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Efficiency and Security of NIVOLUMAB Therapy in Obese Individuals With COVID-19(COrona VIrus Disease) Infection (NIVISCO)

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ClinicalTrials.gov Identifier: NCT04413838
Recruitment Status : Not yet recruiting
First Posted : June 4, 2020
Last Update Posted : June 4, 2020
Sponsor:
Information provided by (Responsible Party):
Hospices Civils de Lyon

Study Description
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Brief Summary:

Although SARS-CoV-2 (Severe Acute Respiratory Syndrome-associated coronavirus) due to COVID-19 evolves poorly towards ARDS (Acute Respiratory Distress Syndrome) and death, there is to date no validated drug available for severe forms of COVID-19. Patients with COVID-19 undergo a drastic decrease of T lymphocytes (LT) count, while the remaining ones display an "exhausted" phenotype, due to immunosuppressive pathway activation among which the Programed cell Death 1 (PD1) receptor pathways. LT exhaustion is responsible for host anergy towards viral infection and leads to increased risk of severe forms of COVID-19. Moreover, while the number of systemic LT PD1+ correlates with poor prognosis clinical stages of COVID-19 infection, healing from COVID-19 associates with LT PD1 expression normalization. Chinese epidemiologic data identified clinical risk factors of poor clinical evolution (i.e. ARDS or death), among which is found obesity, similarly to observation previously obtained during H1N1 infection (flu virus).

Obese persons display meta-inflammation and immune dysfunction, a condition similar to ageing, thus termed "Inflamm-aging", thus also used during obesity. Inflamm-aging, characterized by cytotoxic LT exhaustion and reduced NK cell (Natural Killer cell) cytotoxic function secondary to PD1 pathway activation, could contribute to the poor prognosis observed during cancer and infection in obese individuals. We hypothesize that the immunocompromised profile observed during obesity contribute to their vulnerability towards COVID-19.

In cancer or certain infection diseases, NIVOLUMAB, an anti-PD1 monoclonal antibody, restores exhausted LT immunity. We thus hypothesize that NIVOLUMAB-induced immunity normalization could (i) stimulate anti-viral response also during COVID-19 infection and (ii) prevent ARDS development, which has previously been associated with low LT count concomitant with increased inflammatory cytokine production.

This randomized controlled therapeutic trial, using an add-on strategy to usual standard of care, aims at demonstrating the efficacy and safety of NIVOLUMAB-induced cytotoxic LT normalization, to improve clinical outcomes in hospitalized COVID-19+ adult obese individuals with low LT, since they are at risk of poor prognosis. We postulate that NIVOLUMAB will increase the number of individuals able to stop oxygen therapy at D15


Condition or disease Intervention/treatment Phase
Obesity, COVID-19 Infection Drug: NIVOLUMAB Other: Routine standard of care Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Study of the Efficiency and Security of NIVOLUMAB Therapy, Used in Immuno-stimulation, in Hospitalized Obese Individuals at Risk to Evolve Towards Severe Forms of COVID-19 Infection. Multicentric, Paralleled, Randomized, Controlled Trial
Estimated Study Start Date : June 15, 2020
Estimated Primary Completion Date : June 15, 2021
Estimated Study Completion Date : September 15, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arms and Interventions
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Arm Intervention/treatment
Experimental: NIVOLUMAB on top of routine standard of care
This correspond to COVID-19+ patients diagnosed upon biological testing (PCR Coronavirus SARS-CoV2), hospitalized, obese (BMI≥30kg/m²), with low lymphocyte counts, without high biological probability of macrophage activation syndrome (hemoglobin < 9.2 g/dl AND a blood platelets < 110000/mm3 AND aspartate aminotransferase (AST) > 30 U/l AND ferritin > 600 mg/l) and upon oxygen (either using mask or nasal cannula) but without criteria for ICU admission benefiting from a NIVOLUMAB treatment and routine standard of care for COVID-19 infection at the time of study inclusion
 Drug: NIVOLUMAB
IV injection within 30 minutes of 24ml file (=240 mg) containing NIVOLUMAB BMS(Bristol-Myers Squibb) 10mg/ml (immune check point inhibitor targeting PD-1) on top of routine standard of care for COVID-19 infection
Standard of care for COVID-19 infection
This correspond to COVID-19+ patients diagnosed upon biological testing (PCR Coronavirus SARS-CoV2), hospitalized, obese (BMI≥30kg/m²), with low lymphocyte counts, without high biological probability of macrophage activation syndrome (hemoglobin < 9.2 g/dl AND a blood platelets < 110000/mm3 AND AST > 30 U/l AND ferritin > 600 mg/l) and upon oxygen (either using mask or nasal cannula) but without criteria for ICU admission benefiting from a routine standard of care for COVID-19 infection at the time of study inclusion
 Other: Routine standard of care
No intervention is planned in this arm. Patients will follow routine standard of care for the COVID-19 treatment


