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: two-year outcomes.

OBJECTIVE: To assess at 24 months corrected age (CA) the neurological, respiratory, and general health status of children born prematurely from 27+0 to 33+6 weeks' gestation who were treated in a first-in-human study with a new fully synthetic surfactant (CHF5633) enriched with SP-B and SP-C proteins. OUTCOME MEASURES: Children were assessed using Bayley Scales of Infant Development (BSID), with a score below normal defined as BSID-II Mental Development Index score <70, or BSID-III cognitive composite score <85. In addition, a health status questionnaire was used to check for functional disability including respiratory problems and related treatments, sensory and neurodevelopment assessments, communication skills as well as the number of hospitalizations. RESULTS: 35 of 39 survivors had a neurodevelopmental assessment, 24 infants being evaluated by Bayley's Scales and 11 by health status questionnaires only. 23 children had scores within normal limits and one had BSID-III <85. The remaining 11 were judged clinically to have normal development. Health status questionnaires detected only issues that would normally be expected in preterm-born children. CONCLUSIONS: This assessment offers reassurance that treatment with CHF5633 surfactant was not associated with adverse neurodevelopmental, respiratory, or health outcomes by two years corrected age.

Bronchodilating effects of a new beclometasone dipropionate plus formoterol fumarate formulation via pressurized metered-dose inhaler in asthmatic children: a double-blind, randomized, cross-over clinical study.

A new pediatric fixed combination of beclometasone dipropionate (BDP) 50 µg and formoterol fumarate (FF) 6 µg via pressurized metered-dose inhaler (pMDI) (CHF1535, Chiesi, Italy) was investigated. In a double-blind, randomized, placebo-controlled, cross-over study, a single CHF1535 administration using AeroChamber Plus™ spacer device (2 actuations, total dose BDP 100 µg/FF 12 µg) was compared to the same pMDI free combination in 56 asthmatic children aged ≥ 5 and < 12 years. Primary efficacy variable was forced expiratory volume during the first second (FEV1) area under the curve corrected by time over 12 h following morning dose (AUC0-12h). Further CHF1535 doses (50 µg/6 µg, 100 µg/12 µg, and 200 µg/24 µg) were also explored. Adverse events, electrocardiogram, and vital signs were monitored for safety. CHF1535 was non-inferior to free combination [adjusted mean difference (95% CI) 0.004 L (- 0.050, 0.041] with lower confidence limit greater than the limit set at 0.1 L. FEV1 AUC0-12h of each CHF1535 dose vs placebo were 0.037 L (p = 0.160), 0.119 L (p < 0.001), and 0.094 (p < 0.001) for 50/6, 100/12, and 200/24, respectively. No safety signals were found.Conclusion: CHF1535 was as effective as free combination BDP/FF, with a trend towards a dose-related response. All treatments were safe.Trial registration: ClinicalTrials.gov ID: NCT01584492 What is Known: •Inhaled pressurized metered-dose solutions (pMDI) are the preferred treatment for pediatric asthma. •Combination therapy of inhaled corticosteroids and long-acting ß2- agonists is a well-established approach to control airway inflammation and airway obstruction also in pediatric patients. What is New: •A novel pediatric pMDI fixed combination of beclomethasone dipropionate 50 µg and formoterol fumarate 6 µg (CHF 1535) was non-inferior to the free combination at the same dose in pulmonary function over the 12-h post-dose period in asthmatic children, with trend towards a dose-related response.

Synthetic Surfactant CHF5633 Compared with Poractant Alfa in the Treatment of Neonatal Respiratory Distress Syndrome: A Multicenter, Double-Blind, Randomized, Controlled Clinical Trial.

