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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

Background This study evaluated the efficacy, safety and tolerability of the novel inhaled phosphodiesterase-4 inhibitor CHF6001 added-on to formoterol in patients with chronic obstructive pulmonary disease (COPD). Methods Randomised, double-blind, placebo- and active-controlled, parallel-group study. Eligible patients had symptomatic COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) 30–70% predicted, and history of ≥1 moderate/severe exacerbation. Patients were randomised to extrafine CHF6001 400, 800, 1200 or 1600 μg twice daily (BID), budesonide, or placebo for 24 weeks. Primary objectives: To investigate CHF6001 dose-response for pre-dose FEV1 after 12 weeks, and to identify the optimal dose. Moderate-to-severe exacerbations were a secondary endpoint. Results Of 1130 patients randomised, 91.9% completed. Changes from baseline in pre-dose FEV1 at Week 12 were small in all groups (including budesonide), with no CHF6001 dose-response, and no significant treatment–placebo differences. For moderate-to-severe exacerbations, CHF6001 rate reductions versus placebo were 13–28% (non-significant). In post-hoc analyses, CHF6001 effects were larger in patients with a chronic bronchitis phenotype (rate reductions versus placebo 24–37%; non-significant), and were further increased in patients with chronic bronchitis and eosinophil count ≥150 cells/μL (49–73%, statistically significant for CHF6001 800 and 1600 μg BID). CHF6001 was well tolerated with no safety signal (including in terms of gastrointestinal adverse events). Conclusions CHF6001 had no effect in the primary lung function analysis, although was well-tolerated with no gastrointestinal adverse event signal. Post-hoc analyses focused on exacerbation risk indicate specific patient subgroups who may receive particular benefit from CHF6001. Trial registration ClinicalTrials.gov (NCT02986321). Registered 8 Dec 2016.

Patients with COPD who have higher eosinophil numbers in the airways and peripheral blood demonstrate a greater clinical response to inhaled corticosteroids (ICS) [1–3]. Furthermore, the effect of the oral phosphodiesterase-4 (PDE4) inhibitor roflumilast on exacerbations in severe COPD patients with chronic bronchitis, who are treated with ICS and long-acting bronchodilators, also appears to be greater at higher blood eosinophil counts [4]. The mechanisms responsible for these differential drug effects remain to be defined, but may relate to increased type-2 inflammation and/or decreased presence of colonising airway bacteria in COPD patients with more eosinophils [5, 6], leading to different responses to anti-inflammatory drugs. An association between blood and sputum eosinophils has been observed in some, but not all studies [7–12]. Accurate sputum eosinophil count measurement requires good quality samples to make cytospins where eosinophils can be clearly counted; variable quality of sputum samples, particularly in multicentre studies, will affect the ability to show a relationship with blood eosinophil counts., PDE4 inhibition reduces sputum eosinophils in those COPD patients with higher eosinophil counts. This evidence supports an effect of PDE4 inhibitors on eosinophilic inflammation. https://bit.ly/3airXw7

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 .

Background: Caffeine citrate has been approved in China for the management of apnea of prematurity. This clinical trial was conducted as a condition of regulatory approval. The aim was to confirm the efficacy of caffeine citrate in the treatment of recurrent intermittent hypoxia and bradycardia in preterm newborns with primary apnea.Objectives: The primary outcome was the change from baseline in the number of apnea events after loading dose administration of caffeine citrate. Secondary efficacy outcomes included the change from baseline in apnea events after 2 and 4 weeks of maintenance doses.Methods: This was a multicenter, prospective longitudinal open-label, single-arm study. Neonates who had experienced at least four apnea events during a 24 h period received a loading dose of caffeine citrate 20 mg/kg; those who required additional maintenance doses received 5 mg/kg/day (titrated up to 10 mg/kg/day in case of insufficient response). The number of apnea events was recorded for 6–12 h prior to the loading dose (baseline), and for 12 h post-dose, following the loading dose and at Weeks 2 and 4 (during maintenance).Results: A total of 247 neonates received the loading dose, who had a significant reduction from baseline of 3.9 events (p < 0.001) in the mean number of apnea events. The subset of neonates who required maintenance doses also had significant reductions in the number of events at all visits (p < 0.001 for all). A total of 79.4% of participants had at least one adverse event, but only one non-serious and no serious events were considered related to treatment.Conclusions: In this large, prospective, open-label study, premature infants with a history of apnea who received caffeine citrate were significantly less likely to experience further apnea events.

