The evolving landscape of pulmonary arterial hypertension clinical trials

Although it is a rare disease, the number of available therapeutic options for treating pulmonary arterial hypertension has increased since the late 1990s, with multiple drugs developed that are shown to be effective in phase 3 randomised controlled trials. Despite considerable advancements in pulmonary arterial hypertension treatment, prognosis remains poor. Existing therapies target pulmonary endothelial dysfunction with vasodilation and anti-proliferative effects. Novel therapies that target proliferative vascular remodelling and affect important outcomes are urgently needed. There is need for additional innovations in clinical trial design so that all emerging candidate therapies can be rigorously studied. Pulmonary arterial hypertension trial design has shifted from short-term submaximal exercise capacity as a primary endpoint, to larger clinical event-driven trial outcomes. Event-driven pulmonary arterial hypertension trials could face feasibility and efficiency issues in the future because increasing sample sizes and longer follow-up durations are needed, which would be problematic in such a rare disease. Enrichment strategies, innovative and alternative trial designs, and novel trial endpoints are potential solutions that could improve the efficiency of future pulmonary arterial hypertension trials while maintaining robustness and clinically meaningful evidence.Copyright © 2022 Elsevier Ltd

A fast point-of-care PCR test for infectious diseases, based on aerosol capturing

The COVID-19 pandemic quickly revealed the limitations of existing monitoring and diagnostic capabilities. While rapid antigen tests are not sufficiently reliable, PCR turn-around-time (TAT) typically ranges from hours to days. Standard swab-based tests are also cumbersome and invasive and, worse yet, they detect infection and not transmissibility. A reliable diagnostic test able to discern the infectious phase of COVID-19 could interrupt transmission while limiting isolation requirements. We developed a non-invasive, impaction-based method for capturing aerosols from human breath in one minute of sampling. A proof-of-principle system was used for the detection of viral RNA in breath samples from confirmed positive subjects (=29). A lab setup demonstrated compatibility with on-chip PCR, reducing the TAT to 15-20 minutes. Positive percentage agreement (PPA) between a breath- and nasopharyngeal PCR is 75% overall and 92% in the first 7 days of infection, after which the breath does not contain measurable virus anymore. Breath positivity corresponds to the infectious window. No false positives were noted. Diagnostic accuracy is superior to nasopharyngeal rapid antigen tests. This novel concept of aerosol capturing combined with ultra-fast PCR is proven to be effective to detect SARS-CoV-2 in breath, rivalling the standard nasopharyngeal PCR tests. Combined with a TAT on par with rapid antigen tests, the technology has the potential to become a standard test in the coming years, for COVID-19 or other infectious diseases. A validation study with an advanced setup is currently ongoing, first data should be available during the presentation.

A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in Subjects with Pulmonary Arterial Hypertension (ADVANCE OUTCOMES)

RATIONALE: Pulmonary arterial hypertension (PAH) is a rare, progressive disease leading to right ventricular failure and premature death. The functional limitation and survival of patients with PAH remains unsatisfactory. Ralinepag, an orally available, potent, and selective, nonprostanoid, prostacyclin receptor agonist, is a new chemical entity in development to treat PAH. METHODS: The ADVANCE OUTCOMES (NCT03626688) study is a randomized, double-blind, placebocontrolled, event-driven study evaluating the efficacy and safety of ralinepag in subjects with PAH. In this event-driven, Phase 3 study, approximately 700 subjects with PAH treated with standard of care are randomly assigned (1:1) to receive ralinepag or placebo. Dosing is individualized and titrated based on tolerability and clinical response. The primary objective is to assess the effect of ralinepag on the time to first adjudicated clinical worsening event;a composite endpoint including death, hospitalization due to worsening of PAH, initiation of inhaled or infused prostacyclins, disease progression, or unsatisfactory long-term response. Additional secondary assessments during the study include changes from Baseline to Week 28 in N-terminal pro-brain natriuretic peptide (NT-proBNP), 6-minute walk distance (6MWD), WHO/New York Heart Association (NYHA) Functional Class, and health-related quality of life measures. Exploratory assessments will evaluate biomarkers and pharmacogenetics. Subject safety is evaluated by capturing adverse events, hospitalizations, clinical laboratory, and ECG parameters. Subjects who experience a clinical worsening event or are participating at study closure are eligible to enter an open-label extension study (ROR-PH-303 [NCT03683186]). Long-term survival will be followed for all subjects until study closure. RESULTS: Enrollment is ongoing at approximately 200 sites in 33 countries following implementation of risk mitigation steps related to the Covid-19 pandemic. Enrollment will continue until 228 adjudicated clinical worsening events have occurred. The interim assessment includes 281 subjects randomized in 29 different countries;97% of participants have completed 28 weeks of treatment. The majority of subjects were female (79.4%) with a median age of 48.0 years, were receiving dual background therapy (82.9%), and were classified as Functional Class II (59.3%). Overall, 48 clinical worsening events have been reported at the time of the interim assessment. Of these, 34 subjects elected to continue treatment in the open-label extension study. An independent Data Monitoring Committee reviewed safety data after 50, 100, and 250 subjects were randomized and recommended study continuation without modification. CONCLUSIONS: ADVANCE OUTCOMES will assess whether ralinepag can improve function, delay disease progression, and prolong survival in subjects with PAH.

