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

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

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

Study Overview

• Status: Unknown
• Conditions: Obesity, COVID-19 Infection
• Intervention / Treatment: Drug: NIVOLUMAB; Other: Routine standard of care

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Pierre-Bénite, France, 69495
    • Hôpital Lyon Sud Service Endocrinologie, Diabète et Nutrition

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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
Other: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	15 days after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Readmission	Proportion of in-coming patients in ICU at D7 and D15 post-randomization	7 days and 15 days after randomization
Mortality	Proportion of death at D7 and D15 post-randomization	7 days and 15 days after randomization
Oxygen flow needs	Proportion of patients weaned out of oxygen at D7 post-randomization	7 days after randomization
Requirement of oxygen	Mean oxygen flow needed	7 days and 15 days after randomization
Discharge from hospital	Proportion of out-coming patients from hospitalization at D7 and D15 post-randomization	7 days and 15 days after randomization
Adverse events	Report of all adverse events linked or not to experimental treatment during the study	Within 15 days post-randomization and 90 days and 6 months after randomization
Presence of nasopharyngeal SARS-CoV-2	Presence or not of nasopharyngeal SARS-CoV-2 determined by PCR response	On day 0 before randomization and 15 days after randomization
nasopharyngeal SARS-CoV-2 viral charge	Presence or not of nasopharyngeal SARS-CoV-2 Quantified by PCR	On day 0 before randomization and 15 days after randomization
Number of total Lymphocytes T	Number of total LT (using immuno-phenotyping) will explore the immune response	On day 0 before randomization and 15 days after randomization
Number of CD3+ Lymphocytes T(lymphocyte subpopulation of CD3+ T cells)	Number of CD3+ LT (using immuno-phenotyping) will explore the immune response	On day 0 before randomization and 15 days after randomization
Number of CD4+ Lymphocytes T(lymphocyte subpopulation of CD4+ T cells)	Number of total CD4+ LT (using immuno-phenotyping) will explore the immune response	On day 0 before randomization and 15 days after randomization
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	On day 0 before randomization and 15 days after randomization
Interleukin 6 (IL-6)	Systemic concentration measurement of IL-6 will explore the inflammatory response	On day 0 before randomization and 15 days after randomization
Interleukin 10 (IL-10)	Systemic concentration measurement of IL-10 will explore the inflammatory response	On day 0 before randomization and 15 days after randomization
Tumor Necrosis Factor alpha (TNFα )	Systemic concentration measurement of TNFα will explore the inflammatory response	On day 0 before randomization and 15 days after randomization
Interferon gamma (IFNγ)	Systemic concentration measurement of IFNγ will explore the inflammatory response	On day 0 before randomization and 15 days after randomization
Type I Interferon (type I IFN)	Systemic concentration measurement of type I IFN will explore the inflammatory response	On day 0 before randomization and 15 days after randomization
Tim3 expression	Evaluation of Tim3 expression on CD4+ and CD8+ lymphocytes will explore the fundamental research on obesity and COVID-19	On day 0 before randomization and 15 days after randomization
PD1 expression	Evaluation of PD1 expression on CD4+ and CD8+ lymphocytes will explore the fundamental research on obesity and COVID-19	On day 0 before randomization and 15 days after randomization
PD-L1 expression	Measurement of PD-L1 expression on monocytes will explore explore the fundamental research on obesity and COVID-19	On day 0 before randomization and 15 days after randomization
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	On day 0 before randomization and 15 days after randomization
Production of IFNγ by lymphocytes T	The cytotoxic LT production of IFNγ will explore the fundamental research on obesity and COVID-19	On day 0 before randomization and 15 days after randomization
Production of granzyme B by lymphocytesT	The cytotoxic LT production of granzyme B will explore the fundamental research on obesity and COVID-19	On day 0 before randomization and 15 days after randomization
Lipopolysaccharides (LPS)	Measurement of LPS will explore the endotoxemia and perform fundamental research on obesity and COVID-19	On day 0 before randomization and 15 days after randomization
LBP(LPS-Binding Protein)	Measurement of LBP (endotoxin transporter) will explore the endotoxemia and perform fundamental research on obesity and COVID-19	On day 0 before randomization and 15 days after randomization
sCD14	Measurement of sCD14 (endotoxin transporter) will explore the endotoxemia and perform fundamental research on obesity and COVID-19	On day 0 before randomization and 15 days after randomization
High Density Lipoproteins	Measurement of High Density Lipoproteins proteomic will explore the lipoprotein metabolism and perform fundamental research on obesity and COVID-19	On day 0 before randomization and 15 days after randomization
Apolipoprotein	Measurement of apolipoprotein proteomic will explore the lipoprotein metabolism and perform fundamental research on obesity and COVID-19	On day 0 before randomization and 15 days after randomization

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Anticipated): June 15, 2020
• Primary Completion (Anticipated): June 15, 2021
• Study Completion (Anticipated): September 15, 2021

Study Registration Dates

• First Submitted: June 2, 2020
• First Submitted That Met QC Criteria: June 2, 2020
• First Posted (Actual): June 4, 2020

Study Record Updates

• Last Update Posted (Actual): June 4, 2020
• Last Update Submitted That Met QC Criteria: June 2, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Obesity; Nivolumab; Immunotherapy; COVID-19; Anti-PD1
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; COVID-19; Infections; Communicable Diseases; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: 69HCL20_0478

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No