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To investigate the efficacy and safety of nebulized poractant alfa (at 200 and 400 mg/kg doses) delivered in combination with nasal continuous positive airway pressure compared with nasal continuous positive airway pressure alone in premature infants with diagnosed respiratory distress syndrome.This randomized, controlled, multinational study was conducted in infants at 28In total, 129 infants were randomized. No significant differences were observed for the primary outcome: 24 (57%), 20 (49%), and 25 (58%) infants received endotracheal surfactant and/or mechanical ventilation within 72 hours in the poractant alfa 200 mg/kg, poractant alfa 400 mg/kg, and nasal continuous positive airway pressure groups, respectively. Similarly, secondary respiratory outcomes did not differ among groups. Enrollment was halted early owing to a change in the benefit-risk balance of the intervention. Nebulized poractant alfa was well-tolerated and safe, and no serious adverse events were related to the study treatment.The intervention did not decrease the likelihood of respiratory failure within the first 72 hours of life.ClinicalTrials.gov: NCT03235986.

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 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 .

Fabrizia Mariotti,1 Mirco Govoni,1 Germano Lucci,1 Debora Santoro,1 Marie Anna Nandeuil2 1Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy; 2Global Clinical Development, Chiesi S.A.S., Courbevoie, France Purpose: The purpose of this study was to evaluate safety, tolerability, and pharmacokinetics (PK) of CHF6001, an inhaled phosphodiesterase-4 inhibitor.Materials and methods: Two healthy volunteer, randomized, double-blind, placebo-controlled studies were conducted. In each, Part 1 evaluated single ascending doses, with PK sampling up to 48 hours post-dose; Part 2 evaluated multiple ascending doses (Study 1, 7 days; Study 2, 14 days), with PK sampling up to 24 hours post-dose on first and last day of each period. In Study 1, treatments were administered via single-dose dry-powder inhaler (SDDPI; Aerolizer): Part 1, 20, 100, 200, 400, 800, 1,600, and 2,000 µg or placebo; Part 2, 100, 300, 600, 1,200, and 1,600 µg or placebo once daily (OD). In Study 2, treatments were administered via multi-dose dry-powder inhaler (MDDPI; NEXThaler): Part 1, 2,400, 4,000, and 4,800 µg or placebo; Part 2, 1,200, 2,000, or 2,400 µg twice daily (BID) or placebo. Modeling and simulation then compared OD and BID dosing via MDDPI.Results: There was a clear correlation between CHF6001 dose and plasma concentration, following single and multiple doses and using SDDPI and MDDPI. CHF6001 plasma concentration area under the curve (AUC) was dose proportional, with steady state slopes of the fitted line of 0.95 (90% CI: 0.86, 1.04) for AUC0–24 h in Study 1, and 0.85 (90% CI: 0.38, 1.32) for AUC0–12 h in Study 2. Bioavailability was ~30% higher with MDDPI than SDDPI. The PK simulation confirmed dose proportionality; the same total daily dose OD or BID via MDDPI resulted in similar 24 hours exposure, with BID dosing providing smaller fluctuation and lower maximum concentration. CHF6001 was well tolerated with no relationship between dose and adverse events.Conclusion: CHF6001 demonstrated a good safety profile. There was a clear dose proportionality for systemic exposure, with higher bioavailability via MDDPI, suggesting that the MDDPI provides better pulmonary drug deposition. BID dosing was associated with a better exposure profile. Keywords: healthy volunteers, chronic obstructive pulmonary disease, phosphodiesterase-4 inhibitors, pharmacokinetics

Aim Less invasive surfactant administration (LISA) has been shown to decrease the risk of death and bronchopulmonary dysplasia in preterm neonates. The LISAcath is the first catheter to be specifically developed for LISA, and we compared the clinical impressions of neonatologists using the LISAcath and the commonly used Angiocath in a simulated setting. Methods This was a multinational, multicentre study, conducted in October 2016, which involved 39 neonatologists who were recruited by employees of the sponsor from large, well‐recognised neonatal intensive care units across Europe. LISA was not the standard of care in these units in Austria, Belgium, Poland, Spain and the United Kingdom at the time of the study. After training, participants simulated LISA on a neonatal manikin, once with the LISAcath and once with Angiocath, then answered a 10‐item questionnaire. Results The responses to nine of 10 questions showed that 67‐95% of the respondents preferred the LISAcath to the Angiocath, with most of the remainder indicating no preference. The only exception was the luer connection question, with two‐thirds expressing no preference. The LISAcath was considered potentially safer by 33 of 39 participants, with no votes for the Angiocath. Conclusion Overall, neonatologists preferred using the LISAcath rather than the Angiocath on a neonatal manikin.

Introduction Le CHF6001 est un nouvel inhibiteur de PDE4, puissant et selectif administre a l’aide d’un inhalateur de poudre seche (NEXThaler®), qui a demontre sa securite et sa bonne tolerance chez le sujet sain [1] et chez les patients asthmatiques [2] . L’objectif de cette etude de phase IIb etait d’evaluer l’efficacite et la tolerance de differentes doses de CHF6001 chez des patients presentant une BPCO moderee a severe. Methodes Etude randomisee multicentrique en double aveugle, double placebo en groupes paralleles versus placebo et traitement actif d’une duree de 24 semaines chez des patients presentant une BPCO symptomatique moderee a severe (VEMS post-BD/CVF Resultats Au total, 1130 patients ont ete randomises et 92 % ont termine l’etude. Aucune difference n’a ete observee avec les differentes doses du CHF6001 par rapport au placebo en termes du VEMS pre-dose (critere principal). Des ameliorations cliniquement significatives ont ete observees entre S0 et S24 pour le score focal TDI (moyenne ajustee de 1,28 a 1,54 ; p Conclusion L’administration de differentes doses de CHF6001 en add-on a un traitement d’entretien par formoterol a permis de reduire le taux d’exacerbations moderees a severes versus placebo chez des patients BPCO avec une bronchite chronique au terme de 24 semaines de traitement.

