Pharmacokinetics and Pharmacodynamics of Bimagrumab (BYM338).

Background: Bimagrumab is a human monoclonal antibody binding to the activin type II receptor with therapeutic potential in conditions of muscle wasting and obesity. This phase I study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of various dose regimens of bimagrumab and routes of administration in healthy older adults.

Methods: This was a randomized, double-blind, placebo-controlled, parallel-arm, multiple-dose study in older adult men and women (aged ≥ 70 years, body mass index [BMI] 18-34 kg/m) with stable health and diet.

Test-retest reliability of wireless inertial-sensor derived measurements of knee joint kinematics.

Advances in sensor technology have provided an opportunity to measure gait characteristics using body-worn inertial measurement units (IMUs). Whilst research investigating the validity of IMUs in reporting gait characteristics is extensive, research investigating the reliability of IMUs is limited. This study aimed to investigate the inter-session reliability of wireless IMU derived measures of gait (i.

An Automatic Foot and Shank IMU Synchronization Algorithm: Proof-of-concept.

When using wearable sensors for measurement and analysis of human performance, it is often necessary to integrate and synchronise data from separate sensor systems. This paper describes a synchronization technique between IMUs attached to the shanks and insoles attached at the feet and aims to solve the need to compute the ankle joint angle, which relies on synchronized sensor data. This will additionally enable concurrent analysis using gait kinematic and kinetic features.

Description of the Method for Evaluating Digital Endpoints in Alzheimer Disease Study: Protocol for an Exploratory, Cross-sectional Study.

Background: More sensitive and less burdensome efficacy end points are urgently needed to improve the effectiveness of clinical drug development for Alzheimer disease (AD). Although conventional end points lack sensitivity, digital technologies hold promise for amplifying the detection of treatment signals and capturing cognitive anomalies at earlier disease stages. Using digital technologies and combining several test modalities allow for the collection of richer information about cognitive and functional status, which is not ascertainable via conventional paper-and-pencil tests.

Digital endpoints for self-administered home-based functional assessment in pediatric Friedreich's ataxia.

Background: Friedreich's ataxia is an inherited, progressive, neurodegenerative disease that typically begins in childhood. Disease severity is commonly assessed with rating scales, such as the modified Friedreich's Ataxia Rating Scale, which are usually administered in the clinic by a neurology specialist.

Objective: This study evaluated the utility of home-based, self-administered digital endpoints in children with Friedreich's ataxia and unaffected controls and their relationship to standard clinical rating scales.

Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity: A Phase 2 Randomized Clinical Trial.

Importance: Antibody blockade of activin type II receptor (ActRII) signaling stimulates skeletal muscle growth. Previous clinical studies suggest that ActRII inhibition with the monoclonal antibody bimagrumab also promotes excess adipose tissue loss and improves insulin resistance.

Objective: To evaluate the efficacy and safety of bimagrumab on body composition and glycemic control in adults with type 2 diabetes and overweight and obesity.

Safety and pharmacokinetics of bimagrumab in healthy older and obese adults with body composition changes in the older cohort.

Background: Bimagrumab prevents activity of myostatin and other negative regulators of skeletal muscle mass. This randomized double-blind, placebo-controlled study investigated safety, pharmacokinetics (PK), and pharmacodynamics of bimagrumab in healthy older and obese adults.

Methods: A cohort of older adults (aged 70-85 years) received single intravenous infusions of bimagrumab 30 mg/kg (n = 6) or 3 mg/kg (n = 6) or placebo (n = 4) and was followed for 20 weeks.

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.

An Open-Label Study of the Impact of Hepatic Impairment on the Pharmacokinetics and Safety of Single Oral and Intravenous Doses of Omadacycline.

Omadacycline is a once-daily oral or intravenous (i.v.) aminomethylcycline antibiotic approved in the United States for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) in adults.

Effects of Interleukin-1β Inhibition on Incident Hip and Knee Replacement : Exploratory Analyses From a Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Osteoarthritis is a common inflammatory disorder with no disease-modifying therapies. Whether inhibition of interleukin-1β (IL-1β) can reduce the consequences of large joint osteoarthritis is unclear.

Objective: To determine whether IL-1β inhibition with canakinumab reduces incident total hip or knee replacement (THR/TKR).

Continuous Digital Monitoring of Walking Speed in Frail Elderly Patients: Noninterventional Validation Study and Longitudinal Clinical Trial.

Background: Digital technologies and advanced analytics have drastically improved our ability to capture and interpret health-relevant data from patients. However, only limited data and results have been published that demonstrate accuracy in target indications, real-world feasibility, or the validity and value of these novel approaches.

Objective: This study aimed to establish accuracy, feasibility, and validity of continuous digital monitoring of walking speed in frail, elderly patients with sarcopenia and to create an open source repository of raw, derived, and reference data as a resource for the community.

Activin Type II Receptor Blockade for Treatment of Muscle Depletion in Chronic Obstructive Pulmonary Disease. A Randomized Trial.

Rationale: Bimagrumab is a fully human monoclonal antibody that blocks the activin type II receptors, preventing the activity of myostatin and other negative skeletal muscle regulators.

Objectives: To assess the effects of bimagrumab on skeletal muscle mass and function in patients with chronic obstructive pulmonary disease (COPD) and reduced skeletal muscle mass.

