Bimagrumab vs Optimized Standard of Care for Treatment of Sarcopenia in Community-Dwelling Older Adults: A Randomized Clinical Trial.

Importance: The potential benefit of novel skeletal muscle anabolic agents to improve physical function in people with sarcopenia and other muscle wasting diseases is unknown. Objective: To confirm the safety and efficacy of bimagrumab plus the new standard of care on skeletal muscle mass, strength, and physical function compared with standard of care alone in community-dwelling older adults with sarcopenia. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial was conducted at 38 sites in 13 countries among community-dwelling men and women aged 70 years and older meeting gait speed and skeletal muscle criteria for sarcopenia. The study was conducted from December 2014 to June 2018, and analyses were conducted from August to November 2018. Interventions: Bimagrumab 700 mg or placebo monthly for 6 months with adequate diet and home-based exercise. Main Outcomes and Measures: The primary outcome was the change in Short Physical Performance Battery (SPPB) score after 24 weeks of treatment. Secondary outcomes included 6-minute walk distance, usual gait speed, handgrip strength, lean body mass, fat body mass, and standard safety parameters. Results: A total of 180 participants were recruited, with 113 randomized to bimagrumab and 67 randomized to placebo. Among these, 159 participants (88.3%; mean [SD] age, 79.1 [5.3] years; 109 [60.6%] women) completed the study. The mean SPPB score increased by a mean of 1.34 (95% CI, 0.90 to 1.77) with bimagrumab vs 1.03 (95% CI, 0.53 to 1.52) with placebo (P = .13); 6-minute walk distance increased by a mean of 24.60 (95% CI, 7.65 to 41.56) m with bimagrumab vs 14.30 (95% CI, -4.64 to 33.23) m with placebo (P = .16); and gait speed increased by a mean of 0.14 (95% CI, 0.09 to 0.18) m/s with bimagrumab vs 0.11 (95% CI, 0.05 to 0.16) m/s with placebo (P = .16). Bimagrumab was safe and well-tolerated and increased lean body mass by 7% (95% CI, 6% to 8%) vs 1% (95% CI, 0% to 2%) with placebo, resulting in difference of 6% (95% CI, 4% to 7%) (P < .001). Conclusions and Relevance: This randomized clinical trial found no significant difference between participants treated with bimagrumab vs placebo among older adults with sarcopenia who had 6 months of adequate nutrition and light exercise, with physical function improving in both groups. Bimagrumab treatment was safe, well-tolerated, increased lean body mass, and decreased fat body mass. The effects of sarcopenia, an increasing cause of disability in older adults, can be reduced with proper diet and exercise. Trial Registration: ClinicalTrials.gov Identifier: NCT02333331; EudraCT number: 2014-003482-25.

Delivery characteristics and patients' handling of two single-dose dry-powder inhalers used in COPD.

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.

Telithromycin in the treatment of pneumococcal community-acquired respiratory tract infections: a review.

OBJECTIVES: A pooled analysis of 14 Phase III studies was performed to establish the clinical and bacteriologic efficacy of telithromycin 800 mg once daily in the treatment of pneumococcal community-acquired respiratory tract infections (RTIs). METHODS: Data were examined from 5534 adult/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.

Efficacy and safety of telithromycin 800 mg once daily for 7 days in community-acquired pneumonia: an open-label, multicenter study.

BACKGROUND: Community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality throughout the world. Telithromycin (a new ketolide) has shown good in vitro activity against the key causative pathogens of CAP, including S pneumoniae resistant to penicillin and/or macrolides. METHODS: The efficacy and safety of telithromycin 800 mg orally once daily for 7 days in the treatment of CAP were assessed in an open-label, multicenter study of 442 adults. RESULTS: Of 149 microbiologically evaluable patients, 57 (9 bacteremic) had Streptococcus pneumoniae. Of the 57 S pneumoniae pathogens isolated in these patients, 9 (2 bacteremic) were penicillin- or erythromycin-resistant; all 57 were susceptible to telithromycin and were eradicated. Other pathogens and their eradication rates were: Haemophilus influenzae (96%), Moraxella catarrhalis (100%), Staphylococcus aureus (80%), and Legionella spp. (100%). The overall bacteriologic eradication rate was 91.9%. Of the 357 clinically evaluable patients, clinical cure was achieved in 332 (93%). In the 430 patients evaluable for safety, the most common drug-related adverse events were diarrhea (8.1%) and nausea (5.8%). CONCLUSION: Telithromycin 800 mg once daily for 7 days is an effective and well-tolerated oral monotherapy and offers a new treatment option for CAP patients, including those with resistant S pneumoniae.

Safety and efficacy of sequential i.v. to p.o. moxifloxacin versus conventional combination therapies for the treatment of community-acquired pneumonia in patients requiring initial i.v. therapy.

To compare the efficacy of sequential i.v. to p.o. moxifloxacin with ceftriaxone +/- azithromycin +/- metronidazole for the treatment of patients with community acquired pneumonia (CAP), a multi-centered, prospective, randomized, open label study was performed. CAP patients were randomized to moxifloxacin (400 mg/d-at least one i.v. dose) or ceftriaxone (at least one dose of 2 g i.v. q.d. followed by cefuroxime 500 mg p.o. b.i.d.) +/- azithromycin, +/- metronidazole (cephalosporin/macrolide control: CMC). The primary endpoint was clinical response at test-of-cure (TOC) visit. Bacteriological response at TOC was the secondary endpoint. Clinical cure was found in 83.3% (90/108) of moxifloxacin patients and 79.6% (90/113) of control patients. Microbiological responses were 81.8% (18/22) for moxifloxacin and 60.7% (17/28) for CMC patients. Drug-related adverse events occurred in 18.0% of moxifloxacin and 16% of CMC patients. It is concluded that i.v. to p.o. moxifloxacin is as effective as CMC for treatment of CAP and is a reliable alternative antimicrobial therapy.

Community-acquired respiratory tract infections caused by resistant pneumococci: clinical and bacteriological efficacy of the ketolide telithromycin.

The incidence of community-acquired respiratory tract infections caused by Streptococcus pneumoniae exhibiting antibacterial resistance has increased dramatically in recent years. Telithromycin is the first of a new class of antibacterials, the ketolides, which have been developed specifically to provide effective treatment for these infections. Data were analysed from 3935 patients who had participated in one Japanese Phase II study and 11 US/global Phase III studies in three indications: community-acquired pneumonia, acute exacerbations of chronic bronchitis or acute sinusitis. Patients received either telithromycin 800 mg once daily or a comparator antibacterial. S. pneumoniae isolates considered to be causative for infection were tested for susceptibility to penicillin G and erythromycin A. In per-protocol analyses, telithromycin showed a high level of clinical efficacy against S. pneumoniae, with clinical cure rates of 92.8% for all isolates, 91.7% for those with reduced susceptibility to penicillin G and 86.0% for those with reduced susceptibility to erythromycin A. Bacterial eradication rates were consistent with the clinical outcomes. High rates of clinical cure and bacterial eradication were also observed for infections caused by isolates demonstrating high-level resistance to erythro-mycin A [MICs >/= 512 mg/L: 100% (13/13) clinical cure, 100% (13/13) bacterial eradication]. These results support the use of telithromycin as a first-line oral therapy for the treatment of community-acquired respiratory tract infections caused by S. pneumoniae with reduced susceptibility to penicillin G and erythromycin A.

A comparison of cefditoren pivoxil and amoxicillin/ clavulanate in the treatment of community-acquired pneumonia: a multicenter, prospective, randomized, investigator-blinded, parallel-group study.

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 cefditoren 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.