Suptavumab for the Prevention of Medically Attended Respiratory Syncytial Virus Infection in Preterm Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of childhood medically attended respiratory infection (MARI). METHODS: We conducted a randomized, double-blind, placebo-controlled phase 3 trial in 1154 preterm infants of 1 or 2 doses of suptavumab, a human monoclonal antibody that can bind and block a conserved epitope on RSV A and B subtypes, for the prevention of RSV MARI. The primary endpoint was proportion of subjects with RSV-confirmed hospitalizations or outpatient lower respiratory tract infection (LRTI). RESULTS: There were no significant differences between primary endpoint rates (8.1%, placebo; 7.7%, 1-dose; 9.3%, 2-dose). Suptavumab prevented RSV A infections (relative risks, .38; 95% confidence interval [CI], .14-1.05 in the 1-dose group and .39 [95% CI, .14-1.07] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .0499), while increasing the rate of RSV B infections (relative risk 1.36 [95% CI, .73-2.56] in the 1-dose group and 1.69 [95% CI, .92-3.08] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .12). Sequenced RSV isolates demonstrated no suptavumab epitope changes in RSV A isolates, while all RSV B isolates had 2-amino acid substitution in the suptavumab epitope that led to loss of neutralization activity. Treatment emergent adverse events were balanced across treatment groups. CONCLUSIONS: Suptavumab did not reduce overall RSV hospitalizations or outpatient LRTI because of a newly circulating mutant strain of RSV B. Genetic variation in circulating RSV strains will continue to challenge prevention efforts. CLINICAL TRIALS REGISTRATION: NCT02325791.

Pharmacokinetic and tolerability profiles of tobramycin nebuliser solution 300 mg/4 ml administered by PARI eFlow(®) rapid and PARI LC Plus(®) nebulisers in cystic fibrosis patients.

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 C(max) and AUC(0-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 C(max) and AUC(0-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.

Disease burden and risk factors for hospitalizations associated with rotavirus infection among children in New York State, 1989 through 2000.

OBJECTIVES: To examine trends in hospitalizations for pediatric diarrhea, ascertain the disease burden and risk factors for hospitalizations associated with rotavirus and assess the accuracy of coding for rotavirus hospitalizations in New York State. METHODS: For 1989 through 2000, data were obtained for all diarrhea-associated hospitalizations in New York State among children 1 month through 4 years of age. Characteristics of patients hospitalized with rotavirus were compared with those for hospitalizations with diarrhea from other causes. Medical charts coded as rotavirus diarrhea were reviewed for patients who were discharged during 1997 to determine whether these diagnoses were supported with laboratory results. RESULTS: Diarrhea was reported as a discharge diagnosis in approximately 13% of all hospitalizations for an annual incidence of 83 per 10 000 children. Viruses were the most common etiologic agents reported. Since 1993, when a rotavirus-specific code was introduced, rotavirus infection was coded for 8.7% of all diarrhea-associated hospitalizations. A total of 136 patients with diarrhea died during their hospitalization (hospital fatality rate, 1.6 per 1000), and the 12 deaths among patients with rotavirus had a distinct winter pattern. During 1997 only 46% of the hospitals reporting diarrhea in children used the specific code for rotavirus, and 12% of hospitals reported rotavirus in >30% of all diarrhea-associated hospitalizations. Infants <4 months of age were more likely than older children to be nosocomially infected with rotavirus and had a higher proportion of congenital malformations. CONCLUSION: In New York State diarrhea is a common hospital discharge diagnosis and contributes approximately 13% of all hospitalizations among children <5 years of age. When hospitals with maximum recording were used as a reference point, >30% of diarrhea hospitalizations were recorded as likely the result of rotavirus.

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.

CHF5074 reduces biomarkers of neuroinflammation in patients with mild cognitive impairment: a 12-week, double-blind, placebo-controlled study.

As neuroinflammation is an early event in the pathogenesis of Alzheimer' s disease, new selective antiinflammatory drugs could lead to promising preventive strategies. We evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of CHF5074, a new microglial modulator, in a 12-week, double-blind, placebo-controlled, parallel groups, ascending dose study involving 96 MCI patients. Subjects were allocated into three successive study cohorts to receive ascending, titrated doses of CHF5074 (200, 400 or 600 mg/day) or placebo. Vital signs, cardiac safety, neuropsychological performance and safety clinical laboratory parameters were assessed on all subjects. Plasma samples were collected throughout the study for measuring drug concentrations, soluble CD40 ligand (sCD40L) and TNF-α. At the end of treatment, cerebrospinal fluid (CSF) samples were optionally collected after the last dose to measure drug levels, ß- amyloid1-42 (Aß42), tau, phospho-tau181, sCD40L and TNF-α. Ten patients did not complete the study: one in the placebo group (consent withdrawn), two in the 200-mg/day treatment group (consent withdrawn and unable to comply) and seven in the 400-mg/day treatment group (five AEs, one consent withdrawn and one unable to comply). The most frequent treatment-emergent adverse events were diarrhea, dizziness and back pain. There were no clinically significant treatmentrelated clinical laboratory, vital sign or ECG abnormalities. CHF5074 total body clearance depended by gender, age and glomerular filtration rate. CHF5074 CSF concentrations increased in a dose-dependent manner. At the end of treatment, mean sCD40L and TNF-α levels in CSF were found to be inversely related to the CHF5074 dose (p=0.037 and p=0.001, respectively). Plasma levels of sCD40L in the 600-mg/day group were significantly lower than those measured in the placebo group (p=0.010). No significant differences between treatment groups were found in neuropsychological tests but a positive dose-response trend was found on executive function in APOE4 carriers. This study shows that CHF5074 is well tolerated in MCI patients after a 12-week titrated treatment up to 600 mg/day and dose-dependently affects central nervous system biomarkers of neuroinflammation.