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Background The aim of this study was to investigate safety and immunogenicity of vaccine formulations against respiratory syncytial virus (RSV) containing the stabilized prefusion conformation of RSV fusion protein (RSVPreF3). Methods This phase 1/2, randomized controlled, observer-blind study enrolled 48 young adults (YAs; aged 18–40 years) and 1005 older adults (OAs; aged 60–80 years) between January and August 2019. Participants were randomized into equally sized groups to receive 2 doses of unadjuvanted (YAs and OAs) or AS01-adjuvanted (OAs) vaccine or placebo 2 months apart. Vaccine safety and immunogenicity were assessed until 1 month (YAs) or 12 months (OAs) after second vaccination. Results The RSVPreF3 vaccines boosted humoral (RSVPreF3-specific immunoglobulin G [IgG] and RSV-A neutralizing antibody) responses, which increased in an antigen concentration-dependent manner and were highest after dose 1. Compared to prevaccination, the geometric mean frequencies of polyfunctional CD4+ T cells increased after each dose and were significantly higher in adjuvanted than unadjuvanted vaccinees. Postvaccination immune responses persisted until end of follow-up. Solicited adverse events were mostly mild to moderate and transient. Despite a higher observed reactogenicity of AS01-containing vaccines, no safety concerns were identified for any assessed formulation. Conclusions Based on safety and immunogenicity profiles, the AS01E-adjuvanted vaccine containing 120 μg of RSVPreF3 was selected for further clinical development. Clinical Trials Registration NCT03814590.

Background RSV causes respiratory infections that can lead to serious respiratory complications in older adults (OA). Presently, there is no approved vaccine to prevent RSV infections. RSVPreF3 OA is an investigational vaccine containing 120 µg RSVPreF3 and the AS01E adjuvant. Here we show safety results up to month (M) 6 post-vaccination with RSVPreF3 OA. Methods This phase 3 multi-country ongoing study (NCT04732871) enrolled adults ≥ 60 years of age over a period of 3 years. Participants were randomized (3:1:1) to receive RSVPreF3 OA with different vaccination schedules. All participants received a dose of RSVPreF3 OA on day 1. Solicited and unsolicited adverse events (AEs) were evaluated within 4 and 30 days post-vaccination. All serious AEs (SAEs) and potential immune mediated diseases (pIMDs) were collected up to M6 post-vaccination. SAEs and pIMDs related to vaccination, and fatal AEs are collected up to study end but reported here up to M6. Results Overall, 1653 participants received a dose of RSVPreF3 OA and 1618 completed the M6 follow-up. The mean age was 70.0 (±6.6) years and 54.6% were women. The most frequently reported solicited injection site reaction within 4 days post-vaccination was pain (996 participants; 60.5%, 95% confidence interval [CI]: 58.1–62.9). Twenty-two participants (1.3%, 95% CI: 0.8–2.0) reported grade 3 pain (Figure). The most reported solicited systemic reactions were myalgia (551 participants; 33.5%, 95% CI: 31.2–35.8) and fatigue (517 participants; 31.4%, 95% CI: 29.2–33.7). Twenty-five participants (1.5%) reported fever (no grade 3). Most solicited AEs were transient lasting ∼2 days and were of mild to moderate intensity. Overall, 212 (12.8%, 95% CI: 11.3–14.5) participants reported at least 1 unsolicited AE within 30 days post-vaccination. At least 1 SAE was reported by 65 participants (3.9%, 95% CI: 3.0–5.0). Seven participants (0.4%, 95% CI: 0.2–0.9) reported at least 1 pIMD. Of the SAEs and pIMDs reported, 1 event (Guillain-Barre syndrome) was considered by the investigator as related to vaccination. Fatal SAEs were reported for 6 participants; none related to vaccination. Conclusion One dose of investigational RSVPreF3 OA vaccine was well tolerated and had an acceptable safety profile in adults ≥ 60 years of age. Funding GlaxoSmithKline Biologicals SA. Disclosures Tino F. Schwarz, Prof. Dr. MD, Biogen, Merck-Serono, Pfizer, Alexion, Bavarian Nordic, Janssen-Cilag, AstraZeneca, Biontech, MSD: Grants|GlaxoSmithKline Biologicals SA: Honoraria John E. Ervin, MD, The Alliance for Multispecialty Research – KCM: Contractual agreement for conduct of study protocol Charles Andrews, MD, GlaxoSmithKline Biologicals SA: Institutional grant|Merck and Boehringer Ingelheim: Consulting fees outside of the submitted work Miguel Vicco, PhD MD, GlaxoSmithKline Biologicals SA: Employee|GlaxoSmithKline Biologicals SA: Stocks/Bonds Marc Lievens, MSc, GlaxoSmithKline Biologicals SA: Employee|GlaxoSmithKline Biologicals SA: Stocks/Bonds Céline Maréchal, PhD, GlaxoSmithKline Biologicals SA: Employee|GlaxoSmithKline Biologicals SA: Stocks/Bonds Phoebe Nakanwagi, Master’s in Biostatistics, GlaxoSmithKline Biologicals SA: Employee Veronica Hulstrøm, PhD MD, GlaxoSmithKline Biologicals SA: Employee.

The aim was to investigate safety and immunogenicity of vaccine formulations against respiratory syncytial virus (RSV) containing the stabilized prefusion conformation of RSV fusion protein (RSVPreF3).This phase I/II, randomized, controlled, observer-blind study enrolled 48 young adults (YA; 18-40 years) and 1005 older adults (OA; 60-80 years) between January and August 2019. Participants were randomized into equally sized groups to receive two doses of unadjuvanted (YA and OA) or AS01-adjuvanted (OA) vaccine or placebo two months apart. Vaccine safety and immunogenicity were assessed until one (YA) or 12 months (OA) after second vaccination.The RSVPreF3 vaccines boosted humoral (RSVPreF3-specific IgG and RSV-A neutralizing antibody) responses, which increased in an antigen-concentration-dependent manner and were highest post-dose one. Compared to pre-vaccination, the geometric mean frequencies of polyfunctional CD4+ T-cells increased after each dose and were significantly higher in adjuvanted than unadjuvanted vaccinees. Post-vaccination immune responses persisted until end of follow-up. Solicited adverse events (AEs) were mostly mild-to-moderate and transient. Despite a higher observed reactogenicity of AS01-containing vaccines, no safety concerns were identified for any assessed formulation.Based on safety and immunogenicity profiles, the AS01E-adjuvanted vaccine containing 120 μg of RSVPreF3 was selected for further clinical development.ClinicalTrials.gov NCT03814590; URL: https://clinicaltrials.gov/ct2/show/NCT03814590.

Rationale: Chronic cough remains a major and often debilitating symptom for patients with idiopathic pulmonary fibrosis (IPF). In a phase 2A study, inhaled RVT-1601 (cromolyn sodium) reduced daytime cough and 24-hour average cough counts in patients with IPF. Objectives: To determine the efficacy, safety, and optimal dose of inhaled RVT-1601 for the treatment of chronic cough in patients with IPF. Methods: In this multicenter, randomized, placebo-controlled phase 2B study, patients with IPF and chronic cough for >= 8 weeks were randomized (1:1:1:1) to receive 10, 40, and 80 mg RVT-1601 three times daily or placebo for 12 weeks. The primary endpoint was change from baseline to end of treatment in log-transformed 24-hour cough count. Key secondary endpoints were change from baseline in cough severity and cough-specific quality of life. Safety was monitored throughout the study. Measurements and Main Results: The study was prematurely terminated owing to the impact of the coronavirus disease (COVID-19) pandemic. Overall, 108 patients (mean age 71.0 years, 62.9% males) received RVT-1601 10 mg (n = 29), 40 mg (n = 25), 80 mg (n = 27), or matching placebo (n = 27); 61.1% (n = 66) completed double-blind treatment. No statistically significant difference was observed in the least-square mean change from baseline in log-transformed 24-hour average cough count, cough severity, and cough-specific quality of life score between the RVT-1601 groups and the placebo group. The mean percentage change from baseline in 24-hour average cough count was 27.7% in the placebo group. Treatment was generally well tolerated. Conclusions: Treatment with inhaled RVT-1601 (10, 40, and 80 mg three times a day) did not provide benefit over placebo for the treatment of chronic cough in patients with IPF., Respivant Sciences Inc., Supported by Respivant Sciences Inc.

