Ciclosporin Followed by Low-dose IL-2 in Patients With Recently Diagnosed Type 1 Diabetes (DF-IL2-REP)

Clinical and Biological Responses to Repeated Administration of Low-dose Interleukin-2 in Patients With Type 1 Diabetes and a Residual Insulin Secretion

Type 1 diabetes (T1D) is caused by the destruction of insulin-producing cells by effector T cells (Teffs), due to a deficiency of regulatory T cells (Tregs).

Ciclosporin effectively blocks the Teffs and controls diabetes, but cannot be considered as a long-term treatment. Low-dose interleukin-2 (ld IL-2) activates and expands Tregs in humans.

Hence, Ld IL-2 in patients in whom the autoimmune process was blocked early by a short treatment (2 months) of cyclosporine should restore immune homeostasis and maintain some insulin production over the long term.

Study Overview

• Status: Recruiting
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Drug: ILT101; Drug: Placebo; Drug: Cyclosporin

Detailed Description

Primary Objective :

Tregs' response profile, after 4 administrations of 1MIU/day of IL-2 (Day 63-66) in patients with recently diagnosed type 1 diabetes who have been treated with ciclosporin for 2 months.

Primary assessment criterion:

Change in Tregs values at D67 compared to D63 (post-ciclosporin values)

Secondary objectives and secondary assessment criteria:

• Change in residual insulin secretion

  • AUC plasma C-peptide concentration after a mixed meal tolerance test at Month 6 (Day 179), Month 12 (Day 361) and after treatment discontinuation at Month 18 (Day 536) and Month 24 (Day 719) compared to baseline;
  • Insulin requirement, HbA1c dosage and IDAA1c score at Month 3 (Day 88), Month 6 (Day 179), Month 9 (Day 270), Month 12 (Day 361) and after treatment discontinuation at Month 18 (Day 536) and Month 24 (Day 719) compared to baseline
• Change in Tregs values at Month 3 (Day 88), Month 6 (Day 179), Month 9 (Day 270), Month 12 (Day 361) and after treatment discontinuation at Month 18 (Day 536) and Month 24 (Day 719) compared to baseline and post-ciclosporin values (Day 63)
• Ciclosporin and ILT-101/placebo compliance
• Tolerance

Experimental design:

This is a monocentric, randomized, placebo controlled, double-blind trial in parallel-groups, evaluating a treatment by cyclosporine 7mg/kg/day during 2 months followed by ILT-101/placebo, 1 MIU daily for 5 days and 1 MIU every week, during 10 months.

Population involved:

Male or female, aged between 16 and 35 years, with recent diagnosis of type 1 diabetes (< 3 months).

Number of subjects: 24 Inclusion period: 12 months Duration of patient participation: 24 months (treatment period: 12 months, follow-up period: 12months) Total duration of the study: 37 months

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: David Klatzmann, MD, Ph.D; Phone Number: +33 01 42 17 74 61; Email: david.klatzmann@sorbonne-universite.fr
• Study Contact Backup: Name: Roberta Lorenzon, MD; Phone Number: +33 01 42 17 65 16; Email: roberta.lorenzon@sorbonne-universite.fr

Study Locations

• France
  • Paris, France, 75013
    • Recruiting
    • Lorenzon Roberta
    • Contact: Roberta Lorenzon, MD; Email: roberta.lorenzon@sorbonne-universite.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 45 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• • Age at inclusion between ≥ 16 years old (Tanner 5 pubertal stage) and ≤ 45 years old

  • Type 1 diabetes according to ADA criteria, with at least 1 positive autoantibody among the following: anti-islet, anti-GAD, anti-IA2, anti-ZnT8 and anti-insulin.
  • Diagnosis ≤ 3 months
  • No acid ketosis
  • No weight loss > 10% OR with fasting C-peptide ≥ 0.1 nmol/L (after a period of ≥ 15 days following the initiation of insulin therapy
  • Absence of clinically significant biological abnormalities on hematological, biochemical, hepatic, renal and thyroid tests.
  • No documented history of heart disease, no family history of sudden death, AND normal ECG.
  • Effective contraception in men and women of childbearing potential > 2 weeks prior to first administration of the investigational drug and throughout the treatment period (if sexually active). Specifically for women of childbearing age and sexually active, they must use an effective contraceptive method (Pearl Index < 1). The following methods are acceptable: oral hormonal contraceptives, injectable, or implanted (with the exception of oral minipills: i.e. low doses of gestagens which are not acceptable (lynestrenol and norestisteron), intrauterine contraceptives (e.g. progestin-release systems)),
  • Free, informed and written consent, signed by the patient and the investigator, prior to any examination required by the trial.