Outcome Measures
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Primary Outcome Measures :
  1. Patient's clinical state [ Time Frame: 15 days after randomization ]
    Patient's clinical state will be evaluated by the proportion of patients able to be weaned of oxygen at D15 after randomization (randomization date is the day where the experimental treatment (i.e. NIVOLUMAB) is administered).


Secondary Outcome Measures :
  1. Readmission [ Time Frame: 7 days and 15 days after randomization ]
    Proportion of in-coming patients in ICU at D7 and D15 post-randomization

  2. Mortality [ Time Frame: 7 days and 15 days after randomization ]
    Proportion of death at D7 and D15 post-randomization

  3. Oxygen flow needs [ Time Frame: 7 days after randomization ]
    Proportion of patients weaned out of oxygen at D7 post-randomization

  4. Requirement of oxygen [ Time Frame: 7 days and 15 days after randomization ]
    Mean oxygen flow needed

  5. Discharge from hospital [ Time Frame: 7 days and 15 days after randomization ]
    Proportion of out-coming patients from hospitalization at D7 and D15 post-randomization

  6. Adverse events [ Time Frame: Within 15 days post-randomization and 90 days and 6 months after randomization ]
    Report of all adverse events linked or not to experimental treatment during the study

  7. Presence of nasopharyngeal SARS-CoV-2 [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Presence or not of nasopharyngeal SARS-CoV-2 determined by PCR response

  8. nasopharyngeal SARS-CoV-2 viral charge [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Presence or not of nasopharyngeal SARS-CoV-2 Quantified by PCR

  9. Number of total Lymphocytes T [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Number of total LT (using immuno-phenotyping) will explore the immune response

  10. Number of CD3+ Lymphocytes T(lymphocyte subpopulation of CD3+ T cells) [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Number of CD3+ LT (using immuno-phenotyping) will explore the immune response

  11. Number of CD4+ Lymphocytes T(lymphocyte subpopulation of CD4+ T cells) [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Number of total CD4+ LT (using immuno-phenotyping) will explore the immune response

  12. Number of CD8+ Lymphocytes T(lymphocyte subpopulation of CD8+ T cells) [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Evaluation of number of CD8+ LT (using immuno-phenotyping) will explore the immune response

  13. Interleukin 6 (IL-6) [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Systemic concentration measurement of IL-6 will explore the inflammatory response

  14. Interleukin 10 (IL-10) [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Systemic concentration measurement of IL-10 will explore the inflammatory response

  15. Tumor Necrosis Factor alpha (TNFα ) [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Systemic concentration measurement of TNFα will explore the inflammatory response

  16. Interferon gamma (IFNγ) [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Systemic concentration measurement of IFNγ will explore the inflammatory response

  17. Type I Interferon (type I IFN) [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Systemic concentration measurement of type I IFN will explore the inflammatory response

  18. Tim3 expression [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Evaluation of Tim3 expression on CD4+ and CD8+ lymphocytes will explore the fundamental research on obesity and COVID-19

  19. PD1 expression [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Evaluation of PD1 expression on CD4+ and CD8+ lymphocytes will explore the fundamental research on obesity and COVID-19

  20. PD-L1 expression [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Measurement of PD-L1 expression on monocytes will explore explore the fundamental research on obesity and COVID-19

  21. Human Leukocyte Antigen - DR isotype gene expression (HLA-DR expression) [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Measurement of HLA-DR expression on monocytes will explore explore the fundamental research on obesity and COVID-19

  22. Production of IFNγ by lymphocytes T [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    The cytotoxic LT production of IFNγ will explore the fundamental research on obesity and COVID-19

  23. Production of granzyme B by lymphocytesT [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    The cytotoxic LT production of granzyme B will explore the fundamental research on obesity and COVID-19

  24. Lipopolysaccharides (LPS) [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Measurement of LPS will explore the endotoxemia and perform fundamental research on obesity and COVID-19

