Long-term efficacy and safety of aerosolized tobramycin 300 mg/4 ml in cystic fibrosis.
BACKGROUND
Aerosolized tobramycin is a standard of care for chronic Pseudomonas aeruginosa (Pa) infection in patients with cystic fibrosis (CF).


OBJECTIVE
The long-term safety and efficacy of intermittent (28-day "on"/"off" cycles) inhaled tobramycin nebulization solution 300 mg/4 ml (TNS4, Bramitob(®)/Bethkis(®)) was assessed over 56 weeks in CF patients aged ≥6 years having baseline 1 sec forced expiratory volume (FEV(1)) 40-80% predicted.


METHODS
Patients were initially randomized in an 8-week open-label trial (core phase) to compare TNS4 (N = 159) and tobramycin 300 mg/5 ml (TNS5, TOBI(®)) (N = 165). A subset of patients continued in a 48-week, single-arm extension receiving TNS4 only. The primary endpoint of the core phase was to demonstrate the non-inferiority of TNS4 compared to TNS5 in terms of absolute change from baseline to week 4 in FEV(1) % predicted. The assessment of long-term safety was the primary purpose of the extension phase. Throughout all phases of the study, microbiological assessments, adverse events, and audiometry findings were also evaluated.


RESULTS
In the core phase (N = 321), FEV(1) (% predicted) increased from baseline (absolute change) following a single on-treatment cycle for both TNS4 (7.0%) and TNS5 (7.5%) and the non-inferiority between treatments was met [difference between treatments of -0.5 (95% CI: -2.6; 1.6)]. These improvements were maintained throughout the extension phase (N = 209), ranging throughout the study between 5.1% (95% CI: 3.2; 6.9) and 8.1% (95% CI: 6.8; 9.4) compared to baseline. Pa sputum count reductions ranged between 0.6 (95% CI: 0.2; 0.9) to 2.3 (95% CI: 2.0; 2.6) log10 CFU/g throughout the 56 weeks. No remarkable safety issues were identified throughout both study phases, with similar percentages of patients reporting adverse events in the two treatment groups during the 8-week core phase [TNS4 (31.4%); TNS5 (28.0%)].


CONCLUSIONS
Overall, TNS4 demonstrated short-term clinical benefits similar to TNS5 which were maintained during the long-term use of TNS4 and was also associated with a favorable tolerability profile.
Instytut Gruźlicy i Chorób Pluc, Oddzial Terenowy im. Jana i Ireny Rudników w Rabce-Zdrój, Klinika Pneumonologii i Mukowiscydozy, Rabka-Zdrój, Poland.
Henryk
H
Mazurek
Raphaël
R
Chiron
Tereza
T
Kucerova
Christian
C
Geidel
Katalin
K
Bolbas
Alexander
A
Chuchalin
Marina
M
Blanco-Aparicio
Debora
D
Santoro
Guido
G
Varoli
Marco
M
Zibellini
Helen G
HG
Cicirello
Yuriy G
YG
Antipkin
D000280:Administration, Inhalation; D000293:Adolescent; D000336:Aerosols; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002648:Child; D003550:Cystic Fibrosis / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology / Q000503:physiopathology; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D011552:Pseudomonas Infections / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology / Q000503:physiopathology; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification; D013183:Sputum / Q000382:microbiology; D014031:Tobramycin / Q000008:administration & dosage* / Q000627:therapeutic use; D016896:Treatment Outcome
D000336:Aerosols; D000900:Anti-Bacterial Agents; D014031:Tobramycin
FEV1; Pseudomonas aeruginosa; cystic fibrosis; long-term; nebulization; tobramycin susceptibility