Induction of Regulatory t Cells by Low Dose il2 in Autoimmune and Inflammatory Diseases

Study Overview
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Brief Summary
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TRANSREG will assess the safety and biological efficacy of low-dose IL2 as a Treg inducer in a set of 14 autoimmune and auto-inflammatory diseases, with the aim to select diseases in which further therapeutic development will be performed. Extensive biological- and immune-monitoring pre- and post-IL2 will contribute (i) to define the common or distinct processes responsible for the breakdown of immunological tolerance in these pathologies and (ii) to discover potential biomarkers of the IL2 response.

Detailed Description
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Protocol: TRANSREG is a multicentric, uncontrolled, open-label study, comparing biological and clinical responses to the administration of low doses IL2 across 14 selected pathologies: rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet's disease, Wegener's granulomatosis, Takayasu's disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis, sclerosing cholangitis, Gougerot-sjögren, Systemic Sclerosis and Idiopathic Thrombocytopenic Purpura. Methods: Each patient will receive 1MUI /day of IL2 from Day-1 to Day-5 (the induction period), and then every 2 weeks (except systemic lupus erythematosus's patients will received every week) from Day-15 to Day-180 (the maintenance period). Patients will thereafter be followed up for 12 months (Day-181-Day-540). For each pathology, 6 patients will be included at Pitié-Salpêtrière, Cochin, Saint Antoine, Paul Brousse and Henri Mondor hospitals in Paris and Créteil, France. An interim analysis will be performed in each pathology group when the first six patients have received at least 3 months of treatment. In those pathology groups in which a Treg response will be documented, six additional patients will be included. In total, a minimum of 84 patients and up to 132 patients will be enrolled in this study. Primary efficacy endpoint is the Treg response at Day-8 compared to baseline. Secondary efficacy endpoints are:- evolution of the Treg response during the maintenance period,- the changes in markers of inflammation - the clinical response, evaluated by means of global generic scales [Clinical Global Impression severity scale (CGI-sev) and Clinical Global Impression efficacy index (CGI-eff)] as well as specific clinical and biological evaluations for each disease, - the frequency of relapses, - the assessment of quality of life (scale EuroQL-5). Expected Results: TRANSREG will define which patients respond to IL2, whether per pathology or according to pre-treatment phenomics, allowing to guide further clinical development of low dose IL2 in autoimmune and auto-inflammatory diseases.

Official Title
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Induction of Regulatory t Cells by Low Dose IL2 in Autoimmune and Inflammatory Diseases: a Transnosographic Approach

Conditions
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Rheumatoid Arthritis, Ankylosing Spondylitis, Systemic Lupus Erythematosus, Psoriasis, Behcet's Disease, Wegener's Granulomatosis, Takayasu's Disease, Crohn's Disease, Ulcerative Colitis, Autoimmune Hepatitis, Sclerosing Cholangitis, Gougerot-sjögren, Idiopathic Thrombocytopenic Purpura, Systemic Sclerosis

Intervention / Treatment
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* Drug: Interleukin 2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: age > 18 year male or female documented diagnosis of one AIID among the 14 diseases selected (following consensual specific criteria) stable or moderately active disease (except Lupus) under standard treatment (≥ 2 months) at the time of inclusion (except Sclerosing Cholangitis, Gougerot-sjögren, Takayasu's Disease and Systemic Sclerosis) normal thyroid function (with or without treatment) effective contraception for more than two weeks at inclusion and negative beta HCG test for women of childbearing potential, affiliated to the social security system written informed consent form. Exclusion Criteria: known intolerance for IL2 (see SPC), administration of a non-authorized treatment and/or IV bolus of corticosteroids in the last 2 months, vaccination with live attenuated virus in the months preceding the inclusion or planned during the study other severe or progressive autoimmune/inflammatory pathology, low white blood cell count<2000/mm3, lymphocytes <600/mm3, platelets <80 000/mm3, heart failure (≥ grade III NYHA), renal insufficiency (Cockcroft< 60ml/mn except patients with lupus or Wegener's granulomatosis) or hepatic insufficiency (transaminases> 5N except for patients with autoimmune hepatitis), or lung failure, significant abnormality in chest X-ray other than these linked to the diseases under investigation cancer or history of cancer cured for less than five years (except in situ carcinoma of the cervix or basocellular carcinoma) poor venous access not allowing repeated blood tests, restrictive diet or parenteral nutrition, surgery during the last 2 months or surgery planned during the study, participation in other biomedical research in the last 3 months or planned during the study. pregnant or lactating women, concomitant psychiatric disease or any other chronic illness or drug-abuse that could interfere with the ability to comply with the protocol or to give informed consent, positive HIV serology, active hepatitis B or EBV infection, patients under a measure of legal protection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Interleukin 2<br>Interleukin 2, 1MUI.= Proleukin®, RhIL-2 | Drug: Interleukin 2<br>* Induction period: repeated administration of low-dose IL-2 (1MUI/day, sc) during 5 consecutive days.Maintenance period: treatment with IL-2, 1MUI once every 15 days (except systemic lupus erythematosus's patients every 7 days) for 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentages of Tregs | Change in Treg percentage (percentages of Tregs within the CD4+ lymphocytes) at Day-8 after administration of low-dose of IL2 compared to baseline (Day0) | Day8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentages of Tregs | Changes in Treg percentage at Day 15, 29, 85, 183, 240, 360 and 540 compared to baseline (Day0) | Day 15, 29, 85, 183, 240, 360 and 540 | 
| inflammation markers (CRP and CRP ultra sensible) | Changes in levels of inflammation markers | Day 0, 1, 8, 15, 29, 85, 183, 240, 360 and 540 | 
| markers of inflammatory anemia (Hemoglobin, serum iron level, transferrin) ferritin | Changes in levels of inflammation markers | Day 0, 1, 8, 15, 29, 85, 183, 240, 360 and 540 | 
| Number of relapses |  | up to Day540 | 
| CGI-sev, CGI-activity and CGI-eff scales | Change in the clinical global impression severity and efficacy scale (CGI-sev, CGI-act and CGI-eff scales) at Day 85, 183, 240, 360 and 540 compared to baseline (Day1) | Day 85, 183, 240, 360 and 540 | 
| EuroQL-5 scale | Change in the quality of life (EuroQL-5 scale) | Day 183 | 
| Evolution of clinical, biological or radiological criteria specific to each disease | Changes in disease-specific score and/or evolution of clinical, biological or radiological criteria specific to each disease | up to Day 540 | 
| Safety Assessment | Safety Assessment all along the observation period (Day-1 to Day-240): Safety assessment will include vital signs, adverse events and concomitant medications collection as well as biology during the 6 months of the treatment period; .In addition, the evolution of the disease will be followed up to 1 year after IL2- treatment stop. | up to Day 540 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IL2,, Interleukin 2,, ILT101, Proleukin®, RhIL-2, Auto-immune disease, Inflammatory disease, Inflammation, Regulatory T cells,, Treg, Immunoregulation, Immune tolerance