COVID-19 infection in the elderly in French-speaking Switzerland: an inventory of beliefs, convictions and certainties

Most patients hospitalized for COVID-19 are aged over 70 years old, and half of those who die are over 83 years old. Older patients do not always present with typical symptoms (fever, cough and dyspnoea) but sometimes are and remain asymptomatic (contact screening), or have aspecific presentations (altered general condition, falls, delirium, unusual fatigue). Rectal swab, which minimizes exposition risk, appears useful in long-term care patients with diarrhea. Older age is associated with worse prognosis, but the analysis should be refined by means of prognostic indexes that account for the heterogeneous health, functional, and cognitive status of the elderly population. Gathering elderly patients’ wishes and assessing their remaining life expectancy allows to anticipate care decisions according to the level of tension in the health system.

Symptômes respiratoires et anomalies radiologiques dans le COVID long

Introduction La prévalence et les caractéristiques des symptômes respiratoires persistants après COVID-19 sont en grande partie inconnues. Les objectifs étaient de déterminer la prévalence et les caractéristiques de ces symptômes à distance du COVID-19 et les relations entre dyspnée, anomalies radiologiques et troubles fonctionnels. Méthodes Dans l’étude de cohorte COMEBAC (Consultation Multi-Expertise de Bicêtre Après Covid-19), 478 survivants hospitalisés ont été évalués par téléphone 4 mois après la sortie de l’hôpital et 177 qui avaient été hospitalisés en unité de soins intensifs (USI) ou présentant des symptômes persistants ont été évalués en hôpital de jour (HDJ). La présence d’une dyspnée et d’une toux qui n’existaient pas avant la COVID-19, et les résultats des EFR, de la tomodensitométrie à haute résolution du thorax et de l’échocardiographie ont été recueillis. Résultats Parmi les 478 patients, 78 (16,3 %) ont signalé une dyspnée et 23 (4,8 %) une toux, apparues depuis la COVID-19. Les patients présentant une dyspnée d’apparition récente étaient significativement plus jeunes (56,1±12,3 versus 61,9±16,6 ans), avaient eu une COVID-19 plus sévère (admission en USI 56,4 % versus 24,5 %) et un antécédent d’embolie pulmonaire pendant la COVID-19 plus fréquente (18,0 % versus 6,8 %) (tous les p≤0,001) que les patients sans nouvelle dyspnée et parmi eux 23 (29,5 %) avaient un score de Nijmegen>22. Parmi les patients réévalués en HDJ, la prévalence des lésions fibrosantes pulmonaires était de 19,3 %, avec une étendue lésionnelle<25 % dans 97 % des cas. Les patients présentant des lésions fibrosantes étaient plus âgés (61±11 versus 56±14 ans, p=0,03), plus fréquemment pris en charge en USI (87,9 versus 47,4 %, p<0,001) et avaient une capacité pulmonaire totale inférieure (74,1±13,7 versus 84,9±14,8 %, p<0,001) et une DLCO plus basse (73,3±17,9 versus 89,7±22,8 %, p<0,001). L’association d’une nouvelle dyspnée, de lésions fibrosantes et d’une DLCO<70 % était rarement observée (8/478 patients). Conclusion La dyspnée d’apparition récente et les lésions fibrosantes pulmonaire peu étendues sont fréquentes 4 mois après COVID-19 mais l’association d’une dyspnée avec des lésions fibrosantes et des troubles de la diffusion est rarement retrouvée.