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.

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 (FiO 2 ) ≥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 FiO 2 after dosing and need for poractant-alfa rescue. Results Rapid and sustained improvements in FiO 2 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 viralbronchiolitis 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.

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.

CHF6001 is an inhaled phosphodiesterase 4 (PDE4) inhibitor in development for the treatment of obstructive lung diseases. The efficacy and safety of CHF6001 were investigated in a double blind, placebo controlled, 3-way cross-over study using the allergen challenge model. Thirty-six atopic asthmatics who were not taking inhaled corticosteroids and who demonstrated a late asthmatic response (LAR) to inhaled allergen at screening were randomised to receive CHF6001 400 μg or 1200 μg or placebo administered once a day using a dry powder inhaler. The three treatment periods were 9 days; allergen challenges were performed on day 9 and induced sputum was obtained after 10 h from challenge. Washout periods between treatments were up to 5 weeks. Both CHF6001 doses significantly attenuated the LAR; the primary endpoint analysis showed that CHF6001 400 μg and 1200 μg caused reductions of 19.7% (p = 0.015) and 28.2% (p < 0.001) respectively of the weighted FEV1 AUC4-10h compared with placebo. The difference between the CHF6001 doses was not statistically significant (p = 0.223). Compared with placebo, CHF6001 caused greater reduction in sputum eosinophil counts, although these changes were not statistically significant. CHF6001 was well tolerated, with similar numbers of adverse events in each treatment period. This inhaled PDE4 inhibitor has the potential to provide clinical benefits in patients with atopic asthma.

Francesco Faraldi,1 Vincenzo Papa,2 Daria Rasà,2 Debora Santoro,2 Simona Russo21Struttura Complessa Oculistica III, Presidio Ospedaliero Oftalmico, Torino, Italy; 2Medical Affairs, SIFI SpA, Aci S Antonio, Catania, ItalyPurpose: To compare the efficacy and safety of 0.1% dexamethasone/0.3% netilmicin (Netildex), with that of 0.1% dexamethasone/0.3% tobramycin (Tobradex) in the treatment of external ocular inflammation requiring antibiotic therapy.Methods: In this randomized, double-blind study, 139 subjects with conjunctival inflammation associated with signs of ocular infection were treated with Netildex (n = 71) or Tobradex (n = 68) four times daily for 6 days. The primary efficacy analysis was based on the percentage of patients with at least a 50% decrease in conjunctival hyperemia at the endpoint visit (Day 6 [± 1]) with respect to baseline (responder rate). An equivalence margin of 20% was set for this study. A follow-up visit was performed at Day 14 (± 1). Other efficacy parameters were: conjunctival edema, conjunctival discharge, lid hyperemia, lid edema, presence of ocular infection, and symptoms of ocular discomfort. Safety evaluations included intraocular pressure, visual acuity, and adverse events.Results: At Day 6, a decrease of conjunctival hyperemia was observed in 87.3% and 90.9% of the patients treated with Netildex and Tobradex, respectively. The 95% confidence interval for the difference between groups (–15.3 ÷ 8.0) satisfied the equivalence hypothesis. Subjects treated with Netildex had a better control of lid hyperemia (P = 0.016), tearing (P = 0.001), burning (P = 0.007), and stinging (P = 0.004). No adverse reactions were observed during the study except one case of keratitis in the Tobradex group.Conclusion: Netildex was as effective and safe as Tobradex in reducing signs and symptoms in patients with conjunctival inflammation when ocular infection was suspected.Keywords: conjunctivitis, dexamethasone, netilmicin, red eye

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