Methods: Sixty-seven patients with COPD (mean FEV, 1.

Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophy.

Background: Patients experiencing disuse atrophy report acute loss of skeletal muscle mass which subsequently leads to loss of strength and physical capacity. In such patients, especially the elderly, complete recovery remains a challenge even with improved nutrition and resistance exercise. This study aimed to explore the clinical potential of bimagrumab, a human monoclonal antibody targeting the activin type II receptor, for the recovery of skeletal muscle volume from disuse atrophy using an experimental model of lower extremity immobilization.

Treatment of Sarcopenia with Bimagrumab: Results from a Phase II, Randomized, Controlled, Proof-of-Concept Study.

Objectives: To assess the effects of bimagrumab on skeletal muscle mass and function in older adults with sarcopenia and mobility limitations.

Design: A 24-week, randomized, double-blind, placebo-controlled, parallel-arm, proof-of-concept study.

Setting: Five centers in the United States.

Randomized, Open-Label Study of the Pharmacokinetics and Safety of Oral and Intravenous Administration of Omadacycline to Healthy Subjects.

Omadacycline is a first-in-class aminomethylcycline antibiotic with microbiological activity against Gram-positive and Gram-negative aerobes and anaerobes and atypical bacteria that is being developed for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). The bioavailability of a phase 3 tablet formulation relative to that obtained via intravenous (i.v.

The effects of CYP3A4 induction and inhibition on the pharmacokinetics of alisporivir in humans.

In vitro data suggest that alisporivir is a substrate and inhibitor of CYP3A4 and P-gp. Hence, the potential for drug-drug interactions when alisporivir is co-administered with CYP3A4 and/or P-gp inhibitors such as ketoconazole, azithromycin and CYP3A4 inducers such as rifampin were evaluated in three separate clinical studies. Co-administration with ketoconazole (a strong CYP3A4 inhibitor) increased the Cmax , AUC and terminal elimination half-life of alisporivir by approximately two-, eight- ,and threefold, respectively.

mTOR inhibition improves immune function in the elderly.

Inhibition of the mammalian target of rapamycin (mTOR) pathway extends life span in all species studied to date, and in mice delays the onset of age-related diseases and comorbidities. However, it is unknown if mTOR inhibition affects aging or its consequences in humans. To begin to assess the effects of mTOR inhibition on human aging-related conditions, we evaluated whether the mTOR inhibitor RAD001 ameliorated immunosenescence (the decline in immune function during aging) in elderly volunteers, as assessed by their response to influenza vaccination.

Multicenter, randomized clinical trial to compare the safety and efficacy of LFF571 and vancomycin for Clostridium difficile infections.

Clostridium difficile infection causes serious diarrheal disease. Although several drugs are available for treatment, including vancomycin, recurrences remain a problem. LFF571 is a semisynthetic thiopeptide with potency against C.

Pharmacokinetics of LFF571 and vancomycin in patients with moderate Clostridium difficile infections.

Clostridium difficile infection causes diarrheal disease with potentially fatal complications. Although treatments are available, including vancomycin, metronidazole, and fidaxomicin, the recurrence of disease after therapy remains a problem. LFF571 is a novel thiopeptide antibacterial that shows in vitro potency against C.

Treatment of sporadic inclusion body myositis with bimagrumab.

Objective: To study activin signaling and its blockade in sporadic inclusion body myositis (sIBM) through translational studies and a randomized controlled trial.

Methods: We measured transforming growth factor β signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 patients with sIBM using one dose of bimagrumab (n = 11) or placebo (n = 3).

Randomized, controlled pharmacokinetic and pharmacodynamic evaluation of albinterferon in patients with chronic hepatitis B infection.

Background And Aims: Albinterferon is a fusion of albumin and interferon-α2b developed to improve the pharmacokinetics, convenience, and potential efficacy of interferon-α for the treatment of chronic hepatitis infections.

Methods: This open-label, randomized, active-controlled, multicenter study investigated the safety and efficacy of albinterferon in patients with chronic hepatitis B virus (HBV) infection who were e-antigen (HBeAg) positive. One hundred and forty-one patients received one of four albinterferon doses/regimens or pegylated-interferon-α2a.

Donor hemodynamic profile presages graft survival in donation after cardiac death liver transplantation.

Obligatory exposure to a period of warm ischemia is the defining feature of liver allografts from donation after cardiac death (DCD) donors. We explored novel methods for characterizing the dynamic aspects of donor warm ischemia that might be useful in assessing organ quality. The hemodynamic profile during donor warm ischemia was retrospectively studied for 110 Maastricht category III DCD donors.

Phase I, open-label, single-dose study to evaluate the pharmacokinetics and safety of telbivudine in children and adolescents with chronic hepatitis B.

Telbivudine is a nucleoside analogue that has been approved for the treatment of chronic hepatitis B virus (HBV) infection in adults at 600 mg/day. We conducted a phase I, open-label, first-in-pediatrics study to investigate the safety and pharmacokinetics of a single dose of telbivudine in HBV-infected children and adolescents. Eligible patients were enrolled sequentially from older to younger groups, with evaluation of safety and available pharmacokinetic data after each stratum.