Guido Varoli

A formulation of aerosolized tobramycin (Bramitob®) in the treatment of patients with cystic fibrosis and Pseudomonas aeruginosa infection: A double-blind, placebo-controlled, multicenter study

AbstractBackground and aim Chronic infection with Pseudomonas aeruginosa in patients with cystic fibrosis (CF) causes progressive deterioration in lung function. The purpose of this trial was to assess the efficacy and tolerability of a tobramycin highly concentrated solution for inhalation (TSI) [300mg/4mL; Bramitob®] when added to other antipseudomonal therapies in CF patients with chronic P. aeruginosa infection. Methods In a multinational, double-blind, multicenter study, CF patients with chronic P. aeruginosa infection were randomized to receive nebulized tobramycin or placebo over a 24-week study period in which 4-week treatment periods (‘on’ cycles) were followed by 4-week periods without treatment (‘off’ cycles). Forced expiratory volume in 1 second (FEV1) percentage of predicted normal was used as the primary efficacy outcome parameter. Forced vital capacity (FVC), forced expiratory flow at 25–75% of FVC (FEF25–75%), P. aeruginosa susceptibility, minimum concentration required to inhibit 90% of strains (MIC90), rates of P. aeruginosa-negative culture, P. aeruginosa persistence and superinfection, need for hospitalization and parenteral antipseudomonal antibiotics, loss of school/working days due to the disease, and nutritional status (bodyweight and body mass index) were considered as secondary efficacy outcome parameters. Adverse events reporting, audiometry, and renal function were monitored to evaluate the tolerability and safety of TSI. Results A total of 247 patients were randomized in the study. At endpoint time assessment (week 20), FEV1 was significantly increased in the tobramycin group and the adjusted mean difference between groups (intention-to-treat population) was statistically significant (p < 0.001). At the same time, clinically relevant improvements in FVC and FEF25–75% were detected in the TSI group (p = 0.022 and p = 0.001, respectively). The microbiologic outcomes at the end of the last ‘on’ cycle period were significantly better in the TSI group than the placebo group (p = 0.024), although there was a concomitant trend toward an increase in the MIC of isolated P. aeruginosa strains. The percentage of patients hospitalized as well as the need for parenteral antipseudomonal antibiotics was significantly lower in the TSI group (p = 0.002 and p = 0.009, respectively). Patients treated with TSI had fewer lost school/working days due to the disease (p < 0.001). A favorable effect of tobramycin in terms of an increase in bodyweight and body mass index was also noted, when compared with placebo, at all timepoints (p < 0.01 and p < 0.001, respectively). No significant changes in serum creatinine and auditory function were detected. The proportion of patients with drug-related adverse events was 15% in both treatment groups. Conclusions Long-term, intermittent administration of this aerosolized tobramycin formulation (300mg/4mL) in CF patients with P. aeruginosa chronic infection significantly improved pulmonary function and microbiologic outcome, decreased hospitalizations, increased nutritional status, and was well tolerated.

Efficacy, safety, and local pharmacokinetics of highly concentrated nebulized tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa.

AbstractBackground and aim Progressive respiratory failure due to Pseudomonas aeruginosa colonization is the most significant morbidity in patients with cystic fibrosis (CF). This trial was designed to investigate the efficacy and safety of a highly concentrated (300mg/4mL) tobramycin solution for inhalation (TSI) [Bramitob®] in patients with CF and P. aeruginosa infection. Methods Fifty-nine patients were randomized to receive a 4-week treatment with tobramycin or placebo administered twice daily via the Pari LC Plus® nebulizer and Pari TurboBoy™ compressor, followed by a 4-week run-out phase. Pulmonary function (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and forced expiratory flow at the midportion of vital capacity [FEF25–75%]), P. aeruginosa susceptibility, microbiologic results, and in vitro minimum inhibitory concentration for 90% of strains (MIC90) were the efficacy outcome measures, while safety was monitored by the recording of adverse events, audiometry (bone conduction at 250–8000Hz frequency), laboratory tests, physical examination and general health condition. The concentration of tobramycin attained in sputum was measured in a cohort of 21 patients. Results FEV1 significantly increased from baseline in the tobramycin group compared with no change in the placebo group: the absolute difference between groups (intent-to-treat population) of predicted normal was 13.2% at week 2 (p = 0.002) and 13.3% at week 4 (p = 0.003). Significant differences in favor of the tobramycin group were also observed for FVC and FEF25–75%. The microbiologic results at the end of the treatment period (P. aeruginosa-negative culture, persistence, superinfection) showed a significantly better outcome in the tobramycin group compared with placebo (p = 0.033). The effects of tobramycin on pulmonary function and microbiology were not maintained at the end of the run-out phase.Mean sputum concentrations of tobramycin after the first dose (695.6 ± 817.0 µg/mL) were similar to those measured after the last dose (716.9 ± 799 µg/mL) and were superior to the detected specific MIC90.The proportion of patients with drug-related adverse events was lower in the tobramycin group and no signs of renal or auditory toxicity were observed. Conclusions The 4-week administration of a highly concentrated TSI significantly improved pulmonary function and microbiologic outcome compared with placebo and was well tolerated. The results of this study should be confirmed in further long-term trials in larger populations.

Oral prolonged release beclomethasone dipropionate and prednisone in the treatment of active ulcerative colitis: results from a double-blind, randomized, parallel group study.

