Towards remote monitoring in pediatric care and clinical trials-Tolerability, repeatability and reference values of candidate digital endpoints derived from physical activity, heart rate and sleep in healthy children.

BACKGROUND: Digital devices and wearables allow for the measurement of a wide range of health-related parameters in a non-invasive manner, which may be particularly valuable in pediatrics. Incorporation of such parameters in clinical trials or care as digital endpoint could reduce the burden for children and their parents but requires clinical validation in the target population. This study aims to determine the tolerability, repeatability, and reference values of novel digital endpoints in healthy children. METHODS: Apparently healthy children (n = 175, 46% male) aged 2-16 were included. Subjects were monitored for 21 days using a home-monitoring platform with several devices (smartwatch, spirometer, thermometer, blood pressure monitor, scales). Endpoints were analyzed with a mixed effects model, assessing variables that explained within- and between-subject variability. Endpoints based on physical activity, heart rate, and sleep-related parameters were included in the analysis. For physical-activity-related endpoints, a sample size needed to detect a 15% increase was calculated. FINDINGS: Median compliance was 94%. Variability in each physical activity-related candidate endpoint was explained by age, sex, watch wear time, rain duration per day, average ambient temperature, and population density of the city of residence. Estimated sample sizes for candidate endpoints ranged from 33-110 per group. Daytime heart rate, nocturnal heart rate and sleep duration decreased as a function of age and were comparable to reference values published in the literature. CONCLUSIONS: Wearable- and portable devices are tolerable for pediatric subjects. The raw data, models and reference values presented here can be used to guide further validation and, in the future, clinical trial designs involving the included measures.

Challenges and opportunities of pharmacological interventions for osteoarthritis: A review of current clinical trials and developments.

Objective: Osteoarthritis (OA) is the most common cause of disability in older adults, and leads to a huge unmet medical need, as no registered disease modifying OA drugs (DMOADs), but only symptomatic treatments, are available. New targets and compounds for these targets, are currently under investigation. The objective of this paper is to provide an overview of compounds under investigation for OA in phase II and III. Design: We performed a review of OA trials for pharmacological interventions registered on the National Library of Medicine ClinicalTrials.gov website with a completion date in 2017 or later. Results: The database search yielded 255 results, of which 184 studies were included in this review. These were structured in compounds targeting pain, immunomodulators, stem cell therapy, platelet rich plasma and DMOADs with cartilage and/or bone resorption modifying properties. Conclusions: The results provide an overview of the fields in development and may include future treatment options for OA, by which a registered DMOADs may become more than a utopic vista. Further knowledge on pathophysiology and new approaches of value-based drug development could be an opportunity for the optimization of drug development in OA.

Development of Novel, Value-Based, Digital Endpoints for Clinical Trials: A Structured Approach Toward Fit-for-Purpose Validation.

Novel digital endpoints gathered via wearables, small devices, or algorithms hold great promise for clinical trials. However, implementation has been slow because of a lack of guidelines regarding the validation process of these new measurements. In this paper, we propose a pragmatic approach toward selection and fit-for-purpose validation of digital endpoints. Measurements should be value-based, meaning the measurements should directly measure or be associated with meaningful outcomes for patients. Devices should be assessed regarding technological validity. Most importantly, a rigorous clinical validation process should appraise the tolerability, difference between patients and controls, repeatability, detection of clinical events, and correlation with traditional endpoints. When technically and clinically fit-for-purpose, case building in interventional clinical trials starts to generate evidence regarding the response to new or existing health-care interventions. This process may lead to the digital endpoint replacing traditional endpoints, such as clinical rating scales or questionnaires in clinical trials. We recommend initiating more data-sharing collaborations to prevent unnecessary duplication of research and integration of value-based measurements in clinical care to enhance acceptance by health-care professionals. Finally, we invite researchers and regulators to adopt this approach to ensure a timely implementation of digital measurements and value-based thinking in clinical trial design and health care. SIGNIFICANCE STATEMENT: Novel digital endpoints are often cited as promising for the clinical trial of the future. However, clear validation guidelines are lacking in the literature. This paper contains pragmatic criteria for the selection, technical validation, and clinical validation of novel digital endpoints and provides recommendations for future work and collaboration.

Technical validity and usability of a novel smartphone-connected spirometry device for pediatric patients with asthma and cystic fibrosis.

BACKGROUND: Diagnosis and follow-up of respiratory diseases traditionally rely on pulmonary function tests (PFTs), which are currently performed in hospitals and require trained personnel. Smartphone-connected spirometers, like the Air Next spirometer, have been developed to aid in the home monitoring of patients with pulmonary disease. The aim of this study was to investigate the technical validity and usability of the Air Next spirometer in pediatric patients. METHODS: Device variability was tested with a calibrated syringe. About 90 subjects, aged 6 to 16, were included in a prospective cohort study. Fifty-eight subjects performed conventional spirometry and subsequent Air Next spirometry. The bias and the limits of agreement between the measurements were calculated. Furthermore, subjects used the device for 28 days at home and completed a subject-satisfaction questionnaire at the end of the study period. RESULTS: Interdevice variability was 2.8% and intradevice variability was 0.9%. The average difference between the Air Next and conventional spirometry was 40 mL for forced expiratory volume in 1 second (FEV1) and 3 mL for forced vital capacity (FVC). The limits of agreement were -270 mL and +352 mL for FEV1 and -403 mL and +397 mL for FVC. About 45% of FEV1 measurements and 41% of FVC measurements at home were acceptable and reproducible according to American Thoracic Society/European Respiratory Society criteria. Parents scored difficulty, usefulness, and reliability of the device 1.9, 3.5, and 3.8 out of 5, respectively. CONCLUSION: The Air Next device shows validity for the measurement of FEV1 and FVC in a pediatric patient population.

