Pulmonary Hypertension Association's 2022 International Conference Scientific Sessions Overview.

The considerable progress made in recent years in the diagnosis, risk stratification, and treatment of pulmonary hypertension was highlighted during the most recent edition of the Pulmonary Hypertension Association Scientific Sessions, which was held in Atlanta, Georgia from June 9 to 11, 2022, with the theme: Vision for the PHuture: The Evolving Science and Management of PH. Content presented over the 3-day conference focused on scientific and management updates since the last sessions were held in 2018 and included didactic talks, debates, and roundtable discussions across a broad spectrum of topics related to pulmonary hypertension. This article aims to summarize the key messages from each of the session talks.

Randomised controlled studies in Germany and the world during the COVID-19 pandemic: classic or flexible study design?

Summary Background: During the COVID-19 pandemic, platform trials with a flexible, adaptive design have emerged as an important study design for randomised controlled trials (RCTs) to provide timely, robust findings on new interventions based on large numbers of participants. Since Germany has often been criticised for deficits in clinical research during the pandemic, we compared the study landscape of various countries during the pandemic. Method(s): ClinicalTrials.gov, the U.S. National Library of Medicine's central trial registry and the Cochrane COVID-19 trial registry were searched for interventional RCTs and platform studies on COVID-19 up to 8 February 2022. The results on number, status, number of participants and funding of the countries were compared. Result(s): A total of 1,246 interventional RCTs and 45 platform studies were registered in Germany, France, UK, US and Australia until February 2022. Germany coordinated only a small proportion of initiated trials. In Germany, one RCT per 1 million inhabitants has been identified;whereas more than twice as many have been identified in France and the US. About a quarter of the RCTs initiated in Germany with >500 participants were completed. In the US, 99 % were completed. One platform study per 100 million inhabitants was initiated in Germany, six in US, eleven in Australia and UK and 18 in France. Conclusion(s): Compared to other countries, Germany initiated fewer interventional RCTs and platform studies during the pandemic. The results from platform studies formed a relevant basis for evidence-based recommendations on interventions to treat COVID-19. Germany contributed little evidence to COVID-19 guidelines. Copyright © 2022 DIOmed Verlags GmbH. All rights reserved.

Pandemic vaccine testing: Combining conventional and challenge studies.

Early into COVID, human challenge trials were considered, but usually as alternatives to conventional randomized controlled trials. Instead, assessment of authorized COVID vaccines, of further COVID vaccines, and of vaccines against future pandemics should combine both designs, in five different ways, including a wholly novel one that we elaborate, Viz., combining data from both designs to answer a single question.

Intratumoral OH2, an oncolytic herpes simplex virus 2, in patients with advanced solid tumors: a multicenter, phase I/II clinical trial.

BACKGROUND: OH2 is a genetically engineered oncolytic herpes simplex virus type 2 designed to selectively amplify in tumor cells and express granulocyte-macrophage colony-stimulating factor to enhance antitumor immune responses. We investigated the safety, tolerability and antitumor activity of OH2 as single agent or in combination with HX008, an anti-programmed cell death protein 1 antibody, in patients with advanced solid tumors. METHODS: In this multicenter, phase I/II trial, we enrolled patients with standard treatment-refractory advanced solid tumors who have injectable lesions. In phase I, patients received intratumoral injection of OH2 at escalating doses (106, 107 and 108CCID50/mL) as single agent or with fixed-dose HX008. The recommended doses were then expanded in phase II. Primary endpoints were safety and tolerability defined by the maximum-tolerated dose and dose-limiting toxicities (DLTs) in phase I, and antitumor activity assessed per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and immune-RECIST in phase II. RESULTS: Between April 17, 2019 and September 22, 2020, 54 patients with metastatic cancers were enrolled. Forty patients were treated with single agent OH2, and 14 with OH2 plus HX008. No DLTs were reported with single agent OH2 in phase I. Four patients, having metastatic mismatch repair-proficient rectal cancer or metastatic esophageal cancer, achieved immune-partial response, with two from the single agent cohort and two from the combination cohort. The duration of response were 11.25+ and 14.03+ months for the two responders treated with single agent OH2, and 1.38+ and 2.56+ months for the two responders in the combination cohort. The most common treatment-related adverse event (TRAE) with single agent OH2 was fever (n=18, 45.0%). All TRAEs were of grade 1-2, except one case of grade 3 fever in the 108CCID50/mL group. No treatment-related serious AEs occurred. Single agent OH2 induced alterations in the tumor microenvironment, with clear increases in CD3+ and CD8+ cell density and programmed death-ligand 1 expression in the patients' post-treatment biopsies relative to baseline. CONCLUSIONS: Intratumoral injection of OH2 was well-tolerated, and demonstrated durable antitumor activity in patients with metastatic esophageal and rectal cancer. Further clinical development of OH2 as single agent or with immune checkpoint inhibitors in selected tumor types is warranted.

