
Summary of key phase IV studies.
| Parameters | ETOILES | 2403 | FREE | FR01 | GB01 | BR01 |
|---|---|---|---|---|---|---|
| Study design | Single-arm, open-label, multicenter, phase IV study* | Open-label, crossover, interventional study | Observational, longitudinal, multicenter cohort study | Postmarketing noninterventional, prospective, multicenter study in France | Combined prospective and retrospective, observational study in the United Kingdom | A descriptive study with a cross-sectional approach to assess the contamination profile of home nebulizers in Brazil |
| Objective | To assess the safety of TIP over 6 cycles of treatment in terms of the incidence of treatment-emergent AEs | To compare the ease-of-use of the T-326 Inhaler device used to deliver TIP with nebulizers used to deliver TIS, COLI, or other inhaled medications | To describe the adherence to treatment with TIP in patients with CF using ITA-CFq questionnaire | To evaluate the adherence to treatment with TIP, as measured using the Morisky score | To describe the change in treatment burden domain score of the revised CFQ–R at 1 month and 5 months after initiation of TIP | To evaluate the microbiologic contamination profile of the nebulizer device |
| Treatment arms (28-days-on /28-days-off drug) |
TIP: 112 mg bid | TIP: 112 mg bid; TIS: 300 mg bid; COLI: 1 million or 2 million units bid/tid (cyclical or noncyclical regimen during cycle 1) |
TIP: 112 mg bid | TIP: 112 mg bid; inhaled TIS, COLI and aztreonam | TIP: 112 mg bid | Not applicable |
| Duration | 48 weeks (6 cycles) | 20 weeks | 6 months | 12 months | 6 months | 12 months |
| Patients | 157 patients aged ⩾6 years | 60 patients aged ⩾6 years TIS/TIP (n = 14); COLI/TIP (n = 28); TIP/TIP (n = 18) | 72 patients aged ⩾12 and ⩽35 years | 126 patients aged ⩾6 years | 87 patients aged ⩾14 years | 77 patients aged ⩾6 years (using same nebulizer for at least 3 consecutive months) |
| Primary clinical outcome† | No deaths and no new emerging safety signals were reported over the 1-year study period | Mean total administration time‡ of TIP compared to nebulized antibiotics; TIS/TIP: 37.0
versus 5.0 min; mean difference: −32.7
(23.9) (95% CI: −54.8 to −10.6; p = 0.0112);
COLI/TIP: 16.4 versus 3.8 min; mean difference:
−13.3 (10.4) (95% CI: 20.3–6.4; p =
0.0016); TIP/TIP: 4.2 versus 3.4 min |
Adherence to TIP at the end of cycle 3 as measured by ITA-CFq scores was high (Table 4) | At 12-month follow-up: Adherence was better in children and teenagers compared to adults: 80%, 75% and 48.3%, respectively (Table 4) |
All four domains of TSQM questionnaire were scored high indicating greater patient satisfaction (Table 4) | Cleaning nebulizers under tap water was a risk factor, increasing the chance of contamination by 4.29 (95% CI: 1.13–16.28; p = 0.03) |
| Secondary/exploratory outcome | ||||||
| FEV1 % predicted | FEV1 % predicted decreased from baseline to cycle 6: −1.9% (14.6);p = 0.199 | FEV1 % predicted change: Cycle 1: TIS/TIP and
COLI/TIP: Increase from baseline (2.2% and 3.9%,
respectively); TIP/TIP: Decrease from baseline (−2.8%) Cycle 2: Stable across the treatment arms |
FEV1 % predicted: 73.8 ± 23.9% at enrollment, 78.1 ± 20.7% at first follow-up visit, and 77.2 ± 17.9% at the second follow-up visit | FEV1 % predicted improved in 47.4% of patients, stabilized in 21.6%, and worsened in 30.9% | FEV1 % predicted change: Not statistically significant | Not evaluated |
| Pseudomonas aeruginosa sputum density | After 6 cycles of TIP treatment, significant reductions in CFUs:
Mucoid: 1.4-log10 reduction, p <
0.001 Sum of all biotypes: 1.2-log10 reduction, p < 0.001 |
Sum of all biotypes (cycle 1): TIS/TIP: mean log reduction of
1.4 log10 CFU; COLI/TIP: mean log reduction of 0.6
log10 CFU; TIP/TIP: mean log reduction of 1.7
log10 CFU Cycle 2: slightly lower for the TIS/TIP arm and was similar for the other two arms |
Not evaluated | Not evaluated | Not evaluated | Not evaluated |
| Tobramycin MIC values | MIC50: Stable at 2 μg/ml (no change from baseline); MIC90: Increased 4-fold (from 128 μg/ml at baseline to 512 μg/ml at the end of the study driven by a small subset of patients) | TIS/TIP and COLI/TIP: MIC50 and MIC90:
1-fold dilution increase; TIP/TIP: MIC50
and MIC90 tobramycin values were stable up to cycle 2 |
Increased from enrollment to the second follow-up visit | Not evaluated | Not evaluated | Not evaluated |
| Safety | ||||||
| AEs, n (%) | 134 (85.4)* | Cycle 1: 36 (60.0%); Cycle 2:30 (57.7%) | 26 (31.7) | 42 (35.3) | 51 AEs reported in 43 patients | No AEs were reported during study |
| Cough | 37 (23.6) | Cycle 1: 6 (10 %); Cycle 2: 3 (5.8%) | 3 (3.7) | 18 (15.1) | 3 episodes | |
| Pulmonary exacerbation | 87 (55.4) | Cycle 1: 17 (28.3); Cycle 2: 11 (21.1) |
7 (8.5) | 3 (2.5) | 1 episode | |
| References | Sommerwerck et al.52 | Greenwood et al.51; Greenwood et al.53 | Data on file | Data on file | Data on file | Data on file |
*
Safety was the primary objective of this study. †Patient reported outcomes are described in Table 4. ‡Time including the time required to set up the device, administer the drug, and clean the delivery device.
AE, adverse event; bid, twice daily; CFQ-R, cystic fibrosis questionnaire: revised; CI, confidence interval; CFU, colony forming unit; COLI, colistimethate sodium; FEV1, forced expiratory volume in 1 second; ITA-CFq, Italian Treatment Adherence Cystic Fibrosis Questionnaire; MIC, minimum inhibitory concentration; tid, thrice daily; TIP, tobramycin inhalation powder; TIS, tobramycin inhalation solution.