Biological Activity and Safety of Low Dose IL2 in Relapsing Remitting Multiple Sclerosis

Study Overview
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Brief Summary
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Interleukin-2 (IL-2) was initially discovered and used as a stimulator of effector T lymphocytes (Teffs), but is now viewed as a very promising immunoregulatory drug having the capacity to stimulate regulatory T cells (Tregs). At low dose, Il-2 tips the Treg/Teff balance towards Tregs. Recently, it has been shown that Tregs of MS patients have reduced proliferative potential. MS-IL2 will assess the safety and biological efficacy of low-dose IL2 as a Treg inducer in a Relapsing-Remitting Multiple Sclerosis (RRMS), with the aim to stimulate Treg and define potential clinical benefits

Detailed Description
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In MS-IL2, 30 RRMS patients will be treated in a randomized, double-blind, placebo controlled clinical trial. IL-2 will be administered first as an induction course of IL-2 or placebo each day for 5 days, followed by a maintenance course at the same dose or placebo every two weeks over 6 months. The primary efficacy criteria will be the % change from baseline in Treg at day-5, which is indicative of the biological response to IL-2. The secondary efficacy criteria will be (i) the maintenance of regulatory T cells during the 6 months of treatment with IL-2 vs. placebo and (ii) the stabilization or regression of the disease as determined by disease activity parameters assessed by MRI (cumulative number of new lesions in T1 enhanced by gadolinium after 6 months) in the groups treated with IL-2 compared to placebo. Expected impact: MS-IL2 will define which patient respond to IL2 and which doses prevent relapses in RRMS. In addition, the deep phenomics studies will further provide the foundation for a clinical phase II to define clinical efficacy.

Official Title
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Biological Activity and Safety of Low Dose IL2 in Relapsing Remitting Multiple Sclerosis. Multicentric Randomized Study

Conditions
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Relapsing Remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: IL2
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-65 years old ; Male and Female; Presenting relapsing remitting multiple sclerosis as determined by revised McDonald criteria (2010) ; On MRI : 1) Presenting 1-2 lesions enhanced by gadolinium (Gd+) (T1) without clinical expression of the disease clinique upon inclusion or 6 months prior to inclusion or 2) presenting one new lesion T2 Expanded Disability Status Scale (EDSS) score comprised between 0 and 6; No flare (with or without any corticosteroid therapy) for the past 2 months Under β-Interferon treatment for ≥ 6 months ; or any other first-line treatment of the Relapsing-Remitting Multiple Sclerosis (RRMS): Dimethyl fumarate or teriflunomide treatment for ≥ 6 months or glatiramer acetate for ≥ 9 months For women of childbearing age, contraception for more than 2 weeks upon confirmation of inclusion criteria and negative Beta HCG on inclusion visit (D-30 to D-7); Patient informed consent should be signed by the patient and investigator before performing any clinical examination required for the study. Affiliation to the French Social Security Regimen Exclusion Criteria: Number of lesions enhanced by gadolinium (Gd+) on MRI in T1 > 2 upon inclusion; Known intolerance to IL2 (see SPC): Hypersensibility to active substance or one of the excipients ; Signs of evolving infection requiring treatment Other clinically significant chronic disorders (beside RR-MS) History of organ allograft Administration of a non-authorized treatment; bolus of corticosteroids in the last 2 months, or treatment with cyclophosphamide, mitoxantrone, or rituximab in the last 6 months; Heart failure (≥ grade III NYHA), renal insufficiency, or hepatic insufficiency (transaminase>5N), or lung failure White blood cell count <3000 /mm3, lymphocytes< 1000 /mm3, platelets <150 000 /mm3 Poor venous access not allowing repeated blood tests Vaccination with live attenuated virus in the months preceding the inclusion or planned during the study Surgery with general anaesthesia during the last 2 months or surgery planned during the study Participation in other biomedical research in the last one month or planned during the study 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 Cancer or history of cancer cured for less than five years (except in situ carcinoma of the cervix or basocellular carcinoma) Pregnant or lactating women; Men and women of childbearing potential without effective contraception for the duration of treatment Patients under a measure of legal protection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 : IL2<br>Interleukin-2 (ILT-101) | Drug: IL2<br>* Induction period: repeated administration of low-dose IL-2 Maintenance period: treatment with IL-2<br>|
| Placebo Comparator: 2 : Placebo<br>Placebo | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treg response to low dose IL2 induction course period, expressed as % of total CD4 cells |  | at day5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Treg percentage on D15 after induction (D1-D5) compared to baseline |  | at day15 | 
| Change in Treg percentage from D15 to M6 compared to baseline |  | Day 15 to Day 169 | 
| The cumulative number of new lesions enhanced by Gd+ (Sum of Gd + lesions on T1 MRI on M2, M4 and M6) |  | Day 57, Day 113 and Day 169 | 
| Frequency of patients free of Gd+ lesions at M6 |  | Day 169 | 
| The cumulative number of new T2 lesions |  | Day 169 | 
| Annual relapse rate (number of relapses observed over a 6 month period) |  | Day 169 | 
| % of patients with flare |  | Day 169 | 
| % of disease free patient i.e % of patient with no clinical symptoms and no activity on MRI |  | Day 169 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Interleukin 2, IL2, Relapsing Remitting Multiple Sclerosis, Autoimmune diseases, Regulatory T cells, Tregs