  25. LBP(LPS-Binding Protein) [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Measurement of LBP (endotoxin transporter) will explore the endotoxemia and perform fundamental research on obesity and COVID-19

  26. sCD14 [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Measurement of sCD14 (endotoxin transporter) will explore the endotoxemia and perform fundamental research on obesity and COVID-19

  27. High Density Lipoproteins [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Measurement of High Density Lipoproteins proteomic will explore the lipoprotein metabolism and perform fundamental research on obesity and COVID-19

  28. Apolipoprotein [ Time Frame: On day 0 before randomization and 15 days after randomization ]
    Measurement of apolipoprotein proteomic will explore the lipoprotein metabolism and perform fundamental research on obesity and COVID-19


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients between 18 and 70 years old
  • COVID-19+ patients diagnosed upon biological testing (PCR Coronavirus SARS-CoV2)
  • Hospitalized patients
  • Obese individuals (BMI≥30kg/m²)
  • Lymphocyte counts between 500 and 1500/mm3.
  • Patients upon oxygen (either using mask or nasal cannula).
  • Patients within their first 7 days after the beginning of symptoms.
  • Women of childbearing potential: effective contraception for the duration of the study and 5 months after the administration of treatment.
  • Patient who understands and accepts the need for a long term follow-up,
  • Patients who agrees to be included in the study and who signs the informed consent form,
  • Patients affiliated to a healthcare insurance plan.

Exclusion Criteria:

  • CRITERIA LINKED TO THE DISEASE SEVERITY :

    • Patients hospitalized in ICU or constant care unit.
    • Patients with clinical symptoms requiring ICU admission (respiratory rate>30/min, oxygen requirement> 4Liters/min (using high concentration mask) to reach and maintain O2saturation>90%, qSOFA≥ 2(quick score of Sepsis-related Organ Failure Assessment), or associated multi-visceral failure.
    • Patients with high biological probability of macrophage activation syndrome (hemoglobin < 9.2 g/dl AND a blood platelets < 110000/mm3 AND AST > 30 U/l AND ferritin > 600 mg/l).

CRITERIA LINKED TO THE TREATMENT TOXICITY :

  • Patients currently treated for cancer or with personal history of cancer within the last 3 years.
  • Patients with Chronic Obstructive Pulmonary Disease (COPD) (GOLD 3 and 4 stages).
  • Chronic respiratory insufficiency treated with oxygen.
  • Patients aged above 70 years old.
  • Active smoking.
  • Personal history of thoracic radiotherapy.
  • Patients with known sensibility to NIVOLUMAB or one of its component.
  • Patients upon immunosuppressive dosage of corticoids.
  • Patients upon immunosuppressive therapy or immunosuppressed patients.
  • Patients already presenting severe autoimmune disease, for whom additional immunologic activation response would potentially precipitate lethal prognosis

GENERAL CRITERIA:

  • Minor Patients
  • Mentally unbalanced patients, under supervision or guardianship,
  • Patient deprived of liberty,
  • Patient who does not understand French/ is unable to give consent,
  • Patient already included in a trial who may interfere with the study or in a period of exclusion following participation in a previous study.
  • Pregnant (controlled by a pregnancy test) or lactating woman
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04413838


Contacts
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Contact: Emmanuel DISSE, Pr +33 4 78 86 14 84 emmanuel.disse@chu-lyon.fr
Contact: Dominique DELAUNAY +33.4.72.11.00.64 Dominique.delaunay@chu-lyon.fr

Locations
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France
Hôpital Lyon Sud Service Endocrinologie, Diabète et Nutrition
Pierre-Bénite, France, 69495
Contact: Pr         
Principal Investigator: Emmanuel DISSE         
Sponsors and Collaborators
Hospices Civils de Lyon
More Information
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Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT04413838    
Other Study ID Numbers: 69HCL20_0478
First Posted: June 4, 2020    Key Record Dates
Last Update Posted: June 4, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hospices Civils de Lyon:
COVID-19
Obesity
Nivolumab
Immunotherapy
Anti-PD1
Additional relevant MeSH terms:
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Infections
Communicable Diseases
COVID-19
Disease Attributes
Pathologic Processes
Respiratory Tract Infections
Pneumonia, Viral
Pneumonia
Virus Diseases
Coronavirus Infections
 Coronaviridae Infections
Nidovirales Infections
RNA Virus Infections
Lung Diseases
Respiratory Tract Diseases
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action