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

©Jelena Curcic, Vanessa Vallejo, Jennifer Sorinas, Oleksandr Sverdlov, Jens Praestgaard, Mateusz Piksa, Mark Deurinck, Gul Erdemli, Maximilian Bügler, Ioannis Tarnanas, Nick Taptiklis, Francesca Cormack, Rebekka Anker, Fabien Massé, William Souillard-Mandar, Nathan Intrator, Lior Molcho, Erica Madero, Nicholas Bott, Mieko Chambers, Josef Tamory, Matias Shulz, Gerardo Fernandez, William Simpson, Jessica Robin, Jón G Snædal, Jang-Ho Cha, Kristin Hannesdottir. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 10.08.2022.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. OBJECTIVE: This study aimed to assess the psychometric properties, operational feasibility, and patient acceptance of 10 promising technologies that are to be used as efficacy end points to measure cognition in future clinical drug trials. METHODS: The Method for Evaluating Digital Endpoints in Alzheimer Disease study is an exploratory, cross-sectional, noninterventional study that will evaluate 10 digital technologies' ability to accurately classify participants into 4 cohorts according to the severity of cognitive impairment and dementia. Moreover, this study will assess the psychometric properties of each of the tested digital technologies, including the acceptable range to assess ceiling and floor effects, concurrent validity to correlate digital outcome measures to traditional paper-and-pencil tests in AD, reliability to compare test and retest, and responsiveness to evaluate the sensitivity to change in a mild cognitive challenge model. This study included 50 eligible male and female participants (aged between 60 and 80 years), of whom 13 (26%) were amyloid-negative, cognitively healthy participants (controls); 12 (24%) were amyloid-positive, cognitively healthy participants (presymptomatic); 13 (26%) had mild cognitive impairment (predementia); and 12 (24%) had mild AD (mild dementia). This study involved 4 in-clinic visits. During the initial visit, all participants completed all conventional paper-and-pencil assessments. During the following 3 visits, the participants underwent a series of novel digital assessments. RESULTS: Participant recruitment and data collection began in June 2020 and continued until June 2021. Hence, the data collection occurred during the COVID-19 pandemic (SARS-CoV-2 virus pandemic). Data were successfully collected from all digital technologies to evaluate statistical and operational performance and patient acceptance. This paper reports the baseline demographics and characteristics of the population studied as well as the study's progress during the pandemic. CONCLUSIONS: This study was designed to generate feasibility insights and validation data to help advance novel digital technologies in clinical drug development. The learnings from this study will help guide future methods for assessing novel digital technologies and inform clinical drug trials in early AD, aiming to enhance clinical end point strategies with digital technologies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/35442.Peer reviewe

A note on the power superiority of the restricted likelihood ratio test

Let be a closed convex cone which contains a linear subspace . We investigate the restricted likelihood ratio test for the null and alternative hypotheses based on an n-dimensional, normally distributed random vector (X1,...,Xn) with unknown mean and known covariance matrix [Sigma]. We prove that if the true mean vector satisfies the alternative hypothesis HA, then the restricted likelihood ratio test is more powerful than the unrestricted test with larger alternative hypothesis [real]n. The proof uses isoperimetric inequalities for the uniform distribution on the n-dimensional sphere and for n-dimensional standard Gaussian measure.Order restricted inference Convex cone Gaussian isoperimetric inequality

A 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. Adolescent patients (>12 to 18 years) received a single dose of 600 mg telbivudine as an oral solution, while children aged 2 to 12 years received a single dose of 15 or 25 mg/kg of body weight up to a maximum of 600 mg. Telbivudine was well tolerated; all adverse events were mild, and none occurred in more than one patient. The plasma telbivudine concentration-versus-time profiles in adolescents given 600 mg were similar to the mean profile of healthy adults receiving the same oral dose. Children aged 2 to 12 to 18 years (600 mg) were fitted to a two-compartment 1st-order, microconstant, lag time, 1st-order elimination pharmacokinetic (PK) model. This analysis predicted the following dosages to mimic exposures in healthy adults receiving 600 mg/day: 20 mg/kg/day for children 2 to 12 years and 600 mg/day for adolescents. Studies are ongoing to evaluate the efficacy of the recommended dose in pediatric patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00907894.)

A first-in-human, randomized, double-blind, placebo-controlled, time-lagged, single- and multiple-ascending oral dose study to assess the safety and tolerability of LFF571 in healthy volunteers

Clostridium difficile is the leading cause of hospital-acquired infectious diarrhea. LFF571 is a novel inhibitor of the prokaryotic translation elongation factor Tu (EF-Tu) and is active against a range of bacterial species, including C. difficile. This first-in-human study investigated the safety and pharmacokinetics of single and multiple ascending oral doses of LFF571 in healthy subjects. The study was randomized, double-blind, placebo-controlled, and time-lagged. Except for one cohort, LFF571 was given with a high fat meal in all single dose cohorts (25 mg, 100 mg, 400 mg, 1000 mg). In the multiple dose cohorts (25 mg, 100 mg, 200 mg, every 6 hours for 10 days), LFF571 was given without regard to food. A total of 56 subjects completed the study, with 32 and 25 receiving single and multiple doses, respectively. There were no deaths, no serious adverse events, and no subject discontinued due to an adverse event. The most common adverse event was diarrhea; gastrointestinal pain or distension was also noted. Diarrhea did not develop more frequently among subjects who received LFF571 compared to placebo. LFF571 had limited systemic exposure and high steady-state fecal concentrations. The highest serum concentration of LFF571 (3.2 ng/mL) was observed after the last dose in a subject receiving 200 mg every 6 hours. LFF571 was generally safe and well-tolerated after single and multiple oral doses in healthy subjects. The minimal serum and high fecal concentrations support the further development of LFF571 for the treatment of C. difficile infections