OBJECTIVE: To compare efficacy and safety of a new synthetic surfactant, CHF5633, enriched with surfactant proteins, SP-B and SP-C peptide analogues, with porcine surfactant, poractant alfa, for the treatment of respiratory distress syndrome in infants born preterm. STUDY DESIGN: Neonates born preterm on respiratory support requiring fraction of inspired oxygen (FiO2) ≥0.30 from 240/7 to 266/7 weeks and FiO2 ≥0.35 from 270/7 to 296/7 weeks of gestation to maintain 88%-95% oxygen saturation were randomized to receive 200 mg/kg of CHF5633 or poractant alfa. If necessary, redosing was given at 100 mg/kg. Efficacy end points were oxygen requirement (FiO2, respiratory severity score [FiO2 × mean airway pressure]) in the first 24 hours, 7 and 28 days, discharge home, and/or 36 weeks of postmenstrual age; mortality and bronchopulmonary dysplasia at 28 days and 36 weeks of PMA. Adverse events and immunogenicity were monitored for safety. RESULTS: Of the 123 randomized neonates, 113 were treated (56 and 57 in CHF5633 and poractant alfa groups, respectively). In both arms, FiO2 and respiratory severity score decreased from baseline at all time points (P < .001) with no statistically significant differences between groups. Rescue surfactant use (19 [33.9%] vs 17 [29.8%]), bronchopulmonary dysplasia (31 [55.4%] and 32 [56.1%]), and mortality at day 28 (4 [7.1%] and 3 [5.3%]) were similar in the CHF5633 and poractant alfa groups, respectively. In 2 (3.4%) and 1 (1.7%) neonates, adverse drug reactions were reported in CHF5633 and poractant alfa groups, respectively. No immunogenicity was detected. CONCLUSIONS: Treatment with CHF5633 showed similar efficacy and safety as poractant alfa in neonates born preterm with moderate-to-severe respiratory distress syndrome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02452476.

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.

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.

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

Stepping-across controlled asthmatic patients to extrafine beclometasone/formoterol combination.

BACKGROUND: Asthma management focuses on achieving and maintaining asthma control. Few studies have assessed whether complete and sustained asthma control is maintained in clinical practice after stepping-across ICS/LABA fixed combinations. Aim of this double-blind, double-dummy, randomized, parallel group, controlled study was to demonstrate clinical equivalence between equipotent doses of extrafine beclometasone/formoterol (BDP/F) pMDI and fluticasone/salmeterol (FP/S) Diskus® in maintaining lung function and asthma control. METHODS: A total of 416 asthmatic patients already controlled with FP/S 500/100 µg/day (Diskus®, pMDI or separate inhalers) were randomized to a 12-week treatment with extrafine BDP/F 400/24 µg/day pMDI or FP/S 500/100 µg/day Diskus®. Pre-dose 1-s forced expiratory volume (FEV(1)) was the primary efficacy variable; secondary variables included asthma control questionnaire (ACQ-7) and FEV(1)0-1 h area under the curve (FEV(1)AUC(0-1h)). Safety was assessed through adverse events monitoring and vital signs. RESULTS: After 12 weeks of treatment, pre-dose FEV(1) did not differ between treatments (difference between means 0.01 L; 95% CI -0.03-0.06 L) with no significant changes from baseline in both groups (p = 0.726 and p = 0.783 in BDF/F arm and FP/S, respectively). ACQ-7 score showed that control was maintained after stepping-across to extrafine BDP/F. FEV(1)AUC(0-1h) was significantly higher in BDP/F arm at the beginning (p = 0.004) and at the end of the 12-week treatment period (p = 0.019). No safety issues were reported in both groups. CONCLUSIONS: Patients previously controlled with FP/S in any device formulation can effectively step-across to extrafine BDP/F pMDI, maintaining lung function and asthma control with a 5-min onset of action.

Formoterol by pressurized metered-dose aerosol or dry powder on airway obstruction and lung hyperinflation in partially reversible COPD.