International audience; BackgroundAcute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with changes in the sputum microbiome, including an increased prevalence of pathogenic bacteria. Vaccination against the most frequent bacteria identified in AECOPD might reduce exacerbation frequency. We assessed the efficacy, safety, and immunogenicity of a candidate vaccine containing surface proteins from non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) in patients with COPD.MethodsThis multicentre, randomised, observer-blinded, placebo-controlled, proof-of-concept, phase 2b trial recruited patients with stable COPD, moderate-to-very severe airflow limitation (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 2, 3, or 4), at 67 clinical sites in Belgium, Canada, France, Germany, Italy, Spain, UK, and USA. Eligible patients were aged 40–80 years and had a history of at least one moderate or severe exacerbation in the previous year. Patients were allocated (1:1) using a minimisation algorithm to receive two intramuscular injections of NTHi–Mcat vaccine or placebo 60 days apart, in addition to standard care. The allocation algorithm considered age category, number of previous exacerbations, COPD severity at study entry, and country as minimisation factors, to guarantee treatment balance within each factor. Vaccine recipients and those responsible for evaluating study endpoints were masked to group allocation. In the analysis of efficacy, the primary outcome was the rate of any moderate or severe AECOPD occurring within a 1-year period, starting 1 month after the second dose in patients who received two vaccine doses (modified total vaccinated cohort). Safety was assessed in the total vaccinated cohort. The trial is registered with ClinicalTrials.gov, number NCT03281876, and is complete.FindingsBetween Nov 27, 2017, and Nov 30, 2018, 606 adults were enrolled and included in the total vaccinated cohort (304 in the NTHi–Mcat vaccine group, 302 in the placebo group); 571 received two doses and were included in the primary efficacy analysis (279 in the NTHi–Mcat vaccine group, 292 in the placebo group). 23 participants dropped-out in the NTHi–Mcat vaccine group and 39 in the placebo group; this included 4 patients in the NTHi–Mcat vaccine group and 15 in the placebo group who withdrew from the study because of an adverse event. The primary analysis included 340 exacerbations (in follow-up time 102 123 days) in the NTHi–Mcat vaccine group and 333 (in 104 443 days) in the placebo group, with a yearly rate of moderate or severe AECOPD of 1·22 in the NTHi–Mcat vaccine group and 1·17 in the placebo group, with vaccine efficacy in reducing the yearly rate of moderate or severe AECOPD estimated to be zero (vaccine efficacy point estimate 2·26% [87% CI –18·27 to 11·58]; p=0·82). Solicited local adverse events were more frequent in the NTHi–Mcat vaccine group (216 [72%] of 301 patients) than with placebo (34 [11%] of 299 patients), and the frequency of solicited general adverse events was similar between groups (239 [79%] of 301 vs 235 [79%] of 299 patients). There was one death in the NTHi–Mcat vaccine group (acute respiratory failure, not related to vaccination) and ten in the placebo group (seven due in part to COPD or respiratory failure). There were 158 serious adverse events (89 [29%] of 304 patients) in the NTHi–Mcat vaccine group, not related to vaccination, and 214 (99 [33%] of 302 patients) in the placebo group.InterpretationNTHi–Mcat vaccine administered to patients with COPD did not show efficacy in reducing the yearly rate of moderate or severe exacerbations. No safety concerns were identified.

BackgroundSelective androgen receptor modulators (SARMs) increase muscle mass via the androgen receptor. This phase 2A trial investigated the effects of a SARM, GSK2881078, in conjunction with exercise, on leg strength in patients with chronic obstructive pulmonary disease (COPD) and impaired physical function.Methods47 postmenopausal women and 50 men with COPD (forced expiratory volume in 1 s 30%–65% predicted; short physical performance battery score: 3–11) were enrolled into a randomised double-blind, placebo control trial. Patients were randomised 1:1 to once daily placebo or oral GSK2881078 (females: 1.0 mg; males: 2.0 mg) for 13 weeks with a concurrent home-exercise programme, involving strength training and physical activity. Primary endpoints were change from baseline in leg strength at 90 days (one-repetition maximum; absolute (kg) and relative (% change)) and multiple safety outcomes. Secondary endpoints included lean body mass, physical function and patient-reported outcomes.ResultsGSK2881078 increased leg strength in men. The difference in adjusted mean change from baseline and adjusted mean percentage change from baseline between treatment and placebo were: for women, 8.0 kg (90% CI −2.5 to 18.4) and 5.2% (90% CI −4.7 to 15.0), respectively; for men, 11.8 kg (90% CI −0.5 to 24.0) and 7.0% (90% CI 0.5 to 13.6), respectively. Lean body mass increased, but no changes in patient-reported outcomes were observed. Reversible reductions in high-density lipoprotein-cholesterol and transient elevations in hepatic transaminases were the main treatment-related safety findings.ConclusionsGSK2881078 was well tolerated and short-term treatment increased leg strength, when expressed as per cent predicted, in men with COPD more than physical training alone.Trial registration numberNCT03359473.

BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known.METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo.CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).

Frail older adults are at increased risk of poor clinical outcomes. Frailty assessment is therefore important in clinical trials to understand the benefits and harms of interventions. However, consensus is lacking on how frailty should be assessed. We developed a prospectively specified index using a battery of formal tests and instruments and a retrospectively generated index using medical comorbidities and patient reported outcomes (PROs) within an adjuvanted recombinant zoster vaccine (RZV) trial (NCT02979639). For both frailty indices (FIs), a total deficit score was calculated as the accumulation of deficits and participants were categorized as non-frail, pre-frail and frail. We assessed (1) the feasibility and validity of both FIs; (2) the impact of RZV vaccine reactogenicity by frailty status on Short Form-36 [SF-36] physical functioning (PF) scores. Of 401 participants, aged ≥50 years, 236 (58.9%) were categorized non-frail, 143 (35.7%), pre-frail, and 22 (5.5%) frail using the prospective FI. Corresponding numbers for the retrospective FI were 192 (47.9%), 169 (42.1%) and 40 (10.0%), respectively. Strong concordance was observed between the frailty status assessments (P

Background Herpes zoster and its related complications are associated with significant medical burden, which negatively affects quality of life and daily functioning of the patients. The recently licensed recombinant zoster vaccine (RZV) offers high efficacy but is associated with local and systemic reactions. This study assessed the impact of RZV on the quality of life and daily functioning of participants and implications for caregivers. Methods Four hundred and one adults aged 50 years or older received single RZV doses at 0 and 2 months in this open-label, single-arm, multicenter study (NCT02979639). Change in mean SF-36 Physical Functioning score following first-dose administration, quality of life, reactogenicity, safety, productivity loss, and health care resource utilization was assessed. The current analysis was performed post-vaccine dose-1; safety follow-up will continue until 1 year post-dose-2. Results The most common solicited local symptoms were injection-site pain (77.5%), redness (23.0%), and swelling (13.3%); the most frequent solicited systemic reactions were fatigue (33.5%), headache (28.3%), and myalgia (26.8%). Grade 3 reactogenicity occurred in 9.5% of participants and was associated with a transient clinically important decrease in SF-36 Physical Functioning score (affecting activities such as walking, carrying groceries, climbing stairs) on Days 1 and 2 post-first vaccination. No clinically meaningful reductions in mean SF-36 Physical Functioning scale scores from pre- to post-RZV dose-1 were observed (mean +1.9 points, primary end point), and no overall quality-adjusted-life-year loss was recorded post-dose-1. Five participants reported lost workdays; caregiver workload was not increased. Conclusions Overall, the physical functioning and quality of life of older adults were not affected by a first RZV dose. The observed reactogenicity was consistent with previous studies.