OBJECTIVES:Double-blind study comparing efficacy and safety of the topically acting corticosteroid beclomethasone dipropionate (BDP) to prednisone (PD) in patients with active, mild-to-moderate ulcerative colitis (UC).METHODS:Overall, 282 patients were randomized to receive BDP-prolonged release tablets 5 mg once daily for 4 weeks and then every other day for an additional 4 weeks or oral PD 40 mg once daily for the initial 2 weeks tapered of 10 mg every 2 weeks during the 8-week study period. Efficacy end point was the non-inferiority of BDP vs. PD in terms of Disease Activity Index (DAI) score <3 or reduction by at least 3 points for patients with a baseline DAI ≥7 at week 4. Safety end point was the proportion of patients with steroid-related adverse events (AEs) and cortisol <150 nmol/l at week 4.RESULTS:DAI response rates at week 4 were 64.6% and 66.2% with BDP and PD, respectively, demonstrating non-inferiority of BDP vs. PD (delta: −1.56; 95% confidence interval (CI) −13.00–9.88, P=0.78). Patients with steroid-related AEs and cortisol <150 nmol/l at week 4 were 38.7% in the BDP group and 46.9% in the PD group (P=0.17 between groups). No safety signals were observed in both the groups.CONCLUSIONS:BDP was non-inferior to PD in the treatment of active UC, with a good safety profile in both the groups.

Long-term efficacy and safety of aerosolized tobramycin 300 mg/4 ml in cystic fibrosis.

Aerosolized tobramycin is a standard of care for chronic Pseudomonas aeruginosa (Pa) infection in patients with cystic fibrosis (CF).

A first-in-human clinical study of a new SP-B and SP-C enriched synthetic surfactant (CHF5633) in preterm babies with respiratory distress syndrome

Objective CHF5633 (Chiesi Farmaceutici S.p.A., Parma, Italy) is the first fully synthetic surfactant enriched by peptide analogues of two human surfactant proteins. We planned to assess safety and tolerability of CHF5633 and explore preliminary efficacy. Design Multicentre cohort study. Patients Forty infants from 27+0 to 33+6 weeks gestation with respiratory distress syndrome requiring fraction of inspired oxygen (FiO2) ≥0.35 were treated with a single dose of CHF5633 within 48 hours after birth. The first 20 received 100 mg/kg and the second 20 received 200 mg/kg. Outcome measures Adverse events (AEs) and adverse drug reactions (ADRs) were monitored with complications of prematurity considered AEs if occurring after dosing. Systemic absorption and immunogenicity were assessed. Efficacy was assessed by change in FiO2 after dosing and need for poractant-alfa rescue. Results Rapid and sustained improvements in FiO2 were observed in 39 (98%) infants. One responded neither to CHF5633 nor two poractant-alfa doses. A total of 79 AEs were experienced by 19 infants in the 100 mg/kg cohort and 53 AEs by 20 infants in the 200 mg/kg cohort. Most AEs were expected complications of prematurity. Two unrelated serious AEs occurred in the second cohort. One infant died of necrotising enterocolitis and another developed viral bronchiolitis after discharge. The single ADR was an episode of transient endotracheal tube obstruction following a 200 mg/kg dose. Neither systemic absorption, nor antibody development to either peptide was detected. Conclusions Both CHF5633 doses were well tolerated and showed promising clinical efficacy profile. These encouraging data provide a basis for ongoing randomised controlled trials. Trial registration number ClinicalTrials.gov NCT01651637.

69 Efficacy on lung function and safety of multiple courses of tobramycin 300mg/4mL nebuliser solution (Bramitob) in patients with cystic fibrosis and chronic Pseudomonas aeruginosa infection: results from a 48-week extension phase

Objectives: Chronic treatment with inhaled antibiotics is part of the treatment regimen for cystic fibrosis patients chronically colonized with Pseudomonas aeruginosa. Previously available treatments included nebulized antibiotics, but use of available preparations could be burdensome for patients and families. Two “newgeneration” formulations recently become available in Canada. We describe early experiences with Tobramycin Inhalation Powder (TIP, TOBI® Podhaler®) in a large pediatric CF centre. Methods: Patients who had initiated therapy with TIP were identified by retrospective chart review and demographic information was recorded (patient age, sex, CFTR mutation, culture results over 12 months, and treatment before starting TIP). Patients who ceased using TIP were identified. Data: TIP first became commercially available in Canada in April 2011. There are 170 patients between the ages of 6−18 years enrolled in the CHU-Sainte Justine clinic. As of January 2012, 32 patients had started therapy with TIP (mean age: 13.4 years (range 6−18 years, SD = 3.1 years), 14 females/18 males. 22 DF508 homozygous, 7 others with one DF508 allele). All were chronically colonized with P. aeruginosa; 31 also had other organisms. Before TIP, 12 were treated with TOBI®, 8 tobramycin, 9 colymycin, 1 tobramycin + colymycin, and 2 untreated. Three patients stopped therapy: 1 due to poor Podhaler technique, 1 bronchospasm, and 1 negative cultures for P. aeruginosa for 1 year. Conclusion: Early clinical experience with TIP in our centre has been positive, with initiation of therapy in 32 patients to date. Only 3 have stopped therapy, 2 due to factors associated with TIP.