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

Primary Purpose

Covid-19

Status
Terminated
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Anakinra alone (stages 2b/3)
Anakinra and Ruxolitinib (overcome stage 3)
Standard of care
Sponsored by
Centre Hospitalier Intercommunal de Toulon La Seyne sur Mer
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Covid-19 focused on measuring COVID, SARS-CoV-2, Anakinra, Ruxolitinib, IL-1 inhibitors, JAK inhibitors

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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.

Sites / Locations

  • AP-HM, Hôpital de la Conception
  • Hôpital Sainte-Musse
  • Sainte Anne Teaching Military Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Anakinra +/- Ruxolitinib

Standard of care

Arm Description

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

Treatment with drugs or procedures in routine clinical practice

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Duration of oxygen therapy (days)
Number of days without mechanical ventilation
Number of intensive care units admissions
Number of patients included in stage 2b
Number of days in intensive care units
Number of days in intensive care units for patients managed in intensive care units
Mortality rate
Mortality rate
Total number of days in hospital
Total number of days in hospital
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.
Number of bacterial and/or fungal sepsis
Number of bacterial and/or fungal sepsis

Full Information

First Posted
April 27, 2020
Last Updated
December 11, 2020
Sponsor
Centre Hospitalier Intercommunal de Toulon La Seyne sur Mer
Collaborators
Hôpital d'instruction des armées Sainte-Anne, Assistance Publique Hopitaux De Marseille
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1. Study Identification

Unique Protocol Identification Number
NCT04366232
Brief Title
Efficacy of Intravenous Anakinra and Ruxolitinib During COVID-19 Inflammation
Acronym
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
Study Type
Interventional

2. Study Status

Record Verification Date
December 2020
Overall Recruitment Status
Terminated
Why Stopped
investigator decision
Study Start Date
August 19, 2020 (Actual)
Primary Completion Date
October 2, 2020 (Actual)
Study Completion Date
October 2, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centre Hospitalier Intercommunal de Toulon La Seyne sur Mer
Collaborators
Hôpital d'instruction des armées Sainte-Anne, Assistance Publique Hopitaux De Marseille

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Covid-19
Keywords
COVID, SARS-CoV-2, Anakinra, Ruxolitinib, IL-1 inhibitors, JAK inhibitors

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Assignment to one of two or more groups in parallel during the study No crossover
Masking
None (Open Label)
Allocation
Randomized
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Anakinra +/- Ruxolitinib
Arm Type
Experimental
Arm Description
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
Arm Title
Standard of care
Arm Type
Active Comparator
Arm Description
Treatment with drugs or procedures in routine clinical practice
Intervention Type
Drug
Intervention Name(s)
Anakinra alone (stages 2b/3)
Other Intervention Name(s)
KINERET
Intervention Description
Anakinra 300 mg 1/d Intravenous 5 days then dose tapering
Intervention Type
Drug
Intervention Name(s)
Anakinra and Ruxolitinib (overcome stage 3)
Other Intervention Name(s)
KINERET and JAKAVI
Intervention Description
Anakinra 300 mg od Intravenous (maximum14 days) Ruxolitinib 5 mg bid per os (maximum 28 days)
Intervention Type
Other
Intervention Name(s)
Standard of care
Intervention Description
Routine clinical care for Covid-19
Primary Outcome Measure Information:
Title
Biological criteria
Description
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
Time Frame
7 days from enrolment
Secondary Outcome Measure Information:
Title
Duration of oxygen therapy (days)
Description
Number of days without mechanical ventilation
Time Frame
28 days from enrolment
Title
Number of intensive care units admissions
Description
Number of patients included in stage 2b
Time Frame
28 days from enrolment
Title
Number of days in intensive care units
Description
Number of days in intensive care units for patients managed in intensive care units
Time Frame
28 days from enrolment
Title
Mortality rate
Description
Mortality rate
Time Frame
28 days from enrolment
Title
Total number of days in hospital
Description
Total number of days in hospital
Time Frame
28 days from enrolment
Title
Organ failure score modification (Sepsis-related Organ Failure Assessment (SOFA) score)
Description
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.
Time Frame
28 days from enrolment
Title
Number of bacterial and/or fungal sepsis
Description
Number of bacterial and/or fungal sepsis
Time Frame
28 days from enrolment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David DELARBRE, MD
Organizational Affiliation
French Army Health Service
Official's Role
Principal Investigator
Facility Information:
Facility Name
AP-HM, Hôpital de la Conception
City
Marseille
State/Province
Bouches-du-Rhône
ZIP/Postal Code
13005
Country
France
Facility Name
Hôpital Sainte-Musse
City
Toulon
State/Province
VAR
ZIP/Postal Code
83000
Country
France
Facility Name
Sainte Anne Teaching Military Hospital
City
Toulon
State/Province
Var
ZIP/Postal Code
83000
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32192578
Citation
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. Epub 2020 Mar 16. No abstract available.
Results Reference
result
PubMed Identifier
32091533
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. doi: 10.1001/jama.2020.2648. No abstract available.
Results Reference
result
PubMed Identifier
28895072
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.
Results Reference
result

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Efficacy of Intravenous Anakinra and Ruxolitinib During COVID-19 Inflammation

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