Background: Co-Suspension™ Delivery Technology offers a novel pharmaceutical platform for inhaled drug therapy. This randomized, double-blind, placebo-controlled, single-dose study (NCT01349868) evaluated the efficacy of a range of doses for formoterol fumarate (FF) delivered using Co-Suspension delivery technology via a pressurized metered dose inhaler (MDI) versus placebo in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Secondary objectives included determination of non-inferior efficacy and systemic exposure compared with open-label Foradil® 12 μg (Foradil® Aerolizer®; formoterol fumarate dry powder inhaler). Methods: Patients received each of the 6 study treatments (FF MDI [7.2, 9.6 and 19.2μg], placebo MDI and open-label Foradil® [12 and 24µg]), separated by 3-10 days. Spirometry was performed 60 and 30 minutes prior to and at regular intervals up to 12 hours post-administration of study drug. The primary outcome measure was the change in forced expiratory volume in 1 second (FEV1) area under the curve between 0 and 12 hours (AUC0-12) relative to test day baseline. Results: A total of 50 patients were randomized to study treatment sequences. All doses of FF MDI demonstrated superiority to placebo (p

Background RSV is a common cause of respiratory acute illness in older adults (OA). We evaluated safety and reactogenicity of RSVPreF3 candidate vaccine in young adults (YA) and OA. Methods In this phase I/II, placebo-controlled, multi-country trial (NCT03814590), YA aged 18–40 years were randomized 1:1:1:1 and received 2 doses of Low-, Medium- or High-dose of RSVPreF3 non-adjuvanted vaccine, or placebo, 2 months apart. Following favorable safety evaluation, a staggered enrolment with 2 steps followed in OA aged 60–80 years, who were randomized 1:1:1:1:1:1:1:1:1:1 to receive 1 of the 9 RSV vaccine formulations containing Low-, Medium- or High-dose of RSVPreF3 non-adjuvanted or adjuvanted with AS01E or AS01B, or placebo (same schedule). Safety/reactogenicity up to 1 month post-dose 1 are reported here. Results Exposed set was comprised of 48 YA and 1005 OA. Within 7 days post-dose 1, any solicited/unsolicited adverse event (AE) ranged from 58.3% to 83.3% across YA vaccinees (placebo YA: 58.3%) and from 29.9% to 84.2% across OA vaccinees (placebo OA: 33.7%) (Fig 1). Pain was the most common solicited local AE, being reported in ≤ 58.3% of YA (placebo YA: 0.0%) and at higher rates in the adjuvanted groups (≤ 75.7%) vs non-adjuvanted groups of OA (≤ 14.1%) and placebo OA (4.1%) (Fig 2A). Of solicited general AEs, fatigue (YA: ≤ 41.7% in vaccinees vs 50.0% in placebo; OA: ≤ 48.5% in vaccinees vs 16.3% in placebo) and headache (YA: ≤ 33.3% in vaccinees vs 16.7% in placebo; OA: ≤ 27.7% in vaccinees vs 8.2% in placebo) were most commonly reported (Fig 2B), while fever ≥ 38.0 °C was observed in ≤ 3.0% of OA vaccinees (placebo OA: 0.0%). Grade 3 solicited local and general AEs were observed in OA only, with erythema (≤ 4.9% in vaccinees vs 0.0% in placebo) and fatigue (≤ 2.0% in vaccinees vs 1.0% in placebo) being most common (Fig 2). No serious AEs (SAEs) were reported in YA. A number of 11 OA reported a SAE within 1 month post-dose 1, but none was fatal or assessed as vaccine-related. No clinically significant abnormalities occurred in hematological/biochemical parameters in any group. Figure 1. Percentage of participants presenting at least one type of solicited/unsolicited adverse event (AE) within 7 days post-dose 1 Figure 2. Percentage of participants with at least one type of solicited adverse event (AE) within 7 days post-dose 1 Conclusion First dose of RSVPreF3 candidate vaccine is well tolerated. AE rates tended to be higher after AS01B-adjuvanted formulations compared to other vaccine formulations. No safety concerns were raised. Funding GlaxoSmithKline Biologicals SA Disclosures Jelena Tica, PhD, GSK group of companies (Employee, Shareholder) Javier Ruiz Guiñazú, MD MSc, GSK group of companies (Employee, Shareholder) Charles P. Andrews, MD, GSK group of companies (Scientific Research Study Investigator) Charles Fogarty, MD, GSK group of companies (Grant/Research Support) Edward Kerwin, MD, Amphastar (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)AstraZeneca (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Boehringer Ingelheim (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Chiesi (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Cipla (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)GSK group of companies (Employee, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Mylan (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Novartis (Employee, Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau)other around 40 pharmaceutical companies (Other Financial or Material Support, conducted multicenter clinical research trials)Pearl (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Sunovion (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Theravance (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau) Isabel Leroux-Roels, MD PhD, GSK group of companies (Scientific Research Study Investigator) Corinne Vandermeulen, MD PhD, GSK group of companies (Other Financial or Material Support, My university only received Grant/Research Support) Marie-Pierre David, MSc, GSK group of companies (Employee, Shareholder) Nancy Dezutter, PhD, PharmD, RPh, GSK group of companies (Employee, Shareholder) Laurence Fissette, MSc, GSK group of companies (Employee) Juliane Koch, MD, GSK group of companies (Employee, Shareholder) Narcisa Mesaros, MD, MSc, GSK group of companies (Employee)

Background This study formed part of the dose selection for a glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination formulated using novel Co-Suspension™ Delivery Technology and delivered via a metered dose inhaler (GFF MDI). The study aimed to confirm the optimal dose of GP to formulate with FF 9.6 μg in the fixed-dose combination product, GFF MDI. Methods This multicenter, randomized, double-blind, chronic-dosing, balanced incomplete block, crossover study (NCT01587079) compared five doses of GFF MDI (18/9.6, 9/9.6, 4.6/9.6, 2.4/9.6 and 1.2/9.6 μg, twice daily [BID]) with its monocomponents FF MDI 9.6 μg and GP MDI 18 μg (both BID) and open-label tiotropium (18 μg once daily) as the active control. The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV 1 AUC 0–12 ) on Day 7. Results In total, 159 patients were randomized to treatment and 132 patients (52.2% male, mean age 62.8 years) were included in the intent-to-treat population. All doses of GFF MDI (except 1.2/9.6 μg) resulted in statistically significant improvements in FEV 1 AUC 0–12 versus monocomponents and open-label tiotropium. GFF MDI 18/9.6 μg consistently showing the greatest improvement over monocomponents and open-label tiotropium. Adverse events for each GFF MDI dose were similar versus GP MDI 18 μg, FF MDI 9.6 μg and open-label tiotropium. Conclusions These findings further support selection of GP 18 μg as the optimal dose to combine with FF MDI 9.6 μg for advancement into Phase III clinical trials of GFF MDI.

Background Long-acting muscarinic antagonist/long-acting β2-agonist combinations are recommended for patients whose chronic obstructive pulmonary disease (COPD) is not managed with monotherapy. We assessed the efficacy and safety of glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination delivered via a Co-Suspension™ Delivery Technology-based metered dose inhaler (MDI) (GFF MDI). Methods This was a Phase IIb randomized, multicenter, placebo-controlled, double-blind, chronic-dosing (7 days), crossover study in patients with moderate-to-very severe COPD (NCT01085045). Treatments included GFF MDI twice daily (BID) (GP/FF 72/9.6 μg or 36/9.6 μg), GP MDI 36 μg BID, FF MDI 7.2 and 9.6 μg BID, placebo MDI, and open-label formoterol dry powder inhaler (FF DPI) 12 μg BID or tiotropium DPI 18 μg once daily. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0–12) on Day 7 relative to baseline FEV1. Secondary endpoints included pharmacokinetics and safety. Results GFF MDI 72/9.6 μg or 36/9.6 μg led to statistically significant improvements in FEV1 AUC0–12 after 7 days’ treatment versus monocomponent MDIs, placebo MDI, tiotropium, or FF DPI (p ≤ 0.0002). GFF MDI 36/9.6 μg was non-inferior to GFF MDI 72/9.6 μg and monocomponent MDIs were non-inferior to open-label comparators. Pharmacokinetic results showed glycopyrrolate and formoterol exposure were decreased following administration via fixed-dose combination versus monocomponent MDIs; however, this was not clinically meaningful. GFF MDI was well tolerated. Conclusions GFF MDI 72/9.6 μg and 36/9.6 μg BID improve lung function and are well tolerated in patients with moderate-to-very severe COPD. Trial registration ClinicalTrials.gov NCT01085045. Registered 9 March 2010. Electronic supplementary material The online version of this article (doi:10.1186/s12931-016-0491-8) contains supplementary material, which is available to authorized users.

