Covid19 Clinical Trial
Official title:
An Open Randomized Therapeutic Trial Using ANAKINRA, TOCILIZUMAB Alone or in Association With RUXOLITINIB in Severe Stage 2b and 3 of COVID19-associated Disease
COVID19-associated disease may have different clinical aspects classified in 3 stages. Some
patients initially presenting with a non-hypoxemic viral pneumonia (stage 2a) may evolve
toward a more severe stage 2b or 3 (acute respiratory distress syndrome, ARDS) around the 7th
or 10th day of evolution, with a severe biological inflammatory syndrome (CRP>200 mg/l), and
some times more severe complications such as acute renal insufficiency, consumptive
coagulopathy or shock, requiring increasing oxygen therapy, ICU admission, invasive
mechanical ventilation and possibly leading to death. This detrimental evolution is due to a
host-derived "cytokine storm" with a great excess of circulating inflammatory cytokines. In
animal models of ARDS complicating coronavirus or influenza virus infection, the cytokine
storm has been linked to hyperactivation of the NLRP3 inflammasome. NLRP3 constitutes an
intracellular protein platform which is responsible for caspase1 activation and processing of
interleukin (IL)-1beta and IL-18 . IL-1b is a major proinflammatory cytokine which induces
IL-6, whereas IL-18 is an inducer of interferon gamma (IFNg) production by Th-1 lymphocytes.
A blood IL-1/IL-6 signature can be defined by increased neutrophilia and CRP concentrations,
whereas an IL-18/IFNg signature is characterized by severe hyperferritinemia, consumptive
coagulopathy and cytopenia. A majority of patients with COVID-19 infections seems to have an
IL-1/IL-6 signature, evolving in the more severe forms toward an IL-18/IFNg signature,
mimicking cytokine profiles observed in other inflammatory diseases such as Still's disease
or hemophagocytic syndromes. In Still's disease, therapeutic inhibition of IL-1 or IL-6 has
proven to be very efficient strategies. During hemophagocytic syndromes, inhibition of IFNg
is effective in humans notably through blockade of its receptor signalization, using the JAK
kinase inhibitor ruxolitinib.
Following this strategy, we propose to use biological drugs currently available for
inhibition of IL-1 (anakinra), IL-6 (tocilizumab) or IFNg signaling (ruxolitinib) in the
severe forms of COVID19-associated disease. Our hypothesis is that IL-1, IL-6 or JAK kinase
inhibition will allow:
1. to prevent stage 2b worsening and the need to be admitted in ICU, by decreasing
oxygen-requirement and systemic inflammation
2. to improve stage 3 and extremely severe stage 3, allowing invasive mechanical
ventilation weaning, improving multi-system organ dysfunction, leading to a faster ICU
exit.
We propose an open randomized therapeutic trial (1/1/1) on 216 patients with severe stage 2b
and 3 of the disease
n/a
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