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Low Dose of IL-2 In Acute Respiratory DistrEss Syndrome Related to COVID-19 (LILIADE-COVID)

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ClinicalTrials.gov Identifier: NCT04357444
Recruitment Status : Recruiting
First Posted : April 22, 2020
Last Update Posted : November 20, 2020
Sponsor:
Collaborator:
Iltoo Pharma
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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.

Condition or disease Intervention/treatment Phase
COVID 19 Drug: 1: ILT101 Drug: 2: Placebo Comparator Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Low Dose of IL-2 In Acute Respiratory DistrEss Syndrome Related to COVID-19
Actual Study Start Date : October 23, 2020
Actual Primary Completion Date : November 2, 2020
Estimated Study Completion Date : February 23, 2021


Arm Intervention/treatment
Experimental: 1: ILT101
ILT-101 in Subcutaneous route
Drug: 1: ILT101
Subcutaneous injections, once-daily administration for 10 consecutive days.

Placebo Comparator: 2: Placebo Comparator
Placebo in subcutaneous injections every day during 10 days
Drug: 2: Placebo Comparator
placebo in Subcutaneous route




Primary Outcome Measures :
  1. The PaO2/FiO2 ratio at D11 [ Time Frame: at Day11 ]

Secondary Outcome Measures :
  1. Changes in Tregs between Baseline and Day 7 (expressed in %) [ Time Frame: at Day0 and Day7 ]
  2. Number of days alive with oxygen therapy within 28 days [ Time Frame: at Day28 ]
  3. Maximal oxygen rate within 28 days [ Time Frame: at Day28 ]
  4. Number of days alive free of invasive or non-invasive ventilation within 28 days [ Time Frame: At Day28 ]
  5. Number of days alive outside ICU within 28 days [ Time Frame: at Day28 ]
  6. Number of days alive outside hospital within 28 days [ Time Frame: at Day28 ]
  7. Time (in days) from randomization to death [ Time Frame: through study completion at day 28 ]
  8. Mortality rate at D28 [ Time Frame: at Day28 ]
  9. Difference between CRP levels at randomization and at Day 7 (or at the time of discharge if occurs before Day 7) [ Time Frame: at Day0 and Day7 or at the time of discharge ]
  10. Use of antibiotics for respiratory (proved or suspected) infection within 28 days [ Time Frame: at Day28 ]
  11. Number of prone positioning sessions [ Time Frame: throughout the follow up period at day 28 ]
  12. Changes in Tregs during the different visits between baseline and day 28 [ Time Frame: at Day0, 5, 7, 11, 14 and Day28 ]
  13. Cytokines analysis on plasma samples at Day 0, 7 and 14 [ Time Frame: at Day 0, 7 and 14 ]
    To evaluate selected immune and inflammatory markers: Serum concentrations of cytokines and soluble factors related to the immune response and inflammatory processes will be evaluated and compare to baseline by multiplex immunoprofiling to analyse a larger number of molecules including at least IFNα2, IFNγ, IL-1α, IL-1β, IL-1RA, IL-2, IL-6, IL-8, IL-10, IL-17, TNFα, TNFβ, VEGF-A, TGF-beta, S-RAGE, SP-A, SP-D, Angiopoétine 1 and KGF.

  14. 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. [ Time Frame: at Day0, 5, 7, 11, 14 and Day28 ]
  15. 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. [ Time Frame: at Day0, 5, 7, 11, 14 and Day28 ]
  16. Deep Immunophenotyping of Cellular components in blood samples at Day 0, 7, and 14 [ Time Frame: at Day0, 7 and Day14 ]
    Cellular components will be analysed by flow cytometry covering (i) most of the innate and adaptive immune cells including Tregs, T helper cell subsets including follicular helper cells, B cell subsets, NK cell subsets, (ii) the associated relevant markers of activation/function/differentiation, tissue migration, as well as (iii) unconventional lymphoid cells (NKT/MAIT, innate lymphoid cells), myeloid-derived suppressor cells, classical and non-classical monocytes and dendritic cells (mDC1/2, pDC).

  17. T cell repertoire on Treg, after sorting from blood at Day 7 and Day 14 and compared to baseline [ Time Frame: at Day0, 7 and Day14 ]
  18. T cell repertoire on Teff (CD4 and CD8) after sorting from blood at Day 7 and Day 14 and compared to baseline [ Time Frame: at Day0, 7 and Day14 ]
  19. Single cells sequencing will be performed in BAL at Day 7 and Day 14 and compared to baseline. [ Time Frame: at Day0, 7 and Day14 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female, age ≥ 18 years
  • Laboratory (RT-PCR) confirmed infection with SARS-CoV2
  • Patient is intubated and mechanically ventilated
  • 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
  • Allogeneic bone marrow transplantation
  • 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
  • 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).

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): NCT04357444


Contacts
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Contact: Jean-Michel CONSTANTIN, MD, PhD +33(0) 1 42 16 00 00 Jean-michel.constantin@aphp.fr

Locations
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France
Service Anesthésie Réanimation - Groupe Hospitalier Pitié-Salpêtrière Recruiting
Paris, France, 75013
Contact: Jean-Michel CONSTANTIN, MD, PhD    +33(0) 1 42 16 00 00    Jean-michel.constantin@aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Iltoo Pharma
Investigators
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Principal Investigator: Jean-Michel CONSTANTIN Assistance Publique - Hôpitaux de Paris
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT04357444    
Other Study ID Numbers: APHP200406
2020-001571-32 ( EudraCT Number )
First Posted: April 22, 2020    Key Record Dates
Last Update Posted: November 20, 2020
Last Verified: November 2020

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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 Assistance Publique - Hôpitaux de Paris:
COVID-19
SARS-CoV2
Acute Respiratory Distress Syndrome
Low dose of IL-2
Immunotherapy
Additional relevant MeSH terms:
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Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Acute Lung Injury
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Lung Injury