Long-acting muscarinic antagonist/long-acting β2-agonist combinations are recommended for patients whose chronic obstructive pulmonary disease (COPD) is not managed with monotherapy. We assessed the efficacy and safety of glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination delivered via a Co-Suspension™ Delivery Technology-based metered dose inhaler (MDI) (GFF MDI). This was a Phase IIb randomized, multicenter, placebo-controlled, double-blind, chronic-dosing (7 days), crossover study in patients with moderate-to-very severe COPD ( NCT01085045 ). Treatments included GFF MDI twice daily (BID) (GP/FF 72/9.6 μg or 36/9.6 μg), GP MDI 36 μg BID, FF MDI 7.2 and 9.6 μg BID, placebo MDI, and open-label formoterol dry powder inhaler (FF DPI) 12 μg BID or tiotropium DPI 18 μg once daily. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0–12) on Day 7 relative to baseline FEV1. Secondary endpoints included pharmacokinetics and safety. GFF MDI 72/9.6 μg or 36/9.6 μg led to statistically significant improvements in FEV1 AUC0–12 after 7 days’ treatment versus monocomponent MDIs, placebo MDI, tiotropium, or FF DPI (p ≤ 0.0002). GFF MDI 36/9.6 μg was non-inferior to GFF MDI 72/9.6 μg and monocomponent MDIs were non-inferior to open-label comparators. Pharmacokinetic results showed glycopyrrolate and formoterol exposure were decreased following administration via fixed-dose combination versus monocomponent MDIs; however, this was not clinically meaningful. GFF MDI was well tolerated. GFF MDI 72/9.6 μg and 36/9.6 μg BID improve lung function and are well tolerated in patients with moderate-to-very severe COPD. ClinicalTrials.gov NCT01085045 . Registered 9 March 2010.

Background Herpes zoster (HZ) and its related complications are associated with a significant burden of illness in older adults, which negatively impacts patients’ physical functioning and quality-of-life (QoL). The recombinant zoster vaccine (RZV) shows high efficacy for the prevention of HZ in older adults but is associated with local and systemic reactions. Therefore, this study assessed the impact of RZV reactogenicity upon the physical functioning and QoL of participants. Methods 401 adults aged ≥50 years received a dose of RZV at 0 and 2 months in this open-label, single-arm, multicenter study (NCT02979639). Changes in mean SF-36 Physical Functioning score were assessed between pre-dose-1 vaccination and post-dose-1 vaccination for 7 days (primary endpoint). Decreased scores are associated with decreased physical functioning. QoL, reactogenicity and safety were also assessed. The current analysis was performed post-dose-1 vaccination of the 2-dose RZV schedule. Results No clinically meaningful reductions in overall mean SF-36 Physical Functioning scores from pre- to post-RZV dose-1 were observed (mean +1.9 points) and no overall quality-adjusted-life-year loss was recorded post-dose-1. However, grade 3 reactogenicity occurred in 9.5% of participants, and was associated with a transient, clinically-important decrease in SF-36 Physical Functioning score (impacting activities such as walking, carrying groceries, climbing stairs) on Days 1–2 post-first-vaccination (Table 1). The solicited local symptoms were pain (77.5%), redness (23.0%) and swelling (13.3%); the most frequent solicited systemic reactions were fatigue (33.5%), headache (28.3%) and myalgia (26.8%). Conclusion Overall, the physical functioning and QoL of older adults were not significantly affected by a first RZV dose. Grade 3 reactogenicity was associated with a small transient decrease in physical functioning 1–2 days post-dose-1 that resolved by Day 3 post-vaccination. Funding: GlaxoSmithKline Biologicals SA Disclosures K. E. Schmader, GSK group of companies: Investigator, Research grant. M. J. Levin, GSK group of companies: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. K. Grupping, GSK group of companies: Employee, Salary. S. Matthews, GSK group of companies: Consultant, Consulting fee. M. El Idrissi, GSK group of companies: Employee and Shareholder, Salary. L. A. Fissette, GSK group of companies: Employee, Salary. C. Fogarty, Medical Research: Investigator, Research grant. N. P. Klein, GSK group of companies: Investigator, Research support. M. Nevarez, GSK group of companies: Investigator, Investigator stipend. K. Uusinarkaus, GSK group of companies: Investigator, Research grant. L. Oostvogels, GSK group of companies: Employee, Salary. D. Curran, GSK group of companies: Employee and Shareholder, GSK shares and Salary.

NVA237 is a novel, once daily inhaled long-acting muscarinic antagonist administered via a dry powder inhaler. This study aimed to assess the 24-h bronchodilatory effect following 14 days of treatment with inhaled NVA237 in patients with mild, moderate or severe COPD. This was a randomized, double-blind, placebo-controlled, two-period, crossover, multicenter study. A total of 33 patients (≥ 40 years; smoking history of ≥ 10 pack-years) were randomized to receive NVA237 50 μg once daily followed by placebo or placebo followed by NVA237 50 μg for 14 days. Treatment periods were separated by a 7-14 day washout period. The primary variable was the mean forced expiratory volume in 1 s (FEV(1)) derived from the area under the curve (AUC) between 0 and 24 h post-dose on Day 14. The 24-h FEV(1) profiles showed a consistent bronchodilator effect for NVA237 versus placebo on Day 14. Least square (LS) mean difference in FEV(1) AUC(0-24 h) values between NVA237 and placebo was 163 mL (P < 0.001). There were significant increases in mean FEV(1) AUC(0-12 h) (LS mean difference 165 mL, P = 0.001) and FEV(1) AUC(12-24 h) (161 mL, P < 0.001) versus placebo. NVA237 significantly improved peak FEV(1) (by 208 mL, P < 0.001) and trough FEV(1) (by 154 mL, P = 0.003) versus placebo on Day 14. NVA237 was well tolerated; all adverse events were mild or moderate in intensity and not related to study drug. NVA237 50 μg once daily was well tolerated and showed significant and sustained 24-h bronchodilation in patients with COPD.