A multi-center, randomized clinical trial to compare the safety and efficacy of LFF571 and vancomycin for Clostridium difficile infections

Background: Clostridium difficile cause serious diarrheal disease with potentially fatal complications. Several drugs are available for the treatment of C. difficile, including vancomycin, metronidazole, and fidaxomicin. Recurrences after successful therapy, however, remain a significant problem. LFF571 is a semi-synthetic thiopeptide antibacterial that is potent against C. difficile in vitro and in animal models of infection. Here, we assess the safety and efficacy of LFF571 in patients with primary or first recurrent C. difficile infections. Methods: This was a multi-center, randomized, evaluator-blind, active-controlled study to compare the safety and efficacy of LFF571 to those of vancomycin. Adults aged 18-90 with primary episodes or first recurrences of moderate C. difficile infection were eligible to enroll. Patients were randomized to receive 200 mg LFF571 or 125 mg vancomycin four times daily for 10 days. The primary endpoint was the proportion of clinical cures at the end of therapy, with the primary analysis comparing cure rates in the per-protocol population. Secondary endpoints included time to resolution of diarrhea and the recurrence rate 30 days following completion of treatment. Results: Seventy-two patients were enrolled and randomized, of which 46 were assigned to receive LFF571. Based on the protocol-specified definition, the rates of clinical cure for LFF571 (90.6%) were non-inferior to those of vancomycin (78.3%). The 30-day sustained cure rates for LFF571- and vancomycin- treated patients were 56.7% and 65.0%, respectively, in the per-protocol population and were 58.7% and 60.0%, respectively, in the modified intent-to-treat population. Analysis of recurrence using only toxin-confirmed cases, however, indicated that recurrence rates were lower for LFF571 (19% compared to 25% for vancomycin in the per-protocol population). The incidence of adverse events was higher in the LFF571 group (76.1%) compared to vancomycin (69.2%), although more adverse events in the vancomycin group were suspected to be related to study drug (38.5% versus 32.6% for LFF571). One patient receiving LFF571 discontinued due to an adverse event. Conclusion: LFF571 was non-inferior to vancomycin for the clinical cure of primary or first recurrent moderate C. difficile infections. The sustained cure rates at the end-of-study were slightly lower for LFF571, although toxic-confirmed recurrences were reduced compared to vancomycin. LFF571 was generally safe and well-tolerated in patients with moderate C. difficile infections

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

Background: Clostridium difficile causes diarrheal disease with potentially fatal complications. Although treatments are available, including vancomycin, metronidazole, and fidaxomicin, recurrence of disease after therapy remains a problem. LFF571 is a novel thiopeptide antibacterial that shows in vitro potencies against C. difficile comparable to or greater than other clinically-used antibiotics. Here, we compare the pharmacokinetics (PK) of LFF571 and vancomycin in patients with C. difficile infection as part of an early efficacy study. Methods: This multi-center, randomized, evaluator-blind, active-controlled study evaluated the safety, efficacy and pharmacokinetics of LFF571 in adults with primary episodes or first relapses of moderate C. difficile infections. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. Drug concentrations were measured in serum and fecal samples and PK parameters were calculated. Results: Systemic exposure following oral administration of 200 mg of LFF571 four times per day for ten days in patients with C. difficile infection was limited. The highest LFF571 serum concentration observed was 41.7 ng/mL, whereas levels in the feces at the end of treatment were between 107 and 12900 µg/g. By comparison, the peak vancomycin level observed in the serum was considerably higher at 2.73 µg/mL; levels of vancomycin in the feces were not tested. Conclusion: Similar to healthy volunteers, patients with C. difficile infections exhibited high fecal concentrations and low serum levels of LFF571 after ten days of dosing. These results are consistent with retention of LFF571 in the lumen of the gastrointestinal tract

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. Participants: Community-dwelling adults (N = 40) aged 65 and older with gait speed between 0.4 and 1.0 m/s over 4 m and an appendicular skeletal muscle index of 7.25 kg/m2 or less for men and 5.67 kg/m2 or less for women. Intervention: Intravenous bimagrumab 30 mg/kg (n = 19) or placebo (n = 21). Measurements: Change from baseline in thigh muscle volume (TMV), subcutaneous and intermuscular fat, appendicular and total lean body mass, grip strength, gait speed, and 6-minute walk distance (6MWD). Results: Thirty-two (80%) participants completed the study. TMV increased by Week 2, was sustained throughout the treatment period, and remained above baseline at the end of study in bimagrumab-treated participants, whereas there was no change with placebo treatment (Week 2: 5.15 ± 2.19% vs −0.34 ± 2.59%, P <.001; Week 4: 6.12 ± 2.56% vs 0.16 ± 3.42%, P <.001; Week 8: 8.01 ± 3.70% vs 0.35 ± 3.32%, P <.001; Week 16: 7.72 ± 5.31% vs 0.42 ± 5.14%, P <.001; Week 24: 4.80 ± 5.81% vs −1.01 ± 4.43%, P =.002). Participants with slower walking speed at baseline receiving bimagrumab had clinically meaningful and statistically significantly greater improvements in gait speed (mean 0.15 m/s, P =.009) and 6MWD (mean 82 m, P =.022) than those receiving placebo at Week 16. Adverse events in the bimagrumab group included muscle-related symptoms, acne, and diarrhea, most of which were mild in severity and resolved by the end of study. Conclusion: Treatment with bimagrumab over 16 weeks increased muscle mass and strength in older adults with sarcopenia and improved mobility in those with slow walking speed