NCT04424056: INFLAMMACOV

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

Status unknown Phase 3 Last updated 23 June 2020

What this trial tests

Phase 3 trial testing Anakinra +/- Ruxolitinib (stages 2b/3) in Covid19 in 216 participants. Status unknown.

Timeline

1 September 2020

Primary endpoint
30 September 2022

1 November 2022

Quick facts

Lead sponsor	Assistance Publique Hopitaux De Marseille
Phase	Phase 3
Status	Status unknown
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	216
Start date	1 September 2020
Primary completion	30 September 2022
Estimated completion	1 November 2022
Sites	1 location across France

Drugs / interventions tested

• Anakinra +/- Ruxolitinib (stages 2b/3) — full drug profile →
• Anakinra and Ruxolitinib (Advanced stage 3) — full drug profile →
• Tocilizumab +/- ruxolitinib (stages 2b/3) — full drug profile →
• Tocilizumab and Ruxolitinib (Advanced stage 3) — full drug profile →
• Standard of care

Conditions studied

• Covid19 — all drugs for Covid19 →

Sponsor

Assistance Publique Hopitaux De Marseille — full company profile →

Who can join

Adults 18 to 75, any sex, with Covid19. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own description

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

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. COVID-19 and Cancer: Current Challenges and Perspectives.
   Bakouny Z, Hawley JE, Choueiri TK, Peters S, et al · · 2020 · cited 201× · PMID 33049215 · DOI 10.1016/j.ccell.2020.09.018
2. COVID-19: Characteristics and Therapeutics.
   Chilamakuri R, Agarwal S. · · 2021 · cited 192× · PMID 33494237 · DOI 10.3390/cells10020206
3. An update on drugs with therapeutic potential for SARS-CoV-2 (COVID-19) treatment.
   Drożdżal S, Rosik J, Lechowicz K, Machaj F, et al · · 2021 · cited 186× · PMID 34991982 · DOI 10.1016/j.drup.2021.100794
4. Viral Respiratory Pathogens and Lung Injury.
   Clementi N, Ghosh S, De Santis M, Castelli M, et al · · 2021 · cited 127× · PMID 33789928 · DOI 10.1128/cmr.00103-20
5. JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy.
   Satarker S, Tom AA, Tom AA, Shaji RA, et al · · 2021 · cited 117× · PMID 33245005 · DOI 10.1080/00325481.2020.1855921
6. JAK-STAT signaling in human disease: From genetic syndromes to clinical inhibition.
   Luo Y, Alexander M, Gadina M, O'Shea JJ, et al · · 2021 · cited 92× · PMID 34625141 · DOI 10.1016/j.jaci.2021.08.004
7. The potential of JAK/STAT pathway inhibition by ruxolitinib in the treatment of COVID-19.
   Goker Bagca B, Biray Avci C. · · 2020 · cited 84× · PMID 32636055 · DOI 10.1016/j.cytogfr.2020.06.013
8. Cytokines and Chemokines in SARS-CoV-2 Infections-Therapeutic Strategies Targeting Cytokine Storm.
   Pum A, Ennemoser M, Adage T, Kungl AJ. · · 2021 · cited 70× · PMID 33445810 · DOI 10.3390/biom11010091