Objective: The aim of this study was to compare the efficacy and safety of nebulized arformoterol 15 μg/2 mL twice daily (ARF15 BID) and 30 μg/4 mL once daily (ARF30 QD) in subjects with moderate to severe chronic obstructive pulmonary disease (COPD). Methods: In this single-dose, multicenter, randomized, modified-blind, 2-way crossover study, subjects aged ≥45 years with moderate to severe COPD, a forced expiratory volume in 1 second (FEV 1 ) ≥0.7 L, and ≤65% predicted FEV1, and a FEV 1 :forced vital capacity ratio ≤70% were randomly assigned to receive single-day treatment with ARF15 BID or ARF30 QD in random order, separated by a 5 ± 2-day washout period. The primary efficacy end point was time-normalized AUC of FEV 1 from baseline (hour 0) to 24 hours (FEV 1 AUC 0–24 ). Secondary efficacy end points were time-normalized AUC of FEV 1 from baseline to 12 hours (FEV 1 AUC 0–12 ) and from 12 to 24 hours (FEV 1 AUC 12–24 ), and FEV 1 at 24 hours after administration of the morning dose (trough FEV 1 ). Equivalence of the 2 therapies was assessed by comparing the 90% CI value for the difference of the least squares mean (LSM) to a study-specific predefined equivalence range for change in FEV 1 AUC 0–24 of −0.07 to 0.07 L. Results: A total of 33 subjects were enrolled (20 men, 13 women; mean [SD] age, 64.5 [8.8] years; 15 subjects received ARF15 BID first; 18 received ARF30 QD first). ARF15 BID and ARF30 QD were associated with similar improvements from baseline in (FEV 1 AUC 0–24 , LSM 0.15 and 0.16 L, respectively; Δ, 0.01 L; 90% CI, −0.02 to 0.04) and trough FEV 1 (LSM, 0.15 and 0.12 L, respectively; Δ, −0.03 L; 90% CI, −0.09 to 0.03). FEV 1 AUC 0–12 was improved more with ARF30 QD than ARF15 BID (Δ, 0.06 L; 90% CI, 0.04 to 0.09), and FEV 1 AUC 12–24 was improved more with ARF15 BID than ARF30 Qd (Δ, −0.04 L; 90% CI, −0.08 to 0.01). The 90% CI for FEV 1 AUC 0–24 for the treatment difference between ARF15 BID and ARF30 QD was within the prespecified range of −0.07 to 0.07 L, indicating that both treatments resulted in equivalent FEV 1 AUC 0–24 values. Conclusions: In these subjects with moderate to severe COPD, single-day administrations of ARF15 BID or ARF30 QD were associated with FEV 1 responses over a period of 24 hours that were considered equivalent per the protocol definition employed in the present study. FEV1 improvement over 12 hours was greater for ARF30 QD after the morning dose and for ARF15 BID after the evening dose. ClinicalTrials.gov Identifier: NCT00571428

Objective We sought to compare daptomycin with ceftriaxone for the treatment of patients with community-acquired pneumonia (CAP). Methods Two phase-3 randomized, double-blind trials that enrolled adult patients hospitalized with CAP were conducted. Patients received intravenous daptomycin (4 mg/kg) or ceftriaxone (2 g) once daily for 5-14 days. Aztreonam could be added for patients with gram-negative infections. Clinical responses at the test-of-cure visit among patients in the intent-to-treat and clinically evaluable populations were the primary efficacy end points. Results After combining data from the trials, the intent-to-treat population included 413 daptomycin-treated patients and 421 ceftriaxone-treated patients, and the clinically evaluable population included 369 daptomycin-treated patients and 371 ceftriaxone-treated patients. In the intent-to-treat population, the clinical cure rate among daptomycin-treated patients with CAP was 70.9%, compared with 77.4% among ceftriaxone-treated patients (95% confidence interval for the difference between cure rates, -12.4% to -0.6%). In the clinically evaluable population, the clinical cure rate was lower among daptomycin-treated patients (79.4%) than among ceftriaxone-treated patients (87.9%; 95% confidence interval for the difference between cure rates, -13.8% to -3.2%). A posthoc analysis revealed that, among those who had received up to 24 h of prior effective therapy, cure rates were similar among daptomycin-treated (90.7%) and ceftriaxone-treated patients (88.0%; 95% confidence interval for the difference between cure rates, -6.1% to 11.5%). Conclusions Daptomycin is not effective for the treatment of CAP, including infections caused by Streptococcus pneumoniae and Staphylococcus aureus. The observation that as little as 24 h of prior effective therapy may impact clinical outcome suggests that trials to evaluate CAP treatment may need to exclude patients who have received any potentially effective therapy before enrollment.

Chronic obstructive pulmonary disease (COPD) is a progressive, smoking-related, inflammatory lung disease in which tumor necrosis factor-alpha is overexpressed and has been suggested to play a pathogenic role.To determine if infliximab, an anti-TNF-alpha antibody, results in clinical benefit and has an acceptable safety profile in patients with moderate to severe COPD.In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study, subjects with moderate to severe COPD received infliximab (3 mg/kg [n = 78] or 5 mg/kg [n = 79]) or placebo (n = 77) at Weeks 0, 2, 6, 12, 18, and 24. Efficacy, health status, and safety were assessed through Week 44.Infliximab was generally well tolerated, but showed no treatment benefit as measured by the primary endpoint, Chronic Respiratory Questionnaire total score. Similarly, there was no change in secondary measures, including prebronchodilator FEV(1), 6-min walk distance, SF-36 physical score, transition dyspnea index, or moderate-to-severe COPD exacerbations. Post hoc analysis revealed that subjects who were younger or cachectic showed improvement in the 6-min walk distance. Malignancies were diagnosed during the study in 9 of 157 infliximab-treated subjects versus 1 of 77 placebo-treated subjects. No opportunistic infections were observed, and there were no differences in the occurrence of antibiotic-requiring infections, although the incidence of pneumonia was higher in infliximab-treated subjects. No infection-related mortality was observed. Higher proportions of infliximab-treated subjects discontinued the study agent due to adverse events (20-27%) than did placebo-treated subjects (9%).Subjects with moderate to severe COPD did not benefit from treatment with infliximab. Although not statistically significant, more cases of cancer and pneumonia were observed in the infliximab-treated subjects. The impact of infliximab on malignancy risk in patients with COPD needs to be further elucidated.

SummaryThis retrospective analysis was performed to determine the clinical and bacteriologic efficacy of the ketolide antibacterial telithromycin in patients with community-acquired pneumonia (CAP) with pneumococcal bacteremia. Patients ⩾13 years old with radiologically confirmed CAP and a positive blood culture for Streptococcus pneumoniae at screening were analyzed from eight multicenter Phase III/IV clinical trials. In four open-label, non-comparative studies, patients received telithromycin 800mg once daily for 7–10 days. In four randomized, controlled, double-blind, comparative studies, patients received telithromycin 800mg once daily for 5–10 days or a comparator antimicrobial (amoxicillin 1000mg three times daily, clarithromycin 500mg twice daily, or trovafloxacin 200mg once daily) for 7–10 days. In total, 118 patients (telithromycin, 94/1061 [8.9%]; comparator, 24/244 [9.8%]) had documented pneumococcal bacteremia. Those who were treated with telithromycin achieved a clinical cure rate of 90.2% (74/82, per-protocol population); S. pneumoniae was eradicated in 77/82 (93.9%) bacteremic patients who received telithromycin and 15/19 (78.9%) comparator-treated patients. Clinical cure was also observed among telithromycin-treated bacteremic patients who were infected with penicillin- or erythromycin-resistant strains of S. pneumoniae (5/7 and 8/10, respectively). In conclusion, telithromycin achieves high clinical and bacteriologic cure rates in CAP patients with pneumococcal bacteremia.

Study objectives To demonstrate equivalence in the clinical efficacy of telithromycin vs clarithromycin treatment of outpatients with acute exacerbations of chronic bronchitis (AECB), and to compare the tolerability and respiratory-related health-care resource utilization associated with these treatment regimens. Design and patients A randomized, double-blind, multicenter, clinical study was conducted at 105 centers in 14 countries. Adult outpatients (age ≥ 30 years) received oral telithromycin, 800 mg qd for 5 days (n = 270), or oral clarithromycin, 500 mg bid for 10 days (n = 282), for the treatment of AECB. Clinical and bacteriologic outcomes were assessed at the posttherapy/test-of-cure (TOC) visit (days 17 to 24; per-protocol population). Health-care resource utilization data were collected for each patient by investigators blinded to study medication up to the late posttherapy visit (days 31 to 36). Results Clinical cure rates at the posttherapy/TOC visit were comparable between the groups (telithromycin, 193 of 225 patients [85.8%]; clarithromycin, 206 of 231 patients [89.2%]); bacteriologic outcome was satisfactory for 59 of 72 telithromycin-treated patients (81.9%) vs 63 of 76 clarithromycin-treated patients (82.9%). Health-care resource utilization assessed up to the late posttherapy visit was lower in the telithromycin treatment group than the clarithromycin treatment group, with significantly fewer hospitalizations for respiratory-related causes (one hospitalization vs eight hospitalizations for a total of 4 inpatient days vs 39 inpatient days, respectively), significantly fewer AECB-related emergency department visits (0 vs 8), and fewer unscheduled outpatient visits (11 vs 18). Fewer telithromycin-treated patients reported days lost from work (21 of 91 patients [23.1%]; 133 days) compared with those receiving clarithromycin (30 of 98 patients [30.6%]; 141 days). Telithromycin was well tolerated; adverse events considered possibly related to study medication were reported by 61 of 269 patients (22.7%) and 100 of 280 patients (35.7%) receiving telithromycin and clarithromycin, respectively. Conclusions In this study, 5-day telithromycin treatment was as effective and well tolerated as 10-day clarithromycin treatment for patients with AECB, and was associated with a reduced utilization of health-care resources.

