A Trial Using ANAKINRA, TOCILIZUMAB Alone or in Association With RUXOLITINIB in Severe Stage 2b and 3 of COVID19-associated Disease

Sponsor
Assistance Publique Hopitaux De Marseille
Study ID
NCT04424056
Phase
PHASE3
Status
Unknown

Conditions

Eligibility Criteria

Sex
ALL
Age
18 Years - 75 Years
Healthy Volunteers
Not accepted

Interventions

Study Details

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

Key Dates

Start date
Sep 1, 2020
Status verified
Jun 2020
Primary completion
Sep 30, 2022
Completion
Nov 1, 2022

Study Design

Enrollment
216 participants (estimated)
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT

Arms

  • Experimental: Anakinra +/- Ruxolitinib
    Anakinra +/- Ruxolitinib According to clinical stage (gradual strategy): Stage 2b or 3 : Anakinra +/- ruxolitinib depending of evolution; Advanced stage 3 : Anakinra and Ruxolitinib
  • Experimental: Tocilizumab +/- Ruxolitinib
    Tocilizumab +/- Ruxolitinib According to clinical stage (gradual strategy): Stage 2b or 3 : Tocilizumab +/- ruxolitinib depending of evolution; Advanced stage 3: Tocilizumab +ruxolitinib
  • Active Comparator: Standard of care
    Treatment with drugs or procedures in routine clinical practice

Primary Outcome Measure

Ventilation free days at D28 [ Time Frame: 28 days ]

Central Contacts

Related Studies