Real-life management of atopic dermatitis patients with an inadequate response to on-label use of dupilumab.

In patients with moderate to severe atopic dermatitis (AD) showing an inadequate response to dupilumab 300mg/2weeks, few real-life studies reported the response to alternative regimen maintaining dupilumab. To assess and analyze the response to an increased dose of dupilumab or its combination with cyclosporin A (CsA), methotrexate (MTX), or itraconazole (ITRA), all adult AD patients from 7 French University Hospitals were retrospectively included if they achieved an inadequate response to dupilumab 300mg/2weeks and were subsequently treated with an increased dose of dupilumab (300mg every 7 or 10 days), or a combination of dupilumab 300mg/2weeks with CsA, MTX or ITRA. The response after 3 months, along with epidemiological, clinical, and therapeutic baseline characteristics, were collected. Overall, 68.75% of the 48 included patients achieved an improved response, including 45.8% of complete response (CR). No strategy proved significantly better. Patients showing an initial no response never achieved a further CR versus 52.4% of patients with an initial partial response (p = 0.025). Digestive intolerance and tachycardia led to MTX and ITRA discontinuation in 3 patients. Increasing the dose of dupilumab or combining it with CsA, MTX, or ITRA could be alternative and safe options, to be evaluated in further medico-economic studies.

Regulatory Pathways for Qualification and Acceptance of Digital Health Technology-Derived Clinical Trial Endpoints: Considerations for Sponsors.

Despite widespread interest and substantial investment in the adoption of sensor-based digital health technologies (sDHTs) for remote data capture in drug development trials, no drug has been approved based on an sDHT-derived primary endpoint in the United States (US). One reason for this lack of advancement is the complexity of obtaining regulatory endorsement for those endpoints within current US regulatory pathways. The goal of our review is to describe the two choices currently available to pharmaceutical study Sponsors: (i) they may navigate the traditional route of compiling the evidence to support the sDHT-derived endpoint in their investigational new drug (IND) application, requiring specific expertise and substantial resources; or (ii) they may navigate the drug development tool (DDT) pathway with the goal of qualifying their sDHT-derived endpoint as a biomarker or clinical outcome assessment applicable to a broader context of use (COU), either alone or as part of a partnership or consortium. We describe the nuances of each pathway; the evidentiary requirements for supporting an sDHT-derived endpoint and the technology used to capture it; and the impact that an sDHT's regulatory status may have on a Sponsor's decision to use it for data capture. By systematically comparing the IND and DDT pathways, our over-arching goals are to support the increasing deployment of sDHTs within the clinical research setting and help advance regulatory science in the field of digital medicine.

Hand eczema in glove-wearing patients.

BACKGROUND: Allergic contact dermatitis to gloves is mostly induced by rubber accelerators. The European baseline series (EBS) appears insufficient to detect glove allergy. Since 2017, it is recommended to use the European rubber series (ERS) and to test the patients' own gloves. OBJECTIVES: To investigate the clinical profile of glove-wearing patients with hand eczema (HE) and to evaluate their sensitisation profile to glove allergens and the value of testing the patients' own gloves. METHODS: We conducted a French multicentre study of patients evaluated for HE between 2018 and 2020 and tested with the EBS, the ERS and their own gloves in patch tests and semi-open (SO) tests. RESULTS: A total of 279 patients were included; 32.6% of patients had positive tests to their own gloves or to glove allergens. Almost 45% of the sensitisations to glove allergens were detected only by the ERS. Among the patients tested both in patch tests and SO tests with their own gloves with positive results, 28% had positive SO tests only. Polyvinylchloride (PVC) gloves were positive in four patients. CONCLUSION: Our series confirms the need to test the ERS. All the patients' gloves must also be tested including PVC gloves. SO tests with gloves are useful as a complement to patch tests.

First Regulatory Qualification of a Novel Digital Endpoint in Duchenne Muscular Dystrophy: A Multi-Stakeholder Perspective on the Impact for Patients and for Drug Development in Neuromuscular Diseases.

