Efficacy of Intravenous Anakinra and Ruxolitinib During COVID-19 Inflammation

Covid-19 Clinical Trial

— JAKINCOV  

Official title:

Interleukin-1 (IL-1) and Interferon Gamma (IFNg) Inhibition During COVID 19 Inflammation: Randomized, Controlled Study Assessing Efficacy and Safety of Anakinra and Ruxolitinib

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04366232
• Other study ID #: 2020-CHITS-003
• Secondary ID: 2020-001963-10
• Status: Terminated
• Phase: Phase 2
• Start date: August 19, 2020
• Est. completion date: October 2, 2020

Study information

• Verified date: December 2020
• Source: Centre Hospitalier Intercommunal de Toulon La Seyne sur Mer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

During SARS-Cov2 infection with serious respiratory implication and high systemic inflammation level, intravenous ANAKINRA alone or associated with RUXOLITINIB for severe cases might reduce inappropriate systemic inflammatory response, improve breathing and decrease occurrence or duration of ARDS and associated mortality.

Description:

Two physiopathological phases exist during COVID-19 disease: The early phase is mainly induced by the virus itself. It is imperative not to decrease the immune host response during this phase by prohibiting the use of non steroidal anti-inflammatory drugs or corticosteroids at this stage and developing an anti-viral strategy. The late phase, around Day 7-9, depends only upon host response and is linked to an excessive inflammatory response with a major increase of inflammatory cytokines such as IL-6, MCP-1, GCSF indicative of IL-1b excess, as well as IP-10, MIP-1, indicative of IFNg signature, corresponding to a "cytokine storm". Clinical and biological features during Still's disease (complicated in 10% of cases with hemophagocytosic lymphohistiocytosis inducing cytopenia, hepatic insufficiency, major hyperferritinemia and multi-organ failure) are close to those reported during COVID-19 and underline physiopathological similarities. Anakinra (KINERET) is an IL-1 pathway (IL-1ra) specific inhibitor that has been used for 15 years, also largely blocking IL-18 production. Adult Still's disease is very effectively treated with anakinra. During sepsis with hyperferritinemia, IL-1ra demonstrated patient survival improvement. Ruxolitinib (JAKAVI) inhibits the downstream IFNg pathway targeting JAK kinase receptor. It has recently proved its efficiency in hemophagocytosic lymphohistiocytosis refractory forms associated with a multi-organ failure.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: October 2, 2020
• Est. primary completion date: October 2, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Confirmed respiratory tract SARS-coV-2 infection by at least one PCR on nasopharygeal sample or a bronchoalveolar lavage
• Patient hospitalized with clinical, biological and radiological features corresponding

to the following stages :

• Stage 2b: hypoxic pneumonia (respiratory frequency > 30/mn, Sa02 < 90 mmHg on room air) associated with a clear biological inflammatory syndrome (CRP > 150 mg/l)
• Stage 3: ARDS defined by a patient under mechanical ventilation with a ratio PaO2/FiO2 < 300 for more than 24h
• Evolved stage 3: ARDS according to previous definition associated with another

organ failure or syndrome among:

• A state of shock with noradrenaline dosing > 3mg/h
• Acute kidney failure oligo-anuric or justifying extra-renal purification
• Hepatocellular insufficiency or coagulopathy with a V factor < 50%
• Myocarditis responsible for acute heart failure and or cardiogenic shock
• Hemophagocytic syndrome
• Hyperferritinemia > 5000 ng/mL
• Subject or legal representative having expressed written consent after information
• Subject affiliated to or entitled to a social security regimen
• Patient presenting in a life-threatening emergency situation that does not allow consent to be obtained

Exclusion Criteria:

• Pregnancy or lactation
• Absolute neutrophil count less than 1.5 x 109/L
• Hepatic transaminases AST or ALT greater than 5 times normal values
• Platelet count less than 50,000 per mm3
• Solid organ or hematopoietic stem cell transplant patients
• Patients treated with immunosuppressants or immunomodulators
• Use of oral corticosteroids chronically at doses greater than 10 mg prednisone equivalent per day for a non-COVID-19 related condition.
• Uncontrolled autoimmune disease
• Patients with active, suspected or known, uncontrolled systemic bacterial, viral (excluding COVID-19) or fungal infections
• Hypersensitivity to anakinra and/or ruxolitinib and their excipients
• Vaccinations with live attenuated vaccines in the month prior to inclusion
• Patients with severe pre-existing uncontrolled organ dysfunction (heart, liver or kidney failure)
• Persons deprived of liberty by judicial or administrative decision or major persons under a legal protection measure.
• Person in exclusion period of another research protocol for SARS-CoV-2 infection.
• Person not mastering enough French understanding and reading to be able to consent to participate in the study.
• Persons under psychiatric care pursuant to Articles A3112-1 and L3113-1 who are not covered by the provisions of Article L1121-8
• Every condition which, according to investigator, might increase and compromise the person security in case of study participation or might interfere with research results.

Related Conditions & MeSH terms

• Covid-19
• Inflammation

Intervention

Drug:
• Anakinra alone (stages 2b/3)
Anakinra 300 mg 1/d Intravenous 5 days then dose tapering
• Anakinra and Ruxolitinib (overcome stage 3)
Anakinra 300 mg od Intravenous (maximum14 days) Ruxolitinib 5 mg bid per os (maximum 28 days)

Other:
• Standard of care
Routine clinical care for Covid-19

Locations

Country	Name	City	State
France	AP-HM, Hôpital de la Conception	Marseille	Bouches-du-Rhône
France	Hôpital Sainte-Musse	Toulon	VAR
France	Sainte Anne Teaching Military Hospital	Toulon	Var

Sponsors (3)

Lead Sponsor	Collaborator
Centre Hospitalier Intercommunal de Toulon La Seyne sur Mer	Assistance Publique Hopitaux De Marseille, Hôpital d'instruction des armées Sainte-Anne

Country where clinical trial is conducted

France, 

References & Publications (3)

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Ep — View Citation

Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020 Apr 7;323(13):1239-1242. — View Citation

Zalinger ZB, Elliott R, Weiss SR. Role of the inflammasome-related cytokines Il-1 and Il-18 during infection with murine coronavirus. J Neurovirol. 2017 Dec;23(6):845-854. doi: 10.1007/s13365-017-0574-4. Epub 2017 Sep 11. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Biological criteria	At least 3 parameters are met including CRP and/or Ferritin among: CRP: decrease > 50%; Ferritinemia: decrease > 1/3; Serum creatinine: decrease > 1/3; AST/ALT: decrease > 50%; Eosinophils > 50 /mm3; Lymphocytes > 1000 /mm3	7 days from enrolment
Secondary	Duration of oxygen therapy (days)	Number of days without mechanical ventilation	28 days from enrolment
Secondary	Number of intensive care units admissions	Number of patients included in stage 2b	28 days from enrolment
Secondary	Number of days in intensive care units	Number of days in intensive care units for patients managed in intensive care units	28 days from enrolment
Secondary	Mortality rate	Mortality rate	28 days from enrolment
Secondary	Total number of days in hospital	Total number of days in hospital	28 days from enrolment
Secondary	Organ failure score modification (Sepsis-related Organ Failure Assessment (SOFA) score)	Organ failure score modification (Sepsis-related Organ Failure Assessment (SOFA) score); Sofa score's minimum and maximum values are 0 and 24, the lowest score corresponds to a better outcome.	28 days from enrolment
Secondary	Number of bacterial and/or fungal sepsis	Number of bacterial and/or fungal sepsis	28 days from enrolment