Phase 1 open-label trial of intravenous administration of MVA-BN-brachyury-TRICOM vaccine in patients with advanced cancer.

BACKGROUND: MVA-BN-brachyury-TRICOM is a recombinant vector-based therapeutic cancer vaccine designed to induce an immune response against brachyury. Brachyury, a transcription factor overexpressed in advanced cancers, has been associated with treatment resistance, epithelial-to-mesenchymal transition, and metastatic potential. MVA-BN-brachyury-TRICOM has demonstrated immunogenicity and safety in previous clinical trials of subcutaneously administered vaccine. Preclinical studies have suggested that intravenous administration of therapeutic vaccines can induce superior CD8+ T cell responses, higher levels of systemic cytokine release, and stronger natural killer cell activation and proliferation. This is the first-in-human study of the intravenous administration of MVA-BN-brachyury-TRICOM. METHODS: Between January 2020 and March 2021, 13 patients were treated on a phase 1, open-label, 3+3 design, dose-escalation study at the National Institutes of Health Clinical Center. The study population was adults with advanced solid tumors and was enriched for chordoma, a rare sarcoma of the notochord that overexpresses brachyury. Vaccine was administered intravenously at three DLs on days 1, 22, and 43. Blood samples were taken to assess drug pharmacokinetics and immune activation. Imaging was conducted at baseline, 1 month, and 3 months post-treatment. The primary endpoint was safety and tolerability as determined by the frequency of dose-limiting toxicities; a secondary endpoint was determination of the recommended phase 2 dose. RESULTS: No dose-limiting toxicities were observed and no serious adverse events were attributed to the vaccine. Vaccine-related toxicities were consistent with class profile (ie, influenza-like symptoms). Cytokine release syndrome up to grade 2 was observed with no adverse outcomes. Dose-effect trend was observed for fever, chills/rigor, and hypotension. Efficacy analysis of objective response rate per RECIST 1.1 at the end of study showed one patient with a partial response, four with stable disease, and eight with progressive disease. Three patients with stable disease experienced clinical benefit in the form of improvement in pain. Immune correlatives showed T cell activation against brachyury and other tumor-associated cascade antigens. CONCLUSIONS: Intravenous administration of MVA-BN-brachyury-TRICOM vaccine was safe and tolerable. Maximum tolerated dose was not reached. The maximum administered dose was 109 infectious units every 3 weeks for three doses. This dose was selected as the recommended phase 2 dose. TRIAL REGISTRATION NUMBER: NCT04134312.

Clinical trials on drug repositioning for COVID-19 treatment.

The World Health Organization (WHO) was informed on December 2019 about a coronavirus pneumonia outbreak in Wuhan, Hubei province (China). Subsequently, on March 12, 2020, 125,048 cases and 4,614 deaths were reported. Coronavirus is an enveloped RNA virus, from the genus Betacoronavirus, that is distributed in birds, humans, and other mammals. WHO has named the novel coronavirus disease as COVID-19. More than 80 clinical trials have been launched to test coronavirus treatment, including some drug repurposing or repositioning for COVID-19. Hence, we performed a search in March 2020 of the clinicaltrials.gov database. The eligibility criteria for the retrieved studies were: contain a clinicaltrials.gov base identifier number; describe the number of participants and the period for the study; describe the participants' clinical conditions; and utilize interventions with medicines already studied or approved for any other disease in patients infected with the novel coronavirus SARS-CoV-2 (2019-nCoV). It is essential to emphasize that this article only captured trials listed in the clinicaltrials.gov database. We identified 24 clinical trials, involving more than 20 medicines, such as human immunoglobulin, interferons, chloroquine, hydroxychloroquine, arbidol, remdesivir, favipiravir, lopinavir, ritonavir, oseltamivir, methylprednisolone, bevacizumab, and traditional Chinese medicines (TCM). Although drug repurposing has some limitations, repositioning clinical trials may represent an attractive strategy because they facilitate the discovery of new classes of medicines; they have lower costs and take less time to reach the market; and there are existing pharmaceutical supply chains for formulation and distribution.

