Pharmacokinetic characterization and exposure-response relationship of crovalimab in the COMMODORE 1, 2 and 3 and COMPOSER trials of patients with paroxysmal nocturnal haemoglobinuria.

Aims: Crovalimab is a novel C5 inhibitor administered first intravenously and then subcutaneously in patients with paroxysmal nocturnal haemoglobinuria (PNH) naive to complement inhibition or switching from eculizumab or ravulizumab. Crovalimab showed efficacy and safety comparable to eculizumab in the pivotal COMMODORE 2 and supporting studies.

Methods: We characterized crovalimab pharmacokinetics and the relationship between exposure pharmacokinetic parameters and pharmacodynamic biomarkers, efficacy and safety endpoints using pooled data (healthy volunteers [n = 9], naive [n = 210] and switched [n = 211] patients).

Safety of Crovalimab Versus Eculizumab in Patients With Paroxysmal Nocturnal Haemoglobinuria (PNH): Pooled Results From the Phase 3 COMMODORE Studies.

Objectives: To evaluate the tolerability of crovalimab versus eculizumab in C5 inhibitor (C5i)-naive and -experienced patients with PNH from COMMODORE 2, 3 and 1 (NCT04434092, NCT04654468 and NCT04432584).

Methods: Pooled safety data were assessed in the total crovalimab and eculizumab populations and by C5i-naive versus C5i-switched status in patients receiving crovalimab. Analyses include 6.

A fully automatic tool for development of population pharmacokinetic models.

Population pharmacokinetic (PK) models are widely used to inform drug development by pharmaceutical companies and facilitate drug evaluation by regulatory agencies. Developing a population PK model is a multi-step, challenging, and time-consuming process involving iterative manual model fitting and evaluation. A tool for fully automatic model development (AMD) of common population PK models is presented here.

Impact of covariate model building methods on their clinical relevance evaluation in population pharmacokinetic analyses: comparison of the full model, stepwise covariate model (SCM) and SCM+ approaches.

Covariate analysis in population pharmacokinetics is key for adjusting doses for patients. The main objective of this work was to compare the adequacy of various modeling approaches on covariate clinical relevance decision-making. The full model, stepwise covariate model (SCM) and SCM+ PsN algorithms were compared in a clinical trial simulation of a 383-patient population pharmacokinetic study mixing rich and sparse designs.

Clinical Study of Single-Stranded Oligonucleotide RO7062931 in Healthy Volunteers and Patients With Chronic Hepatitis B.

Background And Aims: RO7062931 is an N-acetylgalactosamine (GalNAc)-conjugated single-stranded locked nucleic acid oligonucleotide complementary to HBV RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This two-part phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO7062931 in healthy volunteers and patients with chronic hepatitis B (CHB) who were virologically suppressed.

Relation of arterial stiffness with postural control in older people.

Purpose: Arterial stiffness generates vascular alterations that may cause balance disorders and falls. This study aimed to investigate the possible link between arterial stiffness and postural control under different sensorial conditions in patients over 65 years.

Methods: Carotid-femoral pulse wave velocity (PWV) was measured in 47 participants aged over 65 years to evaluate their arterial stiffness (high PWV).

cLRT-Mod: An efficient methodology for pharmacometric model-based analysis of longitudinal phase II dose finding studies under model uncertainty.

Within the challenging context of phase II dose-finding trials, longitudinal analyses may increase drug effect detection power compared to an end-of-treatment analysis. This work proposes cLRT-Mod, a pharmacometric adaptation of the MCP-Mod methodology, which allows the use of nonlinear mixed effect models to first detect a dose-response signal and then identify the doses for the confirmatory phase while accounting for model structure uncertainty. The method was evaluated through extensive clinical trial simulations of a hypothetical phase II dose-finding trial using different scenarios and comparing different methods such as MCP-Mod.

Comparison of Model Averaging and Model Selection in Dose Finding Trials Analyzed by Nonlinear Mixed Effect Models.