Phase I study of oral CP-4126, a gemcitabine derivative, in patients with advanced solid tumors.

CP-4126 is a gemcitabine (2',2'-difluorodeoxycytidine; dFdC) 5' elaidic acid ester. The purpose of this dose-escalating study was to assess safety, pharmacokinetics (PK) and preliminary antitumor activity of the oral formulation and to determine the recommended dose (RD) for phase II studies. The study had a two-step design: a non-randomized dose-escalating step I with oral CP-4126 alone, followed by a randomized, cross-over step II that compared oral CP-4126 with dFdC i.v.. CP-4126 was given on days 1,8,15 in a 4-week schedule with increasing doses until the RD was established. 26 patients with different solid tumours were enrolled in step I at seven dose levels (100-3,000 mg/day). The most frequent drug-related AEs were fatigue and dysgeusia, the majority being grade 1-2. One patient experienced a dose limiting toxicity after one dose of CP-4126 at 1,300 mg/day (ASAT grade 3). PK of CP-4126 could not be determined. The metabolites dFdC and dFdU obeyed dose-dependent pharmacokinetics. Exposures to dFdC were about ten-fold lower compared to exposures after comparable doses of dFdC i.v.. Nine patients reached stable disease as best response, whereby in one patient with vaginal carcinoma a 25 % reduction of tumor volume was reached. This study demonstrates that CP-4126 can be safely administered orally to patients up to 3,000 mg/day in a d1,8,15 q4w schedule with a tolerable safety profile. CP-4126 acts as a prodrug for dFdC when given orally, but because of the poor absorption and the rapid pre-systemic metabolism the study was terminated early and no RD could be determined.

Pulsatile drug delivery to ileo-colonic segments by structured incorporation of disintegrants in pH-responsive polymer coatings.

Conventional pH-responsive coatings used for oral drug delivery to the lower parts of the gastro-intestinal tract often show a poor performance. A new system for site-specific pulsatile delivery in the ileo-colonic regions is described. The system is based on the non-percolating incorporation of disintegrants in a coating which consists further of a continuous matrix of pH-responsive polymer (Eudragit S). Extensive in vitro release studies were performed in which coatings with different concentrations and disintegrants were studied and compared to non-disintegrant containing coatings. In vitro data show that the incorporation of swelling agents in an Eudragit S-coating still allows delayed release in the simulated terminal ileum. The pulse time and the robustness could be improved compared to conventional Eudragit S-coatings. The augmented pH-responsiveness of the new coating was related to the swelling index of the applied disintegrant. Based on the in vitro data comparing different swelling agents, Ac-di-sol appears to be the best performing swelling agent. A proof-of-concept study in human subjects was performed to investigate the performance of the new system in vivo. Coated capsules containing the stable isotope (13)C(6)-glucose as the test compound were administered and the occurrence of (13)CO(2) in the breath of the subjects was measured. It could be shown that the coating is able to resist the environmental conditions in the stomach and duodenum and delay release until deeper parts of the intestines are reached. Furthermore, the capsule is able to maintain a pulsatile release profile. It is concluded that the structured incorporation of swelling agents in pH-responsive polymers improves the delayed, pulsatile release kinetics of coated capsules. In a proof-of-concept in vivo study it was shown that the newly developed coating enables pulsatile delivery of the content to the lower parts of the intestines.

A novel dissolution method relevant to intestinal release behaviour and its application in the evaluation of modified release mesalazine products.

Mesalazine (5-ASA) is a compound being used in the therapy of inflammatory bowel disease (IBD). Considering the fact that 5-ASA is locally active and that the location of inflammation in IBD may vary, it is recognized that the release profile of 5-ASA drugs is the dominant factor for adequate local bioavailability. Furthermore, it is hypothesized that systemic absorption of 5-ASA (mainly in the upper intestinal segments) increases the risk of side effects. These facts relate to the conclusion that a method determining the dissolution profile under biorelevant conditions is a valuable tool for evaluation and comparison of 5-ASA-products. We tested several commercially available products (Salofalk tablets, Salofalk granules, Asacol tablets, Pentasa tablets and granules) in a gastro-intestinal simulation system (GISS). The GISS is based on the pharmacopeial dissolution test. The release profiles of all products are in agreement with their technological concepts. The percentage of the dose released in the simulated colon is small in all products. The GISS is a robust system able to discriminate between products which apply different modified-release technologies. Colon-selectivity of modified-release 5-ASA products might further be improved. The commercially available 5-ASA containing oral dosage forms exhibit different release profiles, which suggests that the optimal product may differ per patient.