En diciembre de 2019 fue informado a la Organización Mundial de la Salud (OMS) un brote de neumonía por coronavirus en Wuhan, provincia de Hubei, China. Al 12 de marzo de 2020, se habían notificado 125 048 casos y 4 614 muertes. El coronavirus es un virus ARN envuelto del género Betacoronavirus distribuido en aves, seres humanos y otros mamíferos. La OMS ha denominado a la nueva enfermedad por coronavirus COVID-19. Se han puesto en marcha más de 80 ensayos clínicos para evaluar un tratamiento para el coronavirus, que incluyen algunos ensayos de reposicionamiento de medicamentos para la COVID-19. En marzo de 2020 se llevó a cabo una búsqueda de los ensayos clínicos registrados en la base de datos clinicaltrials.gov. Los criterios de elegibilidad para los estudios recuperados fueron tener un número de identificación de la base de datos clinicaltrials.gov; describir el número de participantes y el período del estudio; describir las condiciones clínicas de los participantes; y emplear intervenciones con medicamentos ya estudiados o aprobados para cualquier otra enfermedad en pacientes infectados con el nuevo coronavirus SARS-CoV-2 (2019-nCoV). Es esencial destacar que este artículo solo recoge los ensayos que figuran en la base de datos clinicaltrials. gov. Se identificaron 24 ensayos clínicos relacionados con más de 20 medicamentos, como inmunoglobulina humana, interferones, cloroquina, hidroxicloroquina, arbidol, remdesivir, favipiravir, lopinavir, ritonavir, oseltamivir, metilprednisolona, bevacizumab y medicina tradicional china. Aunque el reposicionamiento de medicamentos tiene algunas limitaciones, el reposicionamiento de los ensayos clínicos puede representar una estrategia atractiva porque facilita el descubrimiento de nuevas clases de medicamentos; estos tienen costos más bajos y tardan menos en llegar al mercado; y existen cadenas de suministro farmacéutico que apoyan la formulación y la distribución.

A Organização Mundial da Saúde (OMS) foi informada, em dezembro de 2019, sobre um surto de pneumonia por coronavírus em Wuhan, província de Hubei (China). Posteriormente, em 12 de março de 2020, 125 048 casos e 4 614 mortes haviam sido registrados. O coronavírus é um vírus RNA envelopado do gênero Betacoronavírus, distribuído em aves e em humanos e outros mamíferos. A OMS designou a nova doença por coronavírus como COVID-19. Mais de 80 ensaios clínicos foram iniciados para testar tratamentos para o coronavírus, incluindo alguns de reposicionamento de medicamentos para o COVID-19. Assim, em março de 2020 realizou-se uma busca na base de dados clinicaltrials.gov. Os critérios de elegibilidade para os estudos recuperados foram: conter o número identificador da base de dados clinicaltrials.gov; descrever o número de participantes e o período do estudo; descrever as condições clínicas dos participantes; e utilizar intervenções para tratamento de doentes infectados com o novo coronavírus SARS-CoV-2 (2019-nCoV) com medicamentos já estudados ou aprovados para qualquer outra doença. É essencial salientar que este artigo apenas capturou ensaios listados na base de dados clinicaltrials.gov. Foram identificados 24 ensaios clínicos envolvendo mais de 20 medicamentos, tais como imunoglobulina humana, interferons, cloroquina, hidroxicloroquina, arbidol, remdesivir, favipiravir, lopinavir, ritonavir, oseltamivir, metilprednisolona, bevacizumabe e medicamentos chineses tradicionais. Embora o reposicionamento de medicamentos tenha algumas limitações, os ensaios clínicos de reposicionamento podem representar uma estratégia atraente, porque facilitam a descoberta de novas classes de medicamentos, têm custos mais baixos, levam menos tempo para chegar ao mercado e se beneficiam de cadeias de fornecimento farmacêutico já existentes para formulação e distribuição.

Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors.

Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.

Study Design Characteristics and Pharmacological Mechanisms in International Clinical Trials Registry Platform: Registered Clinical Trials on Antiviral Drugs for COVID-19.

OBJECTIVE: This study aimed to evaluate the pharmacological mechanisms of antiviral drugs against the novel coronavirus disease (COVID-19) and the study designs in clinical trials registered with the International Clinical Trials Registry Platform (ICTRP). METHODS: Clinical trials involving antiviral drugs for treating COVID-19 were retrieved from the ICTRP database. For each trial, the study design, number of participants, primary endpoints, source register, antiviral mechanism, and results were evaluated. RESULTS: On June 10, 2020, 145 eligible clinical trials were retrieved from the ICTRP, of which 99 (68.3%) were randomized trials, 109 (75.2%) were parallel assignment trials, 38 (26.2%) were double or single blinded, 130 (89.7%) involved two groups, and 75 (51.6%) included more than 100 participants; and clinical improvement or recovery and virus-negative conversion were the two most common endpoints, accounting for 40.7% and 18.6%, respectively. The drugs were divided according to the antiviral mechanism into HIV reverse transcriptase inhibitors, RNA-dependent RNA polymerase inhibitors, HIV protease inhibitors (PIs), hepatitis C virus NS3 PIs, and anti-influenza drugs. CONCLUSION: The design characteristics of clinical trials of antiviral drugs for treating COVID-19 as well as the mechanism of action and antiviral efficacy of the drugs were evaluated in this study. The results of these trials could constitute a reference for future clinical trials to be executed on COVID-19 treatment and prevention.

The effect of small versus large clog size on emergency response time: A randomized controlled trial.

OBJECTIVES: To assess the effect on healthcare professional emergency response time and safety of small compared to large clog size. DESIGN: Randomized controlled trial. SETTING: The intensive care unit of a single university medical centre in The Netherlands. PARTICIPANTS: Intensive care medicine professionals. INTERVENTIONS: Participants were randomized to wear European size 38 clogs (US male size 6½, US female size 7½) or European size 47 clogs (US male size 13½, US female size 14½) clogs and were required to run a 125 m course from the coffee break room to the elevator providing access to the emergency department. MAIN OUTCOME MEASURES: The primary outcome was the time to complete the running course. Height, shoe size, self-described fitness, age and staff category were investigated as possible effect modifiers. Secondary endpoints were reported clog comfort and suspected unexpected clog-related adverse events (SUCRAEs). RESULTS: 50 participants were randomized (25 to European size 38 clogs and 25 to size 47 clogs). Mean age was 37 years (SD 12) and 29 participants (58%) were female. The primary outcome was 4.4 s (95% CI -7.1; -1.6) faster in the size 5 clogs group compared to the size 12 clogs group. This effect was not modified by any of the predefined participant characteristics. No differences were found in reported clog comfort or SUCRAEs. CONCLUSIONS: European size 38 clogs lead to faster emergency response times than size 47 clogs. TRIAL REGISTRATION: NCT04406220.

Clinical trials for the prevention and treatment of COVID-19: current state of play.

Since coronavirus disease 2019 (COVID-19) emerged in Wuhan, China in December 2019 and spread around the world, over 1100 clinical studies have been registered globally on clinical trials registries, including over 500 randomised controlled trials. Such rapid development and launch of clinical trials is impressive but presents challenges, including the potential for duplication and competition. There is currently no known effective treatment for COVID-19. In order to focus on those studies most likely to influence clinical practice, we summarise the 31 currently registered randomised trials with a target sample size of at least 1000 participants. We have grouped these trials into four categories: prophylaxis; treatment of outpatients with mild COVID-19; treatment of hospitalised patients with moderate COVID-19; and treatment of hospitalised patients with moderate or severe disease. The most common therapeutic agent being trialled currently is hydroxychloroquine (24 trials with potential sample size of over 25 000 participants), followed by lopinavir-ritonavir (seven trials) and remdesevir (five trials) There are many candidate drugs in pre-clinical and early phase development, and these form a pipeline for future large clinical trials if current candidate therapies prove ineffective or unsafe.