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

Primary Purpose

Obesity, COVID-19 Infection

Status

Unknown status

Phase

Phase 2

Locations

France

Study Type

Interventional

Intervention

NIVOLUMAB

Routine standard of care

About this trial

This is an interventional treatment trial for Obesity, COVID-19 Infection focused on measuring COVID-19, Obesity, Nivolumab, Immunotherapy, Anti-PD1

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Hôpital Lyon Sud Service Endocrinologie, Diabète et Nutrition

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

NIVOLUMAB on top of routine standard of care

Standard of care for COVID-19 infection

Arm Description

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

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

Outcomes

Primary Outcome Measures

Patient's clinical state

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

Readmission

Proportion of in-coming patients in ICU at D7 and D15 post-randomization

Mortality

Proportion of death at D7 and D15 post-randomization

Oxygen flow needs

Proportion of patients weaned out of oxygen at D7 post-randomization

Requirement of oxygen

Mean oxygen flow needed

Discharge from hospital

Proportion of out-coming patients from hospitalization at D7 and D15 post-randomization

Adverse events

Report of all adverse events linked or not to experimental treatment during the study

Presence of nasopharyngeal SARS-CoV-2

Presence or not of nasopharyngeal SARS-CoV-2 determined by PCR response

nasopharyngeal SARS-CoV-2 viral charge

Presence or not of nasopharyngeal SARS-CoV-2 Quantified by PCR

Number of total Lymphocytes T

Number of total LT (using immuno-phenotyping) will explore the immune response

Number of CD3+ Lymphocytes T(lymphocyte subpopulation of CD3+ T cells)

Number of CD3+ LT (using immuno-phenotyping) will explore the immune response

Number of CD4+ Lymphocytes T(lymphocyte subpopulation of CD4+ T cells)

Number of total CD4+ LT (using immuno-phenotyping) will explore the immune response

Number of CD8+ Lymphocytes T(lymphocyte subpopulation of CD8+ T cells)

Evaluation of number of CD8+ LT (using immuno-phenotyping) will explore the immune response

Interleukin 6 (IL-6)

Systemic concentration measurement of IL-6 will explore the inflammatory response

Interleukin 10 (IL-10)

Systemic concentration measurement of IL-10 will explore the inflammatory response

Tumor Necrosis Factor alpha (TNFα )

Systemic concentration measurement of TNFα will explore the inflammatory response

Interferon gamma (IFNγ)

Systemic concentration measurement of IFNγ will explore the inflammatory response

Type I Interferon (type I IFN)

Systemic concentration measurement of type I IFN will explore the inflammatory response

Tim3 expression

Evaluation of Tim3 expression on CD4+ and CD8+ lymphocytes will explore the fundamental research on obesity and COVID-19

PD1 expression

Evaluation of PD1 expression on CD4+ and CD8+ lymphocytes will explore the fundamental research on obesity and COVID-19

PD-L1 expression

Measurement of PD-L1 expression on monocytes will explore explore the fundamental research on obesity and COVID-19

Human Leukocyte Antigen - DR isotype gene expression (HLA-DR expression)

Measurement of HLA-DR expression on monocytes will explore explore the fundamental research on obesity and COVID-19

Production of IFNγ by lymphocytes T

The cytotoxic LT production of IFNγ will explore the fundamental research on obesity and COVID-19

Production of granzyme B by lymphocytesT

The cytotoxic LT production of granzyme B will explore the fundamental research on obesity and COVID-19

Lipopolysaccharides (LPS)

Measurement of LPS will explore the endotoxemia and perform fundamental research on obesity and COVID-19

LBP(LPS-Binding Protein)

Measurement of LBP (endotoxin transporter) will explore the endotoxemia and perform fundamental research on obesity and COVID-19

sCD14

Measurement of sCD14 (endotoxin transporter) will explore the endotoxemia and perform fundamental research on obesity and COVID-19

High Density Lipoproteins

Measurement of High Density Lipoproteins proteomic will explore the lipoprotein metabolism and perform fundamental research on obesity and COVID-19

Apolipoprotein

Measurement of apolipoprotein proteomic will explore the lipoprotein metabolism and perform fundamental research on obesity and COVID-19

Full Information

NCT ID

NCT04413838

First Posted

June 2, 2020

Last Updated

June 2, 2020

Sponsor

Hospices Civils de Lyon

1. Study Identification

Unique Protocol Identification Number

NCT04413838

Brief Title

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

Acronym

NIVISCO

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

Study Type

Interventional

2. Study Status

Record Verification Date

May 2020

Overall Recruitment Status

Unknown status

Study Start Date

June 15, 2020 (Anticipated)

Primary Completion Date

June 15, 2021 (Anticipated)

Study Completion Date

September 15, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Hospices Civils de Lyon

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Obesity, COVID-19 Infection

Keywords

COVID-19, Obesity, Nivolumab, Immunotherapy, Anti-PD1

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

120 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

NIVOLUMAB on top of routine standard of care

Arm Type

Experimental

Arm Description

Arm Title

Standard of care for COVID-19 infection

Arm Type

Other

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

NIVOLUMAB

Intervention Description

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

Intervention Type

Other

Intervention Name(s)

Routine standard of care

Intervention Description

No intervention is planned in this arm. Patients will follow routine standard of care for the COVID-19 treatment

Primary Outcome Measure Information:

Title

Patient's clinical state

Description

Time Frame

15 days after randomization

Secondary Outcome Measure Information:

Title

Readmission

Description

Proportion of in-coming patients in ICU at D7 and D15 post-randomization

Time Frame

7 days and 15 days after randomization

Title

Mortality

Description

Proportion of death at D7 and D15 post-randomization

Time Frame

7 days and 15 days after randomization

Title

Oxygen flow needs

Description

Proportion of patients weaned out of oxygen at D7 post-randomization

Time Frame

7 days after randomization

Title

Requirement of oxygen

Description

Mean oxygen flow needed

Time Frame

7 days and 15 days after randomization

Title

Discharge from hospital

Description

Proportion of out-coming patients from hospitalization at D7 and D15 post-randomization

Time Frame

7 days and 15 days after randomization

Title

Adverse events

Description

Report of all adverse events linked or not to experimental treatment during the study

Time Frame

Within 15 days post-randomization and 90 days and 6 months after randomization

Title

Presence of nasopharyngeal SARS-CoV-2

Description

Presence or not of nasopharyngeal SARS-CoV-2 determined by PCR response

Time Frame