JAKINCOV: Efficacy of Intravenous Anakinra and Ruxolitinib During COVID-19 Inflammation

Sponsor

Centre Hospitalier Intercommunal de Toulon La Seyne sur Mer (Other)

Overall Status

Terminated

CT.gov ID

NCT04366232

Collaborator

Hôpital d'instruction des armées Sainte-Anne (Other), Assistance Publique Hopitaux De Marseille (Other)

Enrollment

Locations

Arms

1.4

Actual Duration (Months)

0.7

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Covid-19	Drug: Anakinra alone (stages 2b/3) Drug: Anakinra and Ruxolitinib (overcome stage 3) Other: Standard of care	Phase 2

Detailed 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.

Study Design

Study Type:

Interventional

Actual Enrollment :

2 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Assignment to one of two or more groups in parallel during the study No crossoverAssignment to one of two or more groups in parallel during the study No crossover

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Aug 19, 2020

Actual Primary Completion Date :

Oct 2, 2020

Actual Study Completion Date :

Oct 2, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Anakinra +/- Ruxolitinib According to clinical stage (gradual strategy): Stage 2b or 3 : Anakinra 300 mg IV Overcome stage 3 : Anakinra 300 mg IV and Ruxolitinib 5 mg x 2	Drug: Anakinra alone (stages 2b/3) Anakinra 300 mg 1/d Intravenous 5 days then dose tapering Other Names: KINERET Drug: Anakinra and Ruxolitinib (overcome stage 3) Anakinra 300 mg od Intravenous (maximum14 days) Ruxolitinib 5 mg bid per os (maximum 28 days) Other Names: KINERET and JAKAVI
Active Comparator: Standard of care Treatment with drugs or procedures in routine clinical practice	Other: Standard of care Routine clinical care for Covid-19

Arm

Intervention/Treatment

Experimental: Anakinra +/- Ruxolitinib

According to clinical stage (gradual strategy): Stage 2b or 3 : Anakinra 300 mg IV Overcome stage 3 : Anakinra 300 mg IV and Ruxolitinib 5 mg x 2

Drug: Anakinra alone (stages 2b/3)

Anakinra 300 mg 1/d Intravenous 5 days then dose tapering

Other Names:

KINERET

Drug: Anakinra and Ruxolitinib (overcome stage 3)

Anakinra 300 mg od Intravenous (maximum14 days) Ruxolitinib 5 mg bid per os (maximum 28 days)

Other Names:

KINERET and JAKAVI

Active Comparator: Standard of care

Treatment with drugs or procedures in routine clinical practice

Other: Standard of care

Routine clinical care for Covid-19

Outcome Measures

Primary Outcome Measures

Biological criteria [7 days from enrolment]
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

Secondary Outcome Measures

Duration of oxygen therapy (days) [28 days from enrolment]
Number of days without mechanical ventilation
Number of intensive care units admissions [28 days from enrolment]
Number of patients included in stage 2b
Number of days in intensive care units [28 days from enrolment]
Number of days in intensive care units for patients managed in intensive care units
Mortality rate [28 days from enrolment]
Mortality rate
Total number of days in hospital [28 days from enrolment]
Total number of days in hospital
Organ failure score modification (Sepsis-related Organ Failure Assessment (SOFA) score) [28 days from enrolment]
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.
Number of bacterial and/or fungal sepsis [28 days from enrolment]
Number of bacterial and/or fungal sepsis

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	AP-HM, Hôpital de la Conception	Marseille	Bouches-du-Rhône	France	13005
2	Hôpital Sainte-Musse	Toulon	VAR	France	83000
3	Sainte Anne Teaching Military Hospital	Toulon	Var	France	83000