Pooled data from three randomized, double-blind, multi- centre studies evaluated the efficacy and tolerability of telithromycin 800 mg once daily for 5 days vs. standard comparators (10-day amoxicillin-clavulanate 500/125 mg three times daily, clarithromycin 500 mg or cefuroxime axetil 500 mg twice daily) in the outpatient treatment for acute exacerbations of chronic bronchitis. Per-protocol clinical cure rates at post-therapy/test of cure (days 17-24) were 86.0 and 85.8% for telithromycin and comparators, respectively, and 79.1 and 78.7%, respectively, at late post-therapy (days 31-36). Clinical cure rates were comparable for patients at increased risk, including those of > or =65 years and those with severe infection or significant airway obstruction (telithromycin, > or =77.1%; comparators, > or =75.0%). Telithromycin was well tolerated. Most adverse events considered possibly related to study medication were gastrointestinal and of mild intensity. In conclusion, 5-day telithromycin therapy is as effective and well tolerated as 10-day treatment with standard comparators.

Background: The efficacy of oral telithromycin was assessed in patients with community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae with reduced susceptibility to penicillin and/or erythromycin. Methods: Patients with CAP who had received telithromycin 800 mg once daily for 5 or 7–10 days (n = 2,289) in eight phase III clinical trials, or telithromycin 800 mg once daily for 7 days (n = 50) in a phase II study were included in this pooled analysis. Patients with S. pneumoniae as the cause of infection were identified, with particular focus on those infected with strains with reduced susceptibility to penicillin (intermediate, minimal inhibitory concentration (MIC) 0.12–1.0 mg/l; resistant, MIC ≧2.0 mg/l) and/or resistance to erythromycin (MIC ≧1.0 mg/l). Per-protocol clinical and bacteriological outcomes were assessed 7–14 days post-therapy in the phase III studies, and at 7–21 days post-therapy or at the end of therapy in the phase II study. Results: Of the 327 telithromycin-treated patients with S. pneumoniae infection, 61 (19%) were infected with strains with reduced susceptibility to penicillin and/or erythromycin. Clinical cure and bacterial eradication rates in these patients were 91.8% (56/61) and 93.4% (57/61), respectively. Corresponding clinical cure and bacterial eradication rates overall for all isolates of pneumococci were 94.5% (309/327) and 96.0% (314/327), respectively. All isolates with reduced susceptibility to penicillin and/or erythromycin were susceptible to telithromycin (MIC ≤1.0 mg/l). Conclusion: These results indicate that telithromycin is an effective oral antibacterial for the treatment of CAP caused by pneumococci with reduced susceptibility to penicillin and/or erythromycin.

The efficacy of telithromycin has been assessed in six Phase III studies involving adults with mild to moderate community-acquired pneumonia (CAP) with a degree of severity compatible with oral therapy.Patients received telithromycin 800mg once daily for 7–10 days in three open-label studies (n=870) and three randomized, double-blind, comparator-controlled studies (n=503). Comparator antibacterials were amoxicillin 1000mg three-times daily, clarithromycin 500mg twice daily and trovafloxacin 200mg once daily. Clinical and bacteriological outcomes were assessed 7–14 days post-therapy.Among telithromycin-treated patients, per-protocol clinical cure rates were 93.1 and 91.0% for the open-label and comparative studies, respectively. Telithromycin treatment was as effective as the comparator agents. High eradication and clinical cure rates were observed for infections caused by key pathogens: Streptococcus pneumoniae including isolates resistant to penicillin G and/or erythromycin A (95.4%), Haemophilus influenzae (89.5%) and Moraxella catarrhalis (90%). Telithromycin was also highly effective in patients with infections caused by atypical and/or intracellular pathogens and those at increased risk of morbidity. Telithromycin was generally well tolerated.Telithromycin 800 mg once daily for 7–10 days offers a convenient and well-tolerated first-line oral therapy for the empirical treatment of mild to moderate CAP.

Background: Therapy of nosocomial pneumonia is usually empiric and includes ≥ 1 broad-spectrum antimicrobial agent. When considering the use of fluoroquinolones in these difficult-to-treat infections—in which drug delivery to the site of infection may be impaired or organisms with higher minimum inhibitory concentrations may be present—an agent should be chosen whose pharmacodynamics ensure maximal drug exposure. Use of the 750-mg dose of levofloxacin should enhance therapeutic benefit in patients with nosocomial pneumonia. Objective: The goal of this study was to compare the efficacy and safety of levofloxacin 750 mg and imipenem/cilastatin followed by ciprofloxacin in adult patients with nosocomial pneumonia. Methods: This was a multicenter, prospective, randomized, open-label trial conducted in North America. Patients were randomly assigned to 1 of 2 treatment arms: levofloxacin 750 mg QD given IV and then orally for 7 to 15 days or imipenem/cilastatin 500 mg to 1 g IV every 6 to 8 hours, followed by oral ciprofloxacin 750 mg every 12 hours for 7 to 15 days. Adjunctive antibacterial therapy was mandatory in patients with documented or suspected Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus infection. The primary predefined outcome measure was the clinical response ( cure, improvement, failure, or unable to evaluate ) in microbiologically evaluable patients 3 to 15 days after the end of therapy. Results: The study enrolled 438 adult patients (315 men, 123 women; mean [SD] age, 55.7 [20.04] years). Two hundred twenty patients received levofloxacin, and 218 received the comparator regimen. Demographic and baseline clinical characteristics were similar in the intent-to-treat and clinically evaluable populations. In patients evaluable for microbiologic efficacy, clinical success ( cure or improvement ) was achieved in 58.1% (5493) of patients who received levofloxacin, compared with 60.6% (5794) of patients who received the comparator regimen (95% CI, −12.0 to 17.2). Similar clinical results were seen in patients evaluable for clinical efficacy and in the intent-to-treat population. In the 187 patients evaluable for microbiologic efficacy, eradication was achieved in 66.7% (6293) of patients receiving levofloxacin and 60.6% (5794) of patients receiving the comparator regimen (95% CI, −20.3 to 8.3). Conclusion: In this study, levofloxacin was at least as effective and was as well tolerated as imipenem/cilastatin followed by ciprofloxacin in adult patients with nosocomial pneumonia, as demonstrated by comparable clinical and microbiologic success rates.

