InterLeukin-7 to Improve Clinical Outcomes in Lymphopenic pAtients With COVID-19 Infection FR BL Cohort

Study Overview
=================
Brief Summary
-----------------
Comparison of the effects of CYT107 vs Placebo administered IM at 10μg/ kg twice a week for two weeks on immune reconstitution of lymphopenic COVID-19 patients.

Detailed Description
-----------------
Approximately forty-eight (48) participants will be randomized 1:1 to receive (a) Intramuscular (IM) administration of CYT107 at 3 μg/kg followed, after 48hrs of observation, by 10 μg/kg twice a week for 2 weeks or (b) Intramuscular (IM) placebo (normal saline) at the same frequency. An interim safety review took place after the first 12 patients. Since the CYT107 was well tolerated, the test dose (3 μg/kg) ceased and the initial dose became the same as the rest of the doses (10 μg/kg). So, the remaining patients will be randomized to receive 5 administrations of (a) CYT107 at 10 μg/kg every 3 to 4 days for 2 weeks or (b) Intramuscular (IM) placebo (normal saline) at the same frequency. The aim of the study is to test the ability of CYT107 to produce an immune reconstitution of these patients and observe possible association with a clinical improvement

Official Title
-----------------
A Multicenter, Randomized, Double-blinded Placebo-controlled Study of Recombinant Interleukin-7 (CYT107) for Immune Restoration of Hospitalized Lymphopenic Patients With Coronavirus COVID-19 Infection in France and Belgium

Conditions
-----------------
COVID-19, Lymphocytopenia

Intervention / Treatment
-----------------
* Drug: Interleukin-7
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A written, signed informed consent, or emergency oral consent, by the patient or the patient's legally authorized representative, and the anticipated ability for participant to be re-consented in the future for ongoing Study participation Men and women aged ≥ 25 - 80 (included) years of age Hospitalized patients with one absolute lymphocyte count (ALC) ≤ 1000 cells/mm3, collected at baseline or no more than 72h before baseline Hospitalized patients with moderate to severe hypoxemia requiring oxygen therapy at >4L per minute nasal cannula or greater to keep saturations >90%, non-invasive positive pressure ventilation (e.g., BIPAP) for respiratory failure Confirmed infection with COVID-19 by any acceptable test available/ utilized at each site Patient with medical insurance or government support Exclusion Criteria: Pregnancy or breast feeding; Refusal or inability to practice contraception regardless of the gender of the patient; ALT and/or AST > 5 x ULN Known, active auto-immune disease; Ongoing cancer treatment with chemotherapy / immunotherapy or any cancer therapy within last 3 months and/or ongoing; Patients with past history of Solid Organ transplant. Active tuberculosis, uncontrolled active HBV or HCV infection, HIV with positive viral load. Patients whose respiratory condition is showing significant deterioration as indicated by: 8a requirement for an increase in inspired oxygen concentrations of 20% or more over the past 24 hours to maintain SpO2 at greater than or equal to 88% 8b or need for invasive mechanical ventilation Patients showing an increase of the NEWS2 score by more than 6 points during the screening / baseline period (48 to 72 hrs prior to first administration) Patients with chronic kidney dialysis Patients with a SOFA score ≥ 9 at baseline Patients with a BMI > 40 Patients receiving any agent with immune suppressive effects,such as anti-IL6 treatments like Tocilizumab or Sarilumab which should preferably be minimized Presence of any of the following abnormal laboratory values at screening: absolute neutrophil count (ANC) < 1.5x109/L, Platelets < 50,000 per mm3 Patients with uncontrolled pre-existing severe major organ dysfunction (cardiac, liver or renal failure) Vaccination with live attenuated vaccines in the month preceding the inclusion Use of chronic oral corticosteroids ≥ 10mg prednisone equivalent a day for a non-COVID-19 related condition Patients with baseline Rockwood Clinical Frailty Scale ≥ 6. Patients with known hypersensitivity to natural or recombinant Interleukin-7 or to any of the excipients Patients under guardianship

Ages Eligible for Study
-----------------
Minimum Age: 25 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized controlled of treatment vs placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CYT107<br>Intra-muscular administration of CYT107 twice a week for a total of 5 administrations | Drug: Interleukin-7<br>* Intramuscular (IM) administration of CYT107 at 3 μg/ kg followed, after 48hrs of observation, by 10 μg/kg twice a week for 2 weeks or<br>* Other names: CYT107;|
| Placebo Comparator: Saline<br>Intramuscular (IM) administration of saline at the same volume and same time for a total of 5 administrations | Drug: Placebo<br>* Intramuscular (IM) placebo (normal saline) at the same frequency<br>* Other names: Saline;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of the absolute lymphocyte count (ALC) of lymphopenic (ALC≤1000/mm3) COVID-19 infected participants out to approximately 30 days following initial Study drug administration or Hospital discharge (HD), whichever occurs first | A statistically significant increase of the absolute lymphocyte count (ALC) from randomization to day 30 or Hospital Discharge | 1 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To obtain clinical improvement as defined by an improvement in a 11-points WHO score for Clinical Assessment, through day 30 or HD. | to determine if CYT107 will improve the clinical status of hospitalized COVID-19 patients as measured by 11 steps WHO clinical improvement score | 1 month | 
| a significant decline of SARS-CoV-2 viral load through day 30 or HD | The decrease of SARS-CoV-2 viral load from measurements at baseline and days of treatment dose 4 and dose 5, Day 21 and Day 30 or HD (whichever occurs first) | 1 month or HD (whichever occurs first) | 
| frequency of secondary infections through day 45 compared tp placebo arm | Incidence of secondary infections based on pre-specified criteria as adjudicated by the Secondary Infections Committee (SIC) through Day 45 | 45 days | 
| length of hospitalization compared to placebo arm | Number of days of hospitalization during index hospitalization (defined as time from initial Study drug treatment through HD) | 45 days | 
| length of stay in ICU compared to placebo arm | Number of days in ICU during index hospitalization | 45 days | 
| number of readmissions to ICU compared to placebo arm | Readmissions to ICU through Day 45 | 45 days | 
| organ support free days compared to placebo arm | Organ support free days (OSFDs) during index hospitalization (This includes ventilator assistance free days) | 45 days | 
| Frequency of re-hospitalization through day 45 compared to placebo arm | Number of readmissions to the hospital through Day 45 | 45 days | 
| All-cause mortality through day 45 compared to placebo arm | All-cause mortality through Day 45 | 45 days | 
| CD4+ and CD8+ T cell counts compared to placebo arm | Absolute numbers of CD4+ and CD8+ T-cell counts at timepoints indicated on the Schedule of Activities (SoA) through Day 30 or HD | 30 days | 
| level of other known biomarkers of inflammation: Ferritin compared to placebo arm | Track and evaluate other known biomarkers of inflammation, Ferritin, from baseline to day 30 | 30 days | 
| Level of other known biomarkers of inflammation: CRP compared to placebo arm | Track and evaluate other known biomarkers of inflammation, CRP from baseline to day 30 | 30 days | 
| Level of other known biomarkers of inflammation: D-dimer compared to placebo arm | Track and evaluate other known biomarkers of inflammation, D-dimer from baseline to day 30 | 30 days | 
| Physiological status through NEWS2 evaluation compared to Placebo arm | Evaluate improvement of the NEWS2 score value. Score form 0 to 4: NO Risk Score of 7 or more: High risk | 30 days |