Summary 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 (FEV1) 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 FEV1 % 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), FEV1 (% 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. Pediatr Pulmonol. 2014; 49:1076–1089. © 2014 Wiley Periodicals, Inc.

Background Tobramycin nebuliser solution (TNS) is indicated for maintenance therapy in cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa (PA) infections. Adherence to recommended therapy in CF has always been a challenge and new generation nebulisers are increasingly used “off label” to reduce the time required for inhalation, potentially improving patient compliance. Methods In this open-label, randomised, multi-centre, two-period crossover study, 27 CF patients with PA infection received TNS 300 mg/4 mL (TNS4) via the PARI eFlow® rapid or PARI LC Plus® nebuliser twice daily for 28 days in two study periods separated by a 4-week washout. The pharmacokinetic profile in plasma and sputum were determined after single and multiple dose administration on Day 1 and Day 28, respectively. Nebulisation times and general safety and tolerability profiles were evaluated throughout the study. Results Plasma tobramycin pharmacokinetic profiles were similar for the eFlow and LC Plus nebulisers both on Day 1 and Day 28. After multiple dose administration for 28 days, the eFlow/LC Plus ratio of geometric means for plasma Cmax and AUC0-t, were 85.32 (90% CI, 61.24–118.86) and 87.44 (90% CI, 64.87–117.87), respectively. Despite the high variability, sputum tobramycin Cmax and AUC0-t for the eFlow on Day 28 tended to be higher than for the LC Plus (90% CI for the ratio, 86.11–226.45 and 81.81–236.71), respectively. Nebulisation times were significantly shorter for the eFlow with a median time for nebulisation of 5 min in comparison to 13 min for the LC Plus. Safety data confirmed a favourable safety profile for TNS4, with the majority of the findings being related to the underlying CF disease. Conclusions Plasma and sputum pharmacokinetic data in CF patients with chronic PA infection support comparable pulmonary delivery and safety of TNS4 administered using different nebulisers, with a significantly shorter nebulisation time for the eFlow.

BACKGROUND: CHF 6001 is under development for the treatment of chronic obstructive pulmonary disease (COPD) and asthma. Good safety and tolerability of CHF 6001 was demonstrated up to 2000µg doses in healthy volunteers (HV) (1) . The aim of this study was to assess safety and tolerability of higher doses. METHODS: Three doses (2400, 4000 and 4800µg) of CHF 6001 were administered using NEXThaler ® , a proprietary multidose reservoir dry powder inhaler (DPI) to one cohort of 12 HV (9 active: 3 placebo) according to a randomized, double-blind, single-dose, placebo-controlled ascending design and to three cohorts of 12 HV each (9 active: 3 placebo), as a 2-week twice-daily, sequential dose escalation, parallel-group design. RESULTS: CHF 6001 was well tolerated. No serious adverse events (AEs) were reported. Limited gastrointestinal (GI) AEs were reported: diarrhoea (n=1), abdominal pain (n=1), flatulence (n=1) and oral pain (n=1) out of 27 HV on CHF 6001 versus none out of 9 HV on placebo. CHF 6001 showed dose proportional systemic exposure (C max and AUC). Mean half-life (t 1/2 ) ranged from 40 to 49 h, the steady state was reached within 8 days of treatment with 6 fold higher exposure compared to the first administration. CONCLUSIONS: CHF 6001 was safe and tolerated at daily doses up to 4800µg for 14 days in HV. No significant GI intolerance was observed. CHF 6001 showed linear pharmacokinetics in the tested dose range. (1) O. Esposito et al. – ERS 2013 Poster Presentation.

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

Francesco Faraldi,1 Vincenzo Papa,2 Debora Santoro,2 Daria Rasà,2 Annamaria L Mazza,2 Maria M Rabbione,1 Simona Russo21Department of Ophthalmology III, Presidio Ospedaliero Oftalmico, Torino, Italy; 2SIFI SpA, Catania, ItalyPurpose: The aim of this study was to investigate the effects of an ophthalmic gel containing sodium hyaluronate and xanthan gum in addition to the antibiotic netilmicin in the management of traumatic corneal abrasions.Patients and methods: Patients with traumatic corneal abrasions were randomly treated as follows: Group A (n = 20) with an occlusive patching for 12 hours plus one drop of an eye gel containing 0.15% sodium hyaluronate, 1% xanthan gum and 0.3% netilmicin qid for 5 days; and Group B (n = 20) with an occlusive patching for 2–3 days plus one application of 0.3% netilmicin ophthalmic ointment qid for 5 days. All patients were evaluated after the third and seventh day by slit-lamp examination, fluorescein staining, and corneal defect photograph in order to assess corneal re-epithelialization. Conjunctival hyperaemia, lid oedema, subjective symptoms of discomfort, and conjunctival swabs were also evaluated.Results: No statistically significant difference was observed between the groups in terms of the extent of corneal healing after 3 days of treatment. Both treatments were also highly effective in decreasing the erosion score and the conjunctival hyperemia (P < 0.0001, P < 0.005, respectively) without any significant difference between the two types of treatment. Subjective symptoms of discomfort and conjunctival swabs were also evaluated.Conclusion: In the management of traumatic corneal abrasions, the administration of an eye gel containing sodium hyaluronate and xanthan gum is able to reduce the length of occlusive patching. In addition, the presence of netilmicin guarantees good antibiotic prophylaxis during the wound repair process.Keywords: netilmicin, xanthan gum, wound healing, patching, corneal abrasion