Background: Cefditoren pivoxil is a broad-spectrum cephalosporin that is approved for the treatment of pharyngitis, acute exacerbations of chronic bronchitis, and skin and skin-structure infections. Objective: This study was conducted to examine the efficacy and tolerability of cefditoren in the treatment of community-acquired pneumonia (CAP). Amoxicillin/clavulanate was chosen as a comparator because of its established efficacy and general acceptance as a standard of care in CAP. Methods: This multicenter, prospective, randomized, investigator-blinded, parallel-group trial compared oral cefditoren 200 and 400 mg BID with oral amoxicillin/clavulanate 875/125 mg BID for 14 days in adult outpatients with CAP. Results: Eight hundred two patients (404 men, 398 women; mean age, 50 years; age range, 12–93 years) with CAP were enrolled. Comparable clinical cure rates were observed among evaluable patients in all treatment groups at both the posttreatment and follow-up visits: 88.0% (125/142) for cefditoren 200 mg, 89.9% (143/159) for cefditore 400 mg, and 90.3% (130/144) for amoxicillin/clavulanate at the posttreatment visit, and 86.5% (128/148), 86.8% (138/159), and 87.8% (129/147) for the respective groups at the follow-up visit. Of 82 Streptococcus pneumoniae strains isolated before treatment, 22 (26.8%) had reduced susceptibility to penicillin, 12 (14.6%) of them penicillin resistant. Overall eradication rates at the posttreatment visit for pathogens isolated from microbiologically evaluable patients were 84.0%, 88.6%, and 82.6% for cefditoren 200 mg, cefditoren 400 mg, and amoxicillin/clavulanate, respectively. In the respective treatment groups, 80.6%, 88.6%, and 88.0% of Haemophilus influenzae strains and 95.0%, 96.2%, and 89.5% of S pneumoniae strains were eradicated. The rates of resolution of or improvement in clinical signs and symptoms were comparable between treatment groups. The treatment regimens were well tolerated, with 4.9%, 3.0%, and 5.2% of patients in the respective treatment groups requiring discontinuation of study drug due to an adverse event. Conclusions: In this study in adult outpatients with CAP, both doses of cefditoren demonstrated equivalence to amoxicillin/clavulanate based on rates of clinical and microbiologic cure. All 3 regimens were effective in resolving or improving the clinical signs and symptoms of CAP. Both cefditoren and amoxicillin/clavulanate were well tolerated.

SummaryBackgroundOlodaterol is a novel long-acting β2-agonist (LABA) with ≥24-h duration of action in preclinical and clinical studies.ObjectiveThis Phase II, multicentre, randomised, double-blind, placebo-controlled, parallel-group, dose-finding study evaluated four doses of once-daily olodaterol over 4 weeks in patients with chronic obstructive pulmonary disease (COPD), based on efficacy, safety and pharmacokinetic parameters.MethodsPatients received olodaterol inhalation solution or placebo via Respimat® Soft Mist™ inhaler once daily for 4 weeks. Pulmonary function testing was performed pre-dose (trough) and up to 3 or 6 h post-dose, depending on visit. Primary end point was change from baseline in trough forced expiratory volume in 1 s (FEV1) after 4 weeks' treatment. Secondary end points included change from baseline in peak FEV1 and FEV1 area under the curve from 0 to 6 h.Results405 patients with COPD were randomised and assigned to treatment. Mean baseline post-bronchodilator FEV1 was 1.50 L (54% predicted). All olodaterol doses provided statistically significant increases in trough FEV1 compared to placebo (2 μg: 0.061 L [p = 0.0233]; 5 μg: 0.097 L [p = 0.0003]; 10 μg: 0.123 L [p

Bronchodilator medications are central to the symptomatic management of chronic obstructive pulmonary disease (COPD). Metered-dose inhalers (MDIs) are the most commonly used devices to deliver treatment to patients with COPD and asthma, comprising approximately 70% of bronchodilator prescriptions. Proprietary porous-particle technology permits the formulation of long-acting muscarinic antagonists, long-acting β2-agonists, and a combination of both in hydrofluoroalkane (HFA) MDIs, providing a solution to formulation challenges inherent to the development of HFA MDIs, which have contributed to the development of dry-powder inhalers. In this randomized, double-blind, 4-period, 6-treatment, placebo- and active-controlled, multicenter, crossover study, 4 ascending single doses of a proprietary glycopyrronium (GP) MDI were evaluated compared with Placebo MDI and open-label tiotropium (TIO) in study patients with COPD. Thirty-three study patients were enrolled and received single-dose administration of 4 of the 6 treatments (Placebo MDI, TIO 18 μg, or GP MDI at 14.4, 28.8, 57.6, and 115.2 μg ex-actuator) with an interval of 1 to 3 weeks between doses. The primary efficacy endpoint was peak change in forced expiratory volume in 1 second (FEV1). All 4 doses of GP MDI showed statistically superior efficacy compared with Placebo MDI for peak FEV1 (differences of 146 to 248 mL; P

Kenneth R Chapman1, Charles M Fogarty2, Clare Peckitt3, Cheryl Lassen3, Dalal Jadayel3, Juergen Dederichs4, Mukul Dalvi4, Benjamin Kramer5On behalf of the INDEED (indacaterol: handling and preference evaluation of the Breezhaler device in COPD) study investigators1University of Toronto, Toronto, Canada; 2Spartanburg Medical Research, Spartanburg, SC, United States; 3Novartis Horsham Research Centre, Horsham, West Sussex, UK; 4Novartis Pharma AG, Basel, Switzerland; 5Novartis Pharmaceuticals, East Hanover, NJ, USAAbstract: For optimal efficacy, an inhaler should deliver doses consistently and be easy for patients to use with minimal instruction. The delivery characteristics, patients’ correct use, and preference of two single-dose dry powder inhalers (Breezhaler and HandiHaler) were evaluated in two complementary studies. The first study examined aerodynamic particle size distribution, using inhalation profiles of seven patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The second was an open-label, two-period, 7-day crossover study, evaluating use of the inhalers with placebo capsules by 82 patients with mild to severe COPD. Patients’ correct use of the inhalers was assessed after reading written instructions on Day 1, and after training and 7 days of daily use. Patients’ preference was assessed after completion of both study periods. Patient inhalation profiles showed average peak inspiratory flows of 72 L/minute through Breezhaler and 36 L/minute through HandiHaler. For Breezhaler and HandiHaler, fine particle fractions were 27% and 10%, respectively. In the second study, correct use of Breezhaler and HandiHaler was achieved by >77% of patients for any step after 7 days; 61% of patients showed an overall preference for Breezhaler and 31% for HandiHaler (P = 0.01). Breezhaler is a low-resistance inhaler suitable for use by patients with a range of disease severities. Most patients used both inhalers correctly after 7 days, but more patients showed an overall preference for the Breezhaler compared with the HandiHaler. These are important factors for optimum dose delivery and successful COPD management.Keywords: Breezhaler, HandiHaler, COPD, use, preference, dose delivery

Indacaterol is the first once-daily, long-acting inhaled beta(2)-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease (COPD).To demonstrate greater efficacy of indacaterol versus placebo on FEV(1) at 24 hours post dose (trough) after 12 weeks, to compare efficacy with placebo and tiotropium, and to evaluate safety and tolerability over 26 weeks.Patients with moderate-to-severe COPD were randomized to double-blind indacaterol 150 or 300 microg or placebo, or open-label tiotropium 18 microg, all once daily, for 26 weeks. The primary efficacy outcome was trough FEV(1) at 12 weeks. Additional analyses (not adjusted for multiplicity) included transition dyspnea index (TDI), health status (St George's Respiratory Questionnaire [SGRQ]), and exacerbations. Serum potassium, blood glucose, and QTc interval were measured.A total of 1,683 patients (age, 63.3 yr; post-bronchodilator FEV(1), 56% predicted; FEV(1)/FVC, 0.53) were randomized to the four treatment arms. Trough FEV(1) at Week 12 increased versus placebo by 180 ml with both indacaterol doses and by 140 ml with tiotropium (all P0.001 vs. placebo). At Week 26, for indacaterol 150/300 microg, respectively, versus placebo, TDI increased (1.00/1.18, P0.001) and SGRQ total score decreased (-3.3/-2.4, P0.01); corresponding results with tiotropium were 0.87 (P0.001) for TDI and (-1.0, P = not significant) for SGRQ total score. The incidence of adverse events, low serum potassium, high blood glucose, and prolonged QTc interval was similar across treatments.Indacaterol was an effective once-daily bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for patients with COPD. Clinical trial registered with clinicaltrials.gov (NCT 00463567).

