Clinical trial NCT02424396: Biological Activity and Safety of Low Dose IL2 in Relapsing Remitting Multiple Sclerosis
Official title: Biological Activity and Safety of Low Dose IL2 in Relapsing Remitting Multiple Sclerosis. Multicentric Randomized Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Relapsing Remitting Multiple Sclerosis
Keywords: Interleukin 2, IL2
Relapsing Remitting Multiple Sclerosis
Autoimmune diseases
Regulatory T cells, Tregs
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Fondation ARSEP/AFM
First posted: 2015-04-23
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Treg response to low dose IL2 induction course period, expressed as % of total CD4 cells
timeFrame: at day5
Secondary outcomes:
measure: Change in Treg percentage on D15 after induction (D1-D5) compared to baseline
timeFrame: at day15
measure: Change in Treg percentage from D15 to M6 compared to baseline
timeFrame: Day 15 to Day 169
measure: The cumulative number of new lesions enhanced by Gd+ (Sum of Gd + lesions on T1 MRI on M2, M4 and M6)
timeFrame: Day 57, Day 113 and Day 169
measure: Frequency of patients free of Gd+ lesions at M6
timeFrame: Day 169
measure: The cumulative number of new T2 lesions
timeFrame: Day 169
measure: Annual relapse rate (number of relapses observed over a 6 month period)
timeFrame: Day 169
measure: % of patients with flare
timeFrame: Day 169
measure: % of disease free patient i.e % of patient with no clinical symptoms and no activity on MRI
timeFrame: Day 169
Other outcomes:
Locations:
city: Paris
country: France
facility: Centre d'investigation Clinique - Pitié salpêtrière
city: Paris
country: France
facility: Centre d'investigation clinique Biothérapie Immunologie (CIC-BTi) - Groupe Hospitalier Pitié-Salpêtrière - AP-HP
city: Paris
country: France
facility: Département des maladies du système nerveux et Centre d'investigation clinique - Groupe Hospitalier Pitié-Salpêtrière - AP-HP
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: David Klatzmann
role: PRINCIPAL_INVESTIGATOR
References: