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

Primary Purpose

Rheumatoid Arthritis, Ankylosing Spondylitis, Systemic Lupus Erythematosus

Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Interleukin 2
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis focused on measuring IL2,, Interleukin 2,, ILT101, Proleukin®, RhIL-2, Auto-immune disease, Inflammatory disease, Inflammation, Regulatory T cells,, Treg, Immunoregulation, Immune tolerance

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Service d' Hépato Gastro Entérologie - Hôpital SAINT-ANTOINE
  • Service de Gastro Entérologie - Hôpital SAINT-ANTOINE
  • Service de Rhumatologie - Hôpital SAINT-ANTOINE
  • CIC - Hôpital PITIE SALPETRIERE
  • Service de Médecine Interne - Hôpital PITIE SALPETRIERE
  • Service de Rhumatologie - Hôpital PITIE SALPETRIERE
  • Service de Dermatologie - Hôpital COCHIN
  • Centre Hépato-Biliaire - Hôpital Paul Brousse
  • Henri Mondor - Médecine Interne
  • Médecine interne - Hôpital Saint-Antoine
  • Service de médecine vasculaire - HEGP

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Interleukin 2

Arm Description

Interleukin 2, 1MUI.= Proleukin®, RhIL-2

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

Percentages of Tregs
Changes in Treg percentage at Day 15, 29, 85, 183, 240, 360 and 540 compared to baseline (Day0)
inflammation markers (CRP and CRP ultra sensible)
Changes in levels of inflammation markers
markers of inflammatory anemia (Hemoglobin, serum iron level, transferrin) ferritin
Changes in levels of inflammation markers
Number of relapses
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)
EuroQL-5 scale
Change in the quality of life (EuroQL-5 scale)
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
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.

Full Information

First Posted
November 7, 2013
Last Updated
July 19, 2021
Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Iltoo Pharma
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1. Study Identification

Unique Protocol Identification Number
NCT01988506
Brief Title
Induction of Regulatory t Cells by Low Dose il2 in Autoimmune and Inflammatory Diseases
Acronym
TRANSREG
Official Title
Induction of Regulatory t Cells by Low Dose IL2 in Autoimmune and Inflammatory Diseases: a Transnosographic Approach
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Completed
Study Start Date
January 6, 2014 (Actual)
Primary Completion Date
October 16, 2019 (Actual)
Study Completion Date
April 1, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris
Collaborators
Iltoo Pharma

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
81 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Interleukin 2
Arm Type
Experimental
Arm Description
Interleukin 2, 1MUI.= Proleukin®, RhIL-2
Intervention Type
Drug
Intervention Name(s)
Interleukin 2
Intervention Description
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
Primary Outcome Measure Information:
Title
Percentages of Tregs
Description
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)
Time Frame
Day8
Secondary Outcome Measure Information:
Title
Percentages of Tregs
Description
Changes in Treg percentage at Day 15, 29, 85, 183, 240, 360 and 540 compared to baseline (Day0)
Time Frame
Day 15, 29, 85, 183, 240, 360 and 540
Title
inflammation markers (CRP and CRP ultra sensible)
Description
Changes in levels of inflammation markers
Time Frame
Day 0, 1, 8, 15, 29, 85, 183, 240, 360 and 540
Title
markers of inflammatory anemia (Hemoglobin, serum iron level, transferrin) ferritin
Description
Changes in levels of inflammation markers
Time Frame
Day 0, 1, 8, 15, 29, 85, 183, 240, 360 and 540
Title
Number of relapses
Time Frame
up to Day540
Title
CGI-sev, CGI-activity and CGI-eff scales
Description
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)
Time Frame
Day 85, 183, 240, 360 and 540
Title
EuroQL-5 scale
Description
Change in the quality of life (EuroQL-5 scale)
Time Frame
Day 183
Title
Evolution of clinical, biological or radiological criteria specific to each disease
Description
Changes in disease-specific score and/or evolution of clinical, biological or radiological criteria specific to each disease
Time Frame
up to Day 540
Title
Safety Assessment
Description
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.
Time Frame
up to Day 540

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David KLATZMANN, MD, PhD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Service d' Hépato Gastro Entérologie - Hôpital SAINT-ANTOINE
City
Paris
State/Province
Ile De France
ZIP/Postal Code
75012
Country
France
Facility Name
Service de Gastro Entérologie - Hôpital SAINT-ANTOINE
City
Paris
State/Province
Ile De France
ZIP/Postal Code
75012
Country
France
Facility Name
Service de Rhumatologie - Hôpital SAINT-ANTOINE
City
Paris
State/Province
Ile De France
ZIP/Postal Code
75012
Country
France
Facility Name
CIC - Hôpital PITIE SALPETRIERE
City
Paris
State/Province
Ile De France
ZIP/Postal Code
75013
Country
France
Facility Name
Service de Médecine Interne - Hôpital PITIE SALPETRIERE
City
Paris
State/Province
Ile De France
ZIP/Postal Code
75013
Country
France
Facility Name
Service de Rhumatologie - Hôpital PITIE SALPETRIERE
City
Paris
State/Province
Ile De France
ZIP/Postal Code
75013
Country
France
Facility Name
Service de Dermatologie - Hôpital COCHIN
City
Paris
State/Province
Ile De France
ZIP/Postal Code
75014
Country
France
Facility Name
Centre Hépato-Biliaire - Hôpital Paul Brousse
City
Villejuif
State/Province
Ile De France
ZIP/Postal Code
94800
Country
France
Facility Name
Henri Mondor - Médecine Interne
City
Créteil
ZIP/Postal Code
94010
Country
France
Facility Name
Médecine interne - Hôpital Saint-Antoine
City
Paris
ZIP/Postal Code
75012
Country
France
Facility Name
Service de médecine vasculaire - HEGP
City
Paris
ZIP/Postal Code
75015
Country
France

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
30472651
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.
Results Reference
derived

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

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