Biological Activity and Safety of Low Dose IL2 in Relapsing Remitting Multiple Sclerosis (MS-IL2)

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

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

Study Overview

• Status: Completed
• Conditions: Relapsing Remitting Multiple Sclerosis
• Intervention / Treatment: Drug: Placebo; Drug: IL2

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • Centre d'investigation Clinique - Pitié salpêtrière
  • Paris, France, 75013
    • Centre d'investigation clinique Biothérapie Immunologie (CIC-BTi) - Groupe Hospitalier Pitié-Salpêtrière - AP-HP
  • Paris, France, 75013
    • Département des maladies du système nerveux et Centre d'investigation clinique - Groupe Hospitalier Pitié-Salpêtrière - AP-HP

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Fondation ARSEP/AFM
• Investigators: Principal Investigator: David Klatzmann, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2016
• Primary Completion (Actual): October 11, 2019
• Study Completion (Actual): June 15, 2020

Study Registration Dates

• First Submitted: April 20, 2015
• First Submitted That Met QC Criteria: April 22, 2015
• First Posted (Estimate): April 23, 2015

Study Record Updates

• Last Update Posted (Actual): November 9, 2020
• Last Update Submitted That Met QC Criteria: November 6, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: Relapsing Remitting Multiple Sclerosis; Autoimmune diseases; Interleukin 2, IL2; Regulatory T cells, Tregs
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting
• Other Study ID Numbers: P130102; 2014-000088-82 (Other Identifier: EudractCT)