BACKGROUND: Functional outcome measures used to assess efficacy in clinical trials of investigational treatments for rare neuromuscular diseases like Duchenne muscular dystrophy (DMD) are performance-based tasks completed by the patient during hospital visits. These are prone to bias and may not reflect motor abilities in real-world settings. Digital tools, such as wearable devices and other remote sensors, provide the opportunity for continuous, objective, and sensitive measurements of functional ability during daily life. Maintaining ambulation is of key importance to individuals with DMD. Stride velocity 95th centile (SV95C) is the first wearable acquired digital endpoint to receive qualification from the European Medicines Agency (EMA) to quantify the ambulation ability of ambulant DMD patients aged ≥5 years in drug therapeutic studies; it is also currently under review for the US Food and Drug Administration (FDA) qualification. SUMMARY: Focusing on SV95C as a key example, we describe perspectives of multiple stakeholders on the promise of novel digital endpoints in neuromuscular disease drug development.

Diaphragmatic excursion measurement in emergency department patients with acute dyspnea to predict mechanical ventilation use.

INTRODUCTION: Ultrasound is a feasible and reproducible method for measuring right diaphragmatic excursion (RDE) in ED patients with acute dyspnea (AD). In AD patients, the correlation between the RDE value and the need for mechanical ventilation (MV) is not known. MATERIALS: This was a bicentric, observational prospective study. The RDE measurement was done at admission. The need for MV was defined by the use of MV within 4 h of AD management. An optimal threshold for RDE was determined as the value that minimized the incorrect predictions of the use of MV in the first 4 h as the highest Youden index. RESULTS: We analyzed 102 patients (79 [70; 86] years), 38 (37%) of whom had been ventilated. The RDE value was 1.7 cm [1.4; 2.0] and 2.2 cm [1.8; 2.6] in the ventilated and non-ventilated groups, respectively (p = 0.06). The AUC was 0.68 95% CI [0.57; 0.80]. With a threshold of 2 cm, the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were 76% [60%; 89%], 59% [46%; 71%], 81% [67%; 91%], and 53% [39%; 66%], respectively. In the non-COPD patients, the RDE values were 1.5 cm [1.2; 1.9] and 2.2 cm [1.8; 2.6] (p < 0.01) in the ventilated and not-ventilated groups, respectively. The AUC was 0.77 95% CI [0.64; 0.90]. With a threshold of 2.18 cm, the sensitivity, specificity, NPV, and PPV were 91% [71%; 99%], 51% [36%; 66%], 92% [75%; 99%], and 54% [38%; 69%], respectively. CONCLUSION: The RDE values at ED admission were unable to define a prognostic threshold value associated with subsequent MV need in the AD patients. In non-COPD patients, the NPV was 92%.

Diaphragmatic excursion measurement in emergency patients with acute dyspnea: toward a new diagnostic tool?

INTRODUCTION: During acute dyspnea (AD), respiratory exhaustion is mainly due to diaphragm fatigue. The primary objective was to validate interobserver reproducibility of diaphragmatic excursion (DE) in emergency department (ED) patients admitted for AD. The secondary objectives were to assess the feasibility of DE measurement and intraobserver reproducibility. Finally, we examined whether the DE value was associated with a need for noninvasive ventilation (NIV). MATERIALS: This was a monocentric, prospective, technical reproducibility study. Adult patients in spontaneous ventilation admitted for AD were included. Two operators carried out 2 consecutive diaphragm excursion measurements each on the right and left hemidiaphragms. RESULTS: Twenty-four patients were analyzed. The feasibility was 96% on the right and 67% on the left. The interobserver concordance between the 2 measures was 0.80 (95% confidence interval [CI], 0.59-0.91) (average difference, -0.07±0.48 cm) on the right and 0.59 (95% CI, 0.19-0.82) (average difference, 0.30±0.91 cm) on the left. For right DE values inferior to 2.3 cm, the interobserver concordance between measures was 0.92 (95% CI, 0.78-0.97). The intraobserver concordance was 0.89 (95% CI, 0.81-0.94) (average difference, 0.02±0.35 cm) on the right and 0.90 (95% CI, 0.82-0.95) (average difference,-0.06±0.45 cm) on the left. When the DE was greater than 2 cm, no patient required NIV. CONCLUSION: Diaphragmatic excursion measurement of the right diaphragm is feasible, with good interobserver and intraobserver reproducibility in ED patients admitted for AD. When the DE value is greater than 2 cm at admission, no subsequent NIV is required.