Three patients with bacteremic pneumonia caused by multidrug-resistant Streptococcus pneumoniae were treated unsuccessfully with azithromycin. One S. pneumoniae isolate carried a mef determinant for an efflux pump; a second isolate had an erm determinant. All 3 patients were successfully treated with levofloxacin, an antipneumococcal fluoroquinolone.

Formoterol fumarate is a long-acting β2-agonist that is an effective bronchodilator for the maintenance management of patients with chronic obstructive pulmonary disease. The safety profile of the newly developed nebulized formoterol was evaluated over a twelve-month period in an open-label, active-control study. After completing a twelve-week double-blind double-dummy period, 569 subjects with chronic obstructive pulmonary disease entered an open-label extension study and received twice-daily 20 µg formoterol fumarate inhalation solution for nebulization (FFIS) or 12 µg formoterol fumarate dry powder inhalation (FA) for 52 weeks. Most of the FFIS-treated subjects (86%) completed at least six months of open-label treatment with over 90% compliance, comparable to the FA group (88%). Results of safety monitoring for adverse events, laboratory values, and cardiac changes were similar between treatment groups. Three hundred forty (73%) of FFIS-treated subjects and 83 (78%) of FA-treated subjects experienced an adverse event over the course of the study, the majority of which were mild to moderate and considered unrelated to treatment. COPD exacerbation occurred in 15.8% of FFIS-treated and 17.9% of FA-treated subjects. Deaths, serious adverse events, and discontinuations for adverse events occurred in 1.3, 16.2, and 5.4% of the nebulized group versus 1.9, 17.9, and 7.5% of the inhaled group, respectively. There were no clinically important changes from baseline in laboratory tests, including serum potassium and glucose, or vital signs and no treatment-related increases in cardiac arrhythmias, heart rate, or QTc prolongation. We conclude that nebulized formoterol fumarate twice daily is well tolerated over long-term treatment in moderate-to-severe COPD subjects and has a similar safety profile to the DPI formulation.

The objectives of this study were to determine the effect of single and repeat dosing with oral ondansetron, a 5-HT3-specific receptor blocker, on the degree and duration of bronchodilation induced by inhaled ipratropium bromide in patients with COPD. Five clinics and university medical centers in four countries participated in the study; 47 patients with COPD were randomized to treatment; 44 completed all treatments. Patients had a baseline (pre-bronchodilator) FEV1>1L and post-bronchodilator (200mcg salbutamol) FEV1

The efficacy of oral telithromycin 800mg once daily for 7 days was evaluated in a multicentre, multinational study in patients with community-acquired pneumonia caused by Streptococcus pneumoniae resistant to penicillin and/or erythromycin. Per-protocol clinical and bacteriological outcomes were assessed 10–17 days post-therapy. Of the 129 patients with S. pneumoniae infection, 16 were infected with strains resistant to penicillin and/or erythromycin. Fifteen of these 16 patients (93.8%) were assessed as clinically and bacteriologically cured at the post-therapy visit.

Summary Objectives A pooled analysis of 14 Phase III studies was performed to establish the clinical and bacteriologic efficacy of telithromycin 800mg once daily in the treatment of pneumococcal community-acquired respiratory tract infections (RTIs). Methods Data were examined from 5534adult/adolescent patients with community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), or acute bacterial sinusitis, who had received telithromycin for 5–10 days or a comparator antibacterial. Results Streptococcus pneumoniae was identified in 704/2060 (34.2%) bacteriologically evaluable patients. The respective per-protocol clinical cure rates for telithromycin and comparators were 94.3% and 90.0% (CAP); 81.5% and 78.9% (AECB); 90.1% and 87.5% (acute sinusitis); 92.7% and 87.6% (all indications). Clinical cure rates were 28/34 (82.4%) and 5/7, respectively, for penicillin-resistant infections, and 44/52 (84.6%) and 11/14, respectively, for erythromycin-resistant infections. Of 82 patients with pneumococcal bacteremia, 74 (90.2%) were clinically cured after telithromycin treatment, including 5/7 and 8/10 with penicillin- or erythromycin-resistant strains, respectively. Adverse events considered possibly related to study medication were reported by 1071/4045 (26.5%) telithromycin and 505/1715 (29.4%) comparator recipients. These events were generally of mild/moderate severity, and mainly gastrointestinal in nature. Conclusions As S. pneumoniae is the leading bacterial cause of community-acquired RTIs, and antibacterial resistance is increasing among this species, these findings support the use of telithromycin as first-line therapy in this setting.

To assess the effect of megestrol acetate (MA), a progestational appetite stimulant commonly used in patients with AIDS and cancer, on body weight and composition, respiratory muscle strength, arterial blood gas levels, and subjective perceptions in COPD patients.Prospective, double-blind, randomized, placebo-controlled trial conducted on an outpatient basis at 18 sites.Underweight (95% ideal body weight) COPD patientsor = 40 years old.Either MA, 800 mg/d oral suspension, or placebo at a 1:1 ratio for 8 weeks.Of 145 randomized patients (63% men), 128 patients completed the trial. Body weight increased by 3.2 kg in the MA group and 0.7 kg in the placebo group (p0.001). Anthropometric and dual-energy radiograph absorptiometry assessments confirmed that weight gain was mainly fat. Spirometry and maximal voluntary ventilation showed no significant changes from baseline in either group, and the difference in the change in maximum inspiratory pressure between groups was not significant. The 6-min walk distances did not differ statistically between groups at week 2 and week 4, but were greater in the placebo group at week 8 (p = 0.012). Consistent with the known ability of MA to stimulate ventilation, PaCO(2) decreased (4.6 mm Hg, p0.001) and PaO(2) increased (2.8 mm Hg, p0.04) in the MA group. Questionnaires revealed that body image and appetite improved in the MA group but not the placebo group. Adverse event frequency and type were similar in both groups, but cortisol and testosterone (in men) levels decreased substantially in the MA group.We conclude that MA safely increased appetite and body weight, stimulated ventilation, and improved body image in underweight COPD patients, but did not improve respiratory muscle function or exercise tolerance.

Background: The ideal duration of antibiotic therapy for acute exacerbation of chronic bronchitis (AECB) remains controversial. Objective: This study compared short-course, 5-day gatifloxacin treatment with standard 10-day clarithromycin treatment in patients with AECB; 7-day gatifloxacin therapy was a secondary comparator. Methods: This was a multicenter, prospective, randomized, double-blind study in which adult outpatients with AECB were randomized to 1 of 3 treatment groups: 5 days of gatifloxacin, 7 days of gatifloxacin, or 10 days of clarithromycin. Clinical cure and microbiologic eradication rates were determined 7 to 14 days after the completion of antibiotic treatment. Results: A total of 527 patients with AECB were enrolled and treated with study drug (174, gatifloxacin 5-day; 175, gatifloxacin 7-day; 178, clarithromycin 10-day). Most patients (82%) had type 1 (severe) exacerbations, and a bacterial pathogen was isolated from pretreatment sputum samples in 59% of patients. The overall clinical cure rates among clinically evaluable patients were comparable between groups: 89% (135/151 patients) in the gatifloxacin 5-day group; 88% (136/154) in the gatifloxacin 7-day group; and 89% (145/163) in the clarithromycin 10-day group. The 95% CIs for the differences in response rates were −6.1 to 7.0 for gatifloxacin 5-day versus clarithromycin, −8.9 to 5.0 for gatifloxacin 7-day versus clarithromycin, and −5.5 to 8.0 for gatifloxacin 5-day versus 7-day. These observations did not appear to be affected by use of corticosteroids or smoking status, type of exacerbation, or duration of current episode. The microbiologic eradication rate among microbiologically evaluable pathogens was > 90% in all treatment groups. No clinically meaningful differences were noted in the incidence of drug-related adverse events. Conclusion: Short-course, 5-day gatifloxacin therapy in patients with AECB resulted in clinical cure and microbiologic eradication rates comparable to those of standard 7- and 10-day therapies.