Clinical trial NCT04357444: Low Dose of IL-2 In Acute Respiratory DistrEss Syndrome Related to COVID-19
Official title: Low Dose of IL-2 In Acute Respiratory DistrEss Syndrome Related to COVID-19
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID 19
Keywords: COVID-19
SARS-CoV2
Acute Respiratory Distress Syndrome
Low dose of IL-2
Immunotherapy
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Iltoo Pharma
First posted: 2020-04-22
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose is to demonstrate the efficacy of low-dose interleukin 2 (Ld-IL2) administration in improving clinical course and oxygenation parameters in patients with SARS-CoV2-related ARDS.

Detailed description: About 25% of hospitalized patients with SARS-CoV2 infection presented life-threatening respiratory conditions. Of these, 60% met ARDS criteria leading to death in 25% to 63% of the cases. SARS-CoV2-related ARDS is caused by a massive inflammatory cell infiltration leading to dysregulated cytokine/chemokine responses with lung immunopathological changes. To date, there is no treatment available.

Regulatory T cells (Treg) are a subpopulation of CD4+ T cells playing a crucial role in the control of immune responses, in part by preventing excessive inflammation. Depletion of Treg cells in models of lung infection or after berylium exposure exacerbated lung inflammation. In contrast, a beneficial role for Treg during early ARDS and its resolution has been observed.

Low-dose interleukin 2 (Ld-IL2) is the first therapy driving Treg-specific expansion and activation. Ld-IL2 was successfully tested in a wide range of preclinical models of inflammatory diseases, including beryllium-induced lung inflammation. Moreover, Ld-IL2 has been shown to be safe and free of serious adverse events when administered in patients with various autoimmune diseases. Importantly, in our previous work, we observed only very low concentrations of IL-2 in the blood (0.1 pg/mL \[0.0-2.0\]) as well as in the BAL supernatant (0.8 pg/mL \[0.4-1.3\]) collected from patients during the early phase of ARDS, suggesting that additional IL-2 could be beneficial for Treg expansion/activation.

Our objective is therefore to investigate the therapeutic benefit of Ld-IL2 as a Treg inducer for controlling SARS-CoV2-related ARDS.

After admission of patients to the intensive care unit at one of the recruiting centers, the eligibility criteria will be checked by the investigating physician and participation in the study will be proposed to the patient or parent/family member/trusted person. If the patient is unable to consent and there is no parent/family member/trusted person, the patient may be included in the emergency procedure.

After inclusion (J0), the patient will be randomized to one of the 2 treatment arms (low dose IL-2 or placebo).

The experimental treatment will be daily administered to the patient from D1 to D10.

The patient will be monitored daily until D28 during hospitalization.

Eligibility criteria: Inclusion Criteria:

* Male or female, age ≥ 18 years
* Laboratory (RT-PCR) confirmed infection with SARS-CoV2
* Patient is either under invasive or non-invasive mechanical ventilation (including high flow nasal oxygen therapy).
* Diagnosis of ARDS according to the Berlin definition of ARDS
* Onset of ARDS \<96 hours
* Patient with French Social Security System
* A written informed consent by the designated substitute decision maker, if present. In the event of absence, the patient can be included by investigator's decision alone.

Exclusion Criteria:

* Previous history of ARDS in the last month
* Chronic respiratory diseases requiring long-term oxygen therapy and/or long-term respiratory assistance
* History of organ allograft.
* Active cancer
* Liver cirrhosis with basal Child and Pugh of C
* Pulmonary fibrosis
* Patient with end-of-life decision
* Patient not expected to survive for 24 hours
* Woman known to be pregnant, lactating or with a positive (urine or serum test) or indeterminate (serum test) pregnancy test
* Patient already enrolled in another interventional pharmacotherapy protocol on COVID-19
* Patient with known hypersensitivity to natural or recombinant Interleukin-2 or to any of the excipients
* Presence of any of the following abnormal laboratory values at screening: absolute neutrophil count (ANC) less than 1.5x109/L, AST or ALT greater than 5 x ULN, platelets \<50,000 per mm3
* Use of chronic oral corticosteroids \> 10 mg prednisone equivalent a day for a non-COVID-19-related condition
* Current uncontrolled autoimmune disease
* Patients with uncontrolled suspected or known active systemic bacterial or fungal infections
* Patient with severe, uncontrolled pre-existing (chronic) organ failure (myocardial, hepatic or renal)
* Vaccination with live attenuated vaccines in the month preceding the inclusion
* Patient with burns to ≥ 15% of their total body surface area
* Patient receiving extra-corporeal membrane oxygenation, high-frequency oscillatory ventilation or any form of extra-corporeal lung support
* Patient under legal protection (protection of the court, or in curatorship or guardianship).

Primary outcomes:
measure: The PaO2/FiO2 ratio at D11
timeFrame: at Day11
Secondary outcomes:
measure: Changes in Tregs between Baseline and Day 7 (expressed in %)
timeFrame: at Day0 and Day7
measure: Number of days alive with oxygen therapy within 28 days
timeFrame: at Day28
measure: Maximal oxygen rate within 28 days
timeFrame: at Day28
measure: Number of days alive free of invasive or non-invasive ventilation within 28 days
timeFrame: At Day28
measure: Number of days alive outside ICU within 28 days
timeFrame: at Day28
measure: Number of days alive outside hospital within 28 days
timeFrame: at Day28
measure: Time (in days) from randomization to death
timeFrame: through study completion at day 28
measure: Mortality rate at D28
timeFrame: at Day28
measure: Difference between CRP levels at randomization and at Day 7 (or at the time of discharge if occurs before Day 7)
timeFrame: at Day0 and Day7 or at the time of discharge
measure: Use of antibiotics for respiratory (proved or suspected) infection within 28 days
timeFrame: at Day28
measure: Number of prone positioning sessions
timeFrame: throughout the follow up period at day 28
measure: Changes in Tregs during the different visits between baseline and day 28
timeFrame: at Day0, 5, 7, 11, 14 and Day28
measure: Cytokines analysis on plasma samples at Day 0, 7 and 14
timeFrame: at Day 0, 7 and 14
measure: Tregs numbers during induction period and throughout the follow up period at day 5, 7, 11, 14 and 28 compared to baseline before the first IL-2 injection.
timeFrame: at Day0, 5, 7, 11, 14 and Day28
measure: Tregs percentages during induction period and throughout the follow up period at day 5, 7, 11, 14 and 28 compared to baseline before the first IL-2 injection.
timeFrame: at Day0, 5, 7, 11, 14 and Day28
measure: Deep Immunophenotyping of Cellular components in blood samples at Day 0, 7, and 14
timeFrame: at Day0, 7 and Day14
measure: T cell repertoire on Treg, after sorting from blood at Day 7 and Day 14 and compared to baseline
timeFrame: at Day0, 7 and Day14
measure: T cell repertoire on Teff (CD4 and CD8) after sorting from blood at Day 7 and Day 14 and compared to baseline
timeFrame: at Day0, 7 and Day14
measure: Single cells sequencing will be performed in BAL at Day 7 and Day 14 and compared to baseline.
timeFrame: at Day0, 7 and Day14
Other outcomes:
Locations:
city: Paris
country: France
facility: Service Anesthésie Réanimation - Groupe Hospitalier Pitié-Salpêtrière
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Jean-Michel CONSTANTIN
role: PRINCIPAL_INVESTIGATOR
References: