COVID-19 Clinical Trials and Expanded Access

Background: There are no proven therapies specific for pulmonary dysfunction in patientswith acute hypoxemic respiratory failure (AHRF) caused by infections (includingCovid-19). The full spectrum of AHRF ranges from mild respiratory tract illness to severepneumonia, acute respiratory distress syndrome (ARDS), multiorgan failure, and death. Theefficacy of corticosteroids in AHRF and ARDS caused by infections remains controversial.Methods: This is a multicenter, randomized, controlled, open-label clinical trial testingdexamethasone in mechanically ventilated adult patients with established AHRF (includingARDS) caused by confirmed pulmonary or systemic infections, admitted in a network ofSpanish ICUs. Eligible patients will be randomly assigned to receive dexamethasone:either 6 mg/d x 10 days or 20 mg/d x 5 days followed by 10 mg/d x 5 days. The primaryoutcome is 60-day mortality. The secondary outcome is the number of ventilator-free daysat 28 days. All analyses will be done according to the intention-to-treat principle.

Time to recover of Anosmia and / or ageusia and early corticosteroid use

The purpose of this umbrella study is to evaluate isatuximab when combined with novelagents with or without dexamethasone in participants with relapsed or refractory myeloma.Substudy 01 is the control Substudy. Substudies 02, 03, and 06 are controlledexperimental substudies. Substudies 04 and 05 are independent experimental substudies.

This is a first-in-human study, Phase 1, randomized, placebo-controlled, double blindedstudy that will be conducted in 2 parts.

Prospective, single center, randomized, open label, parallel group, 2-arm study assessingthe clinical benefit in term of enhancement of overall response rate of Isatuximab incombination with CellProtect as compared to Isatuximab for the treatment of patients withnewly diagnosed multiple myeloma who are eligible for stem cell transplantation (SCT) asmaintenance after SCT.

Currently, there is no approved treatment for COVID-19 in France, either for the acutephase, nor for the late chronic phase. the investigator suggest that nintedanib has thepotential to block the development of lung fibrosis when initiated early enough toinhibit the activation of mesenchymal cells and the progression of virus-inducedpulmonary fibrosis. Computerized Tomography (CT) manifestations of fibrosis or fibrousstripes are described in COVID-19 (Ye, Eur Radiol 2020). Pan et al observed fibrousstripes in 17% patients in the early phase of the disease (Pan, Eur Radiol 2020). Ye etal observed bronchiectasis in 2 patients (15.4%) and evidence of pulmonary fibrosis in 3patients (23.7%) at HRCT performed at 4 weeks (Ye, Eur Radiol 2020). Long term data arestill lacking in patients with COVID-19 and the investigators do not know how manypatients will have fibrotic sequelae from the acute illness.

The goal of this project is to rapidly screen promising agents, in the setting of anadaptive platform trial, for treatment of critically ill COVID-19 patients. In this phase2 platform design, agents will be identified with a signal suggesting a big impact onreducing mortality and the need for, as well as duration, of mechanical ventilation.

COVID-19 is a community acquired pneumonia caused by infection with a novel coronavirus,SARS CoV2 and is a serious condition with high mortality in hospitalised patients, forwhich there is no currently approved treatment other than supportive care. Urgentinvestigation of potential treatments for this condition is required.This protocol describes an overarching and adaptive trial designed to provide safety,pharmacokinetic (PK)/ pharmacodynamic (PD) information and exploratory biologicalsurrogates of efficacy which may support further development and deployment of candidatetherapies in larger scale trials of COVID-19 positive patients receiving normal standardof care.Given the spectrum of clinical disease, community based infected patients or hospitalisedpatients can be included. Products requiring parenteral administration will only beinvestigated in hospitalised patients. Patients will be divided into cohorts, a)community b) hospitalised patients with new changes on a chest x-ray (CXR) or a computedtomography (CT) scan or requiring supplemental oxygen and c) hospitalised requiringassisted ventilation. Participants may be recruited from all three of these cohorts,depending on the experimental therapy, its route of administration and mechanism ofaction. The relevant cohort(s) for any given therapy will be detailed in thetherapy-specific appendix.Candidate therapies can be added to the protocol and previous candidates removed fromfurther investigation as evidence emerges. The trial will be monitored by an independentData Monitoring Committee (DMC) to ensure patient safety.Each candidate cohort will include a small cohort of patients randomised to candidatetherapy or existing standard of care management dependent on disease stage at entry.Cohort numbers will be defined in the protocol appendices.This is a Phase IIa experimental medicine trial and as such formal sample sizecalculations are not appropriate.

This Phase 2 Randomized Placebo Controlled Trial will determine if administeringnebulized Dornase Alpha (rhDNase) to COVID-19 patients with respiratory failure is safeand will reduce 28-day mortality.

Patients suffering lung failure, possibly from COVID-19 or hypoxic lung failure, willneed life-saving support from a breathing machine. Any patient needing this supportrequires drugs to keep them sleepy, or "sedated" to be comfortable on this machine.Sedation is made possible by using drugs given through a vein. Unfortunately, these drugsare in short supply worldwide due to the high number of COVID-19 patients needing thesemachines.Another way to provide sleep is by using gases that are breathed in. These are used everyday in operating rooms to perform surgery. These gases, also called "inhaled agents" canalso be used in intensive care units and may have several important benefits for patientsand the hospital. Research shows they may reduce swelling in the lung and increase oxygenlevels, which allows patients to recover faster and reduce the time spent on a breathingmachine. In turn, this allows the breathing machine to be used again for the next sickpatient. These drugs may also increase the number of patients who live through theirillness. Inhaled agents are widely available and their use could dramatically lesson thepressure on limited drug supplies.This research is a study being carried out in a number of hospitals that will compare howwell patients recover from these illnesses depending on which type of sedation drug theyreceive. The plan is to evaluate the number who survive, their time spent on a breathingmachine and time in the hospital. This study may show immediate benefits and may providea cost effective and practical solution to the current challenges caring for patients andthe hospital space, equipment and drugs to the greatest benefit. Furthermore, the studywill be investigating inflammatory profile and neuro-cognitive profiles in ventilatedpatients. Finally, this trial will be a team of experts in sedation drugs who care forpatients with proven or suspected COVID-19 who need lifesaving treatments.