G. Angyalosi

Safety, efficacy and convenience of tobramycin inhalation powder in cystic fibrosis patients: The EAGER trial

BACKGROUND A light-porous-particle, dry-powder formulation of tobramycin was developed, using PulmoSphere® technology, to improve airway delivery efficiency, substantially reduce delivery time, and improve patient convenience and satisfaction. We evaluated the safety, efficacy and convenience of tobramycin inhalation powder (TIP™) versus tobramycin inhalation solution (TIS, TOBI®) for treating Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients aged ≥6 years. METHODS In this open-label study, 553 patients were randomized 3:2 to TIP (total 112mg tobramycin) via the Novartis T-326 Inhaler or TIS 300mg/5mL via PARI LC® PLUS nebulizer twice daily for three treatment cycles (28 days on-drug, 28 days off-drug). Safety, efficacy, and treatment satisfaction outcomes were evaluated. RESULTS TIP was generally well-tolerated; adverse events were similar in both groups. The rate of cough suspected to be study drug related was higher in TIP-treated patients (TIP: 25.3%; TIS: 4.3%), as was the overall discontinuation rate (TIP: 26.9%; TIS: 18.2%). Increases in FEV(1)% predicted from baseline to Day 28 of Cycle 3 were similar between groups; the mean reduction in sputum P. aeruginosa density (log(10) CFU/g) on Day 28 of Cycle 3 was also comparable between groups. Administration time was significantly less for TIP (mean: 5.6 versus 19.7min, p<0.0001). Treatment satisfaction was significantly higher for TIP for effectiveness, convenience, and global satisfaction. CONCLUSIONS TIP has a safety and efficacy profile comparable with TIS, and offers a far more convenient treatment option for pseudomonas lung infection in CF.

Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial

Rationale Antibiotic therapy for early Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF) is effective, but the optimal therapeutic regimen and duration for early treatment remains unclear. The EarLy Inhaled Tobramycin for Eradication (ELITE) study was designed to assess the efficacy and safety of two regimens (28 and 56 days) of tobramycin inhalation solution (TIS) 300 mg/5 ml twice daily for the treatment of early onset P aeruginosa infection in patients with CF. Methods In this open-label randomised multicentre study, patients with CF (aged ≥6 months) with early P aeruginosa infection were treated for 28 days with TIS twice daily administered by the PARI LC PLUS (PARI GmbH, Starnberg, Germany) jet nebuliser. After 28 days, patients were randomised 1:1 to either stop TIS (n=45) or to receive a further 28 days of TIS (n=43). The primary endpoint was the median time to recurrence of P aeruginosa (any strain). Secondary endpoints included the proportion of patients free of P aeruginosa infection 1 month after cessation of therapy and safety assessments. Results The median time to recurrence of P aeruginosa (any strain) was similar between the two groups. In total, 93% and 92% of the patients were free of P aeruginosa infection 1 month after the end of treatment and 66% and 69% remained free at the final visit in the 28-day and 56-day groups, respectively. TIS was well tolerated. Conclusions Treatment with TIS for 28 days is an effective and well tolerated therapy for early P aeruginosa infection in patients with CF. Trial registration number NCT00391976.

Tobramycin inhalation powder for P. aeruginosa infection in cystic fibrosis: the EVOLVE trial.

Tobramycin inhalation solution is used to treat chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients. We evaluated the efficacy and safety of a novel, light‐porous particle, dry‐powder formulation of tobramycin, which was developed to improve delivery efficiency to the airways and substantially reduce the delivery time. In this randomized, double‐blind study, patients with CF (age 6–21 years) received tobramycin inhalation powder (112 mg tobramycin) twice daily (n = 46) or placebo (n = 49) via the T‐326 Inhaler for one cycle, followed by two open‐label cycles (all patients). Cycles were 28 days on, 28 days off treatment. The primary endpoint was change in forced expiratory volume in 1 sec (FEV1) % predicted from baseline to Day 28 of Cycle 1. The study was terminated early based on positive results in the interim analysis. Tobramycin inhalation powder significantly improved FEV1 % predicted versus placebo at Day 28 (difference 13.3, 95% CI: 5.31–21.28; P = 0.0016). Similar changes in FEV1 were seen in patients switching from placebo to tobramycin inhalation powder in Cycle 2; improvements were maintained over time. Tobramycin inhalation powder also reduced sputum P. aeruginosa density, respiratory‐related hospitalization and antipseudomonal antibiotic use versus placebo. The most common adverse event was cough; the frequency of cough was higher in patients receiving placebo (26.5%) versus tobramycin inhalation powder (13.0%) in Cycle 1. Tobramycin inhalation powder was not associated with ototoxicity or nephrotoxicity. Administration time was between 4 and 6 min. In conclusion, tobramycin inhalation powder was effective and well tolerated in CF patients, and may offer an important treatment option to decrease the treatment burden of CF pseudomonas lung infections. Pediatr Pulmonol. 2011; 46:230–238.