If the patient is a minor, the signatures of both parents and of the child will be collected (or the legal representative if only one parent is alive).

Exclusion Criteria:

• Known contraindications to IL2 treatment:

  • Hypersensitivity to the active substance or to one of the excipients.
  • Signs of active infection requiring antibiotics
  • Documented history of clinical autoimmune disease
  • Oxygen saturation ≤ 90%
  • Existence of a serious dysfunction in a vital organ
  • History of organ allograft,
• Known contraindications to treatment with cyclosporine
• Presence of unauthorized treatment, i.e. cytotoxic drugs, products known for their impact on blood glucose levels or for their interactions with the treatments under trial
• Patients who have received anti-diabetic treatment other than insulin for more than 3 consecutive months.
• Anti-thyroperoxidase positive and abnormal TSH and T4 at inclusion
• Anti-transglutaminase positive at inclusion
• EBV viral load > 2000 IU/ml
• CMV viral load > 400 IU/ml
• HBV, HCV or HIV infection
• Lymphopenia ≤ 1000/ mm3
• Presence or history of cancer that has been cured for less than five years, except in situ cervical or basal cell carcinoma in early stage management,
• Participation in other intervention research involving humans < 3 months,
• Pregnant or breastfeeding women
• Lack of social security affiliation (as a beneficiary or assignee)
• Vaccination with live attenuated virus during the last 4 weeks before the start of the experimental treatment and during the entire treatment phase.
• Patient with active SARS-CoV-2 infection
• Patient with chronic respiratory disease
• Subject under legal protection (such as tutorship, curatorship, or judicial safeguard)
• Subject hospitalized without consent, unable to express consent or deprived of liberty

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: Ciclosporin/ILT-101; Ciclosporin during 2 months (for all patients) followed by ILT-101 during 10 months	Drug: ILT101; • ILT-101: 1MIU/day in a volume of 1 ml; subcutaneous injection every day during 5 consecutive days and then every week between Day 63 and Day 354.; Drug: Cyclosporin; • Ciclosporin: 5mg/kg, twice a day, oral, between Day 1 and Day 60
Placebo Comparator: Ciclosporin/placebo; Ciclosporin during 2 months (for all patients) followed by placebo during 10 months	Drug: Placebo; • Placebo with an identical formulation and regimen of injections i.e. Subcutaneous injection every day (5 consecutive days) then then every week between Day 63 and Day 354.; Drug: Cyclosporin; • Ciclosporin: 5mg/kg, twice a day, oral, between Day 1 and Day 60

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treg variation	Change in Tregs values at Day 67 compared to Day 63 (post-ciclosporin value)	From Day 63 to Day 67

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Area under curve (AUC (T0-T120) of serum C-peptide at month 6	Change in Area under curve (AUC (T0-T120) of serum C-peptide after mixed-meal tolerance test compared to baseline 2. Variation in HbA1c value (in %) 3. Variation in IDAA1c score (IDAA1c score = HbA1c (in %) + [4 × insulin dose (in international units per kilogram per 24 h)]. 4. Change in Insulin requirement (insulin dose in international units per kilogram per 24 h 5. Change in Tregs values (in %/CD4+) at month 3, month 6, month 9, month 12 and after treatment interruption at month 18 and month 24 compared to baseline and post-cyclosporin values (Day 63)	up to month 6
Change in Area under curve (AUC (T0-T120) of serum C-peptide at month 12	Change in Area under curve (AUC (T0-T120) of serum C-peptide after mixed-meal tolerance test compared to baseline 2. Variation in HbA1c value (in %) 3. Variation in IDAA1c score (IDAA1c score = HbA1c (in %) + [4 × insulin dose (in international units per kilogram per 24 h)]. 4. Change in Insulin requirement (insulin dose in international units per kilogram per 24 h 5. Change in Tregs values (in %/CD4+) at month 3, month 6, month 9, month 12 and after treatment interruption at month 18 and month 24 compared to baseline and post-cyclosporin values (Day 63)	up to month 12
Change in Area under curve (AUC (T0-T120) of serum C-peptide at month 24	Change in Area under curve (AUC (T0-T120) of serum C-peptide after mixed-meal tolerance test compared to baseline 2. Variation in HbA1c