BACKGROUND: We compared the efficacy and safety of formoterol given by a pressurized metered-dose inhaler (pMDI) (Atimos®, Chiesi Farmaceutici, Italy), using a chlorine-free hydrofluoroalkane (HFA-134a) propellant developed to provide stable and uniform dose delivery (Modulite™, Chiesi Farmaceutici, Italy), with formoterol by dry powder inhaler (DPI) (Foradil® Aerolizer®, Novartis Pharmaceuticals) and placebo, in reducing airflow obstruction and lung hyperinflation, in moderate-to-severe, partially reversible chronic obstructive pulmonary disease (COPD). METHODS: Forty-eight patients were randomized to a 1-week, double-blind, double-dummy, three-period crossover study with 12 µg b.i.d. of formoterol given by pMDI or DPI, or placebo. Spirometry, specific airway conductance, and lung volumes were measured at the beginning and at the end of each treatment period from predose to 4 h postdose. A 6-min walking test was carried out 4 h after the first and the last dose, with dyspnea assessed by Borg scale. Safety was assessed through adverse events monitoring electrocardiography and vital signs. RESULTS: The two formulations of formoterol were significantly superior to placebo but not different from each other in increasing 1-sec forced expiratory volume, specific airway conductance, inspiratory capacity, and inspiratory-to-total lung capacity ratio. The two active treatments were also equivalent and superior to placebo in reducing dyspnea at rest and on exertion. No differences in terms of safety between the two active forms and placebo were detected. CONCLUSIONS: Formoterol given with chlorine-free pMDI was equivalent to DPI in reducing airway obstruction and lung hyperinflation in COPD patients. Both formoterol formulations confirmed the good safety profile similar to placebo.

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

BACKGROUND 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 [FEV(1)], forced vital capacity [FVC], and forced expiratory flow at the midportion of vital capacity [FEF(25-75%)]), P. aeruginosa susceptibility, microbiologic results, and in vitro minimum inhibitory concentration for 90% of strains (MIC(90)) were the efficacy outcome measures, while safety was monitored by the recording of adverse events, audiometry (bone conduction at 250-8,000Hz 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: FEV(1) 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 FEF(25-75%). 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 microg/mL) were similar to those measured after the last dose (716.9 +/- 799 microg/mL) and were superior to the detected specific MIC(90). 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.

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.

BACKGROUND 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 (FEV(1)) percentage of predicted normal was used as the primary efficacy outcome parameter. Forced vital capacity (FVC), forced expiratory flow at 25-75% of FVC (FEF(25)(-)(75%)), P. aeruginosa susceptibility, minimum concentration required to inhibit 90% of strains (MIC(90)), 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), FEV(1) 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 FEF(25-75%) 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 time points (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.

Topical treatment of distal active ulcerative colitis with beclomethasone dipropionate or mesalamine: a single-blind randomized controlled trial.

GOALS: Therapy for active ulcerative colitis (UC) usually involves rectal formulations of corticosteroids (CS), which are characterized by the risk of systemic steroid-related adverse effects. BACKGROUND: To compare the efficacy and safety of the topically acting CS beclomethasone dipropionate (BDP) versus mesalamine (5-ASA) in the treatment of active UC. STUDY: Patients with mild to moderate distal active UC were randomized to a 6-week treatment with BDP 3 mg enema o.d. or 5-ASA 1 g enema daily in a single-blind, multicenter, parallel-group, controlled study. The primary efficacy variable was the decrease in Disease Activity Index (DAI) score. Safety variables were adrenal function, monitoring of adverse events, vital signs, and laboratory parameters. RESULTS: A total of 217 patients were enrolled and treated with BDP (n = 111) or 5-ASA (n = 106). A significant decrease in the DAI score (P < 0.05) was observed in both treatment groups, with a clinical remission rate of 36.7% in the BDP group and of 29.2% in the 5-ASA group. Both treatments were well tolerated. No changes from baseline in morning cortisol levels were observed in the BDP group. CONCLUSIONS: BDP administered as a rectal enema over a 6-week treatment period was efficacious and safe in patients with active UC, without interference with pituitary adrenal axis.