In drug development, pharmacometric approaches consist in identifying via a model selection (MS) process the model structure that best describes the data. However, making predictions using a selected model ignores model structure uncertainty, which could impair predictive performance. To overcome this drawback, model averaging (MA) takes into account the uncertainty across a set of candidate models by weighting them as a function of an information criterion.

Item Response Theory as an Efficient Tool to Describe a Heterogeneous Clinical Rating Scale in De Novo Idiopathic Parkinson's Disease Patients.

Purpose: This manuscript aims to precisely describe the natural disease progression of Parkinson's disease (PD) patients and evaluate approaches to increase the drug effect detection power.

Methods: An item response theory (IRT) longitudinal model was built to describe the natural disease progression of 423 de novo PD patients followed during 48 months while taking into account the heterogeneous nature of the MDS-UPDRS. Clinical trial simulations were then used to compare drug effect detection power from IRT and sum of item scores based analysis under different analysis endpoints and drug effects.

Risk factors of hand climbing-related injuries.

This study aimed to investigate the protective mechanisms or risk factors that can be related to the occurrence of hand climbing-related injuries (CRIH ). CRIH (tendon, pulley, muscle, and joint injuries) were retrospectively screened in 528 adult climbers. The questionnaire contained anthropometric items (e.

Study of Mini-Mental State Exam evolution in community-dwelling subjects aged over 60 years without dementia.

Objective: In recent years, the Mini-Mental State Examination (MMSE) has been widely used and has been proposed for cognitive decline screening in the framework of a systematic geriatric evaluation in health centers. The aim of the present longitudinal study was to identify the potential determinants of MMSE score and its evolution over a 4-year period in a population aged over sixty years with good general health without dementia and consulting for a health check-up.

Design: Longitudinal study.

A simple clinical scale to stratify risk of recurrent falls in community-dwelling adults aged 65 years and older.

Background: Correct identification of people at risk for recurrent falls facilitates the establishment of preventive and rehabilitative strategies in older adults.

Objective: The purposes of this study were: (1) to develop and validate a simple clinical scale to stratify risk for recurrent falls in community-dwelling elderly people based on easily obtained social and clinical items and (2) to evaluate the added value of 3 clinical balance tests in predicting this risk.

Design: This was a prospective measurement study.

Blood pressure and pulse wave velocity values in the institutionalized elderly aged 80 and over: baseline of the PARTAGE study.

Objective: The aim of the longitudinal study PARTAGE (predictive values of blood pressure and arterial stiffness in institutionalized very aged population) was to determine the predictive value of blood pressure (BP) and arterial stiffness for overall mortality, major cardiovascular events and cognitive decline in a large population of institutionalized patients aged 80 and over. In the study herein, we present the baseline data values of this study.

Methods: A total of 1130 patients were recruited (878 women), living in French and Italian nursing homes.

Clinical determinants of failure in balance tests in elderly subjects.

We assessed the role of clinical and biological parameters on performance in four balance tests in elderly subjects. An observational study was conducted in the Center for Preventive Medicine of Nancy (France) in 2368 community-living elderly subjects aged 60 and older. Body mass index (BMI), Mini-Mental State Examination (MMSE), clock test, "Health score" and use of psychotropic drugs (UPD) were assessed.

Posturography and risk of recurrent falls in healthy non-institutionalized persons aged over 65.

Background: A poor postural stability in older people is associated with an increased risk of falling. The posturographic tool has widely been used to assess balance control; however, its value in predicting falls remains unclear.

Objective: The purpose of this prospective study was to determine the predictive value of posturography in the estimation of the risk of recurrent falls, including a comparison with standard clinical balance tests, in healthy non-institutionalized persons aged over 65.

Current physical activity improves balance control during sensory conflicting conditions in older adults.

Aging process is characterized by difficulties in ensuring balance control, especially in conditions of reduced or conflicting sensory information, leading to an increased risk of falling. Conversely, the practise of physical activities (PA) has been recognized as a good approach to improve the quality of balance control. This study aimed to investigate the influence of current and/or past PA on balance-related neurosensorial organization in older adults on the maintenance of the upright stance, especially during sensory conflicting situations.