Tobramycin inhalation powder manufactured by improved process in cystic fibrosis: the randomized EDIT trial

Abstract Background: Tobramycin inhalation powder (TIP) was reported to be effective in two Phase III studies in patients with cystic fibrosis (CF) chronically infected with Pseudomonas aeruginosa (Pa). The EDIT study evaluated the efficacy and safety of TIP manufactured by an improved process in CF subjects aged 6–21 years. Methods: CF patients with a forced expiratory volume in 1 second (FEV1) ≥25% to ≤80% predicted, positive Pa cultures and inhaled antipseudomonal therapy naïve (or at least for past 4 months) were enrolled into this double-blind, multicenter trial. Patients were randomized to receive TIP or placebo (1:1) twice daily for one treatment cycle (28.5 days on drug, 28 days off drug). The primary endpoint was relative change in FEV1 percentage predicted from baseline to day 29. A pre-specified sensitivity analysis evaluated absolute change in FEV1% predicted. Other endpoints included Pa sputum density and safety. Results: A total of 62 patients out of a target of 100 (mean age 12.9 years, baseline FEV1 59.2% predicted, Pa sputum density 7.4 log10 colony forming units [CFU] per gram) were randomized. Mean treatment differences (TIP - placebo) were 5.9% (p = 0.148) and 4.4% (p < 0.05) for relative and absolute change in FEV1% predicted respectively. TIP significantly reduced Pa sputum density by −1.2 log10 CFU (p = 0.002). Treatment with TIP was well tolerated. Conclusions: Relative change in FEV1% predicted with TIP treatment was in the expected range based on the literature, but did not reach statistical significance versus placebo. Placebo control and use of treatment naïve patients led to significant recruitment challenges and an underpowered study with consequent impact on the generated data. However, significant improvements in other outcomes including absolute change in FEV1% predicted and reduction in Pa sputum density indicate that TIP is efficacious and well tolerated in CF patients. ClinicalTrials.gov identifier: ClinicalTrials.gov identifier: NCT00918957.

A network meta-analysis of the efficacy of inhaled antibiotics for chronic Pseudomonas infections in cystic fibrosis

BACKGROUND Various inhaled antibiotics are currently used for treating chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients, however their relative efficacies are unclear. We compared the efficacy of the inhaled antibiotics tobramycin (TIP, TIS-T, TIS-B), colistimethate sodium (colistin) and aztreonam lysine for inhalation (AZLI) based on data from randomised controlled trials. METHODS In the base case, efficacies of antibiotics were compared using a network meta-analysis of seven trials including change from baseline in forced expiratory volume in 1 second (FEV(1)) % predicted, P. aeruginosa sputum density and acute exacerbations. RESULTS The tobramycin preparations, AZLI and colistin, showed comparable improvements in efficacy in terms of FEV1% predicted at 4 weeks; the difference in % change from baseline (95%CrI) for TIP was compared to TIS-T (-0.55, -3.5;2.4), TIS-B (-0.64, -7.1;5.7), AZLI (3.64, -1.0;8.3) and colistin (5.77, -1.2;12.8). CONCLUSION We conclude that all studied antibiotics have comparable efficacies for the treatment of chronic P. aeruginosa lung infection in CF.

Tobramycin inhalation powder in cystic fibrosis patients: response by age group.

BACKGROUND: Tobramycin powder for inhalation (TIP) is a drug-device combination designed to reduce treatment time and improve ease of use compared with tobramycin inhalation solution (TIS) in cystic fibrosis (CF) patients. However, the ability of patients to use dry powder inhalers, and the efficacy of the treatments, may vary by age. METHODS: The “Establish a New Gold Standard for Efficacy and Safety With Tobramycin in Cystic Fibrosis” (EAGER) trial was a randomized, 24-week, multicenter, open-label, parallel-group study designed to evaluate the safety of TIP versus TIS in 553 subjects, ages ≥ 6 years, with CF and P. aeruginosa infection. The main efficacy end point was percent-of-predicted FEV1 at week 20 (end of third cycle of treatment). A post hoc analysis was undertaken in 517 subjects who took ≥ 1 dose of study medication, to evaluate the relative efficacy and safety of TIP and TIS by age group: ≥ 6 to < 13 y (children, n = 46); ≥ 13 to < 20 y (adolescents, n = 114); and ≥ 20 y (adults, n = 357). RESULTS: Improvements in percent-of-predicted FEV1 from baseline to end of cycle 3 were greatest in the children for both TIP and TIS. The treatment differences (TIP − TIS) were 4.7% (85% CI −1.2 to 10.6), 3.7% (85% CI −0.1 to 7.5), and −0.8% (85% CI −3.1 to 1.5) in children, adolescents, and adults, respectively. Sputum P. aeruginosa density decreased from baseline with both treatments, with comparable treatment differences across the age groups after 3 cycles: children −0.93 (85% CI −2.4 to 0.5), adolescents −0.17 (85% CI −1.2 to 0.8), and adults −0.89 (85% CI −1.3 to −0.4). Overall, subject satisfaction scores were greater in all subjects with TIP, irrespective of age group. With the exception of cough and dysphonia, the safety profile of TIP was comparable to TIS, irrespective of age. CONCLUSIONS: TIP is comparable to TIS in efficacy outcomes and safety profile but had greater patient satisfaction in all the age groups.

One-year safety and efficacy of tobramycin powder for inhalation in patients with cystic fibrosis.

This is an integrated analysis of data from patients with cystic fibrosis (CF) aged 6–21 years who were treated with up to seven cycles of tobramycin powder for inhalation (TIPTM) over a period of at least 1 year. Safety and key efficacy endpoints were analyzed. Results: The improvement in lung function and decrease in sputum P. aeruginosa (Pa) density from baseline were sustained over the 1‐year treatment period. The number of adverse events (AEs) was low and did not increase with additional cycles of TIP treatment. Some increase in tobramycin minimum inhibitory concentration (MIC) was observed, but there was no significant increase in emergence of resistant strains based on the parenteral breakpoint for tobramycin. Conclusion: Efficacy of TIP was maintained for up to seven cycles. Long‐term treatment with TIP was generally safe and well tolerated with no increase in AEs. Pediatr Pulmonol. 2016;51:372–378.

WS5.6 A challenging double-blind, placebo-controlled study of tobramycin inhalation powder in cystic fibrosis: results of the EDIT trial

WS5.5 A randomised, open label phase 3 study to evaluate the efficacy and safety of a dry powder formulation of inhaled colistimethate sodium (Colobreathe®) versus tobramycin nebuliser solution (TNS) in cystic fibrosis subjects with chronic Pseudomonas aeruginosa lung infection M. Goldman1, A. Schuster2, C. Halliburn3, G. Doring4, The Freedom Study Group. 1Forest Laboratories UK Ltd, Medical, Dartford, Kent, United Kingdom; 2University of Dusseldorf, Paediatrics, Dusselfdorf, Germany; 3Hartington Data Managment and Statitistics, Statistics, London, United Kingdom; 4University of Tubingen, Institute of Medical Microbiology and Hygiene, Tubingen, Germany

Long-term safety of tobramycin inhalation powder in patients with cystic fibrosis: phase IV (ETOILES) study

Abstract Objective: Long-term treatment with inhaled antibiotics is recommended for chronic Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) patients. The ETOILES study (Clinicaltrials.gov identifier: NCT01519661) evaluated the safety of tobramycin inhalation powder (TIP) for 1 year. Research design and methods: This single-arm, open-label, multicenter, phase IV trial, enrolled CF patients aged ≥6 years, with baseline FEV1 ≥25%–≤75% predicted and Pa infection, and assessed the safety of TIP over six cycles in terms of the incidence of treatment-emergent adverse events (AEs) and serious AEs (SAEs). Secondary endpoints included presence of airway reactivity, relative change in FEV1% predicted, and change in sputum Pa density (log10 colony forming units/g sputum). Results: A total of 157 patients were enrolled, and 96 patients (61.1%) completed the study. The most commonly reported AE was infective pulmonary exacerbation of CF (55.4%). Cough was reported as an AE in 23.6% of patients; a majority were mild or moderate and two were severe (1.3%). SAEs were reported by 31.2% of patients. No deaths were reported during the study. There were no clinically meaningful changes reported in airway reactivity. Most frequently reported post-inhalation event was cough at all time points; however, it was of short duration (<4 minutes) and decreased over the course of the study, possibly due to patients becoming more experienced with the administration of TIP. The post-inhalation events resolved without intervention in most cases. FEV1% predicted remained stable from Cycles 1 to 4 and tended to decrease thereafter, although it was not statistically significant (change from baseline to study end mean [SD] = −1.9% [14.55]; P = 0.199). Conclusions: This was one of the largest studies with long-term TIP exposure. The majority of patients enrolled were adults with more advanced CF lung disease than those in previous TIP studies. No new emerging safety signals were seen and efficacy was sustained during the year.

The road for survival improvement of cystic fibrosis patients in Arab countries

Cystic fibrosis (CF) is a lethal, monogenic disorder that affects multiple organ systems of the body. The incidence has been described before in the Middle East to be 1 in 2000 to 1 in 5800 live births, and the median survival was estimated to be from 10 to 20 years of age. The present article attempts to revisit various facets of this disease and specifically highlights the most important lacunae that exist in treating CF. In addition, it also tries to emphasize the steps in improving the median survival of patients with CF, in these countries.