Clinical trial NCT01988506: Induction of Regulatory t Cells by Low Dose il2 in Autoimmune and Inflammatory Diseases
Official title: Induction of Regulatory t Cells by Low Dose IL2 in Autoimmune and Inflammatory Diseases: a Transnosographic Approach
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Keywords: IL2,
Interleukin 2,
ILT101
Proleukin®, RhIL-2
Auto-immune disease
Inflammatory disease
Inflammation
Regulatory T cells,
Treg
Immunoregulation
Immune tolerance
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Iltoo Pharma
First posted: 2013-11-20
Enrollment: 81
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentages of Tregs
timeFrame: Day8
Secondary outcomes:
measure: Percentages of Tregs
timeFrame: Day 15, 29, 85, 183, 240, 360 and 540
measure: inflammation markers (CRP and CRP ultra sensible)
timeFrame: Day 0, 1, 8, 15, 29, 85, 183, 240, 360 and 540
measure: markers of inflammatory anemia (Hemoglobin, serum iron level, transferrin) ferritin
timeFrame: Day 0, 1, 8, 15, 29, 85, 183, 240, 360 and 540
measure: Number of relapses
timeFrame: up to Day540
measure: CGI-sev, CGI-activity and CGI-eff scales
timeFrame: Day 85, 183, 240, 360 and 540
measure: EuroQL-5 scale
timeFrame: Day 183
measure: Evolution of clinical, biological or radiological criteria specific to each disease
timeFrame: up to Day 540
measure: Safety Assessment
timeFrame: up to Day 540
Other outcomes:
Locations:
city: Paris
country: France
facility: Service d' Hépato Gastro Entérologie - Hôpital SAINT-ANTOINE
state: Ile De France
city: Paris
country: France
facility: Service de Gastro Entérologie - Hôpital SAINT-ANTOINE
state: Ile De France
city: Paris
country: France
facility: Service de Rhumatologie - Hôpital SAINT-ANTOINE
state: Ile De France
city: Paris
country: France
facility: CIC - Hôpital PITIE SALPETRIERE
state: Ile De France
city: Paris
country: France
facility: Service de Médecine Interne - Hôpital PITIE SALPETRIERE
state: Ile De France
city: Paris
country: France
facility: Service de Rhumatologie - Hôpital PITIE SALPETRIERE
state: Ile De France
city: Paris
country: France
facility: Service de Dermatologie - Hôpital COCHIN
state: Ile De France
city: Villejuif
country: France
facility: Centre Hépato-Biliaire - Hôpital Paul Brousse
state: Ile De France
city: Créteil
country: France
facility: Henri Mondor - Médecine Interne
city: Paris
country: France
facility: Médecine interne - Hôpital Saint-Antoine
city: Paris
country: France
facility: Service de médecine vasculaire - HEGP
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: David KLATZMANN, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Rosenzwajg M, Lorenzon R, Cacoub P, Pham HP, Pitoiset F, El Soufi K, RIbet C, Bernard C, Aractingi S, Banneville B, Beaugerie L, Berenbaum F, Champey J, Chazouilleres O, Corpechot C, Fautrel B, Mekinian A, Regnier E, Saadoun D, Salem JE, Sellam J, Seksik P, Daguenel-Nguyen A, Doppler V, Mariau J, Vicaut E, Klatzmann D. Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Ann Rheum Dis. 2019 Feb;78(2):209-217. doi: 10.1136/annrheumdis-2018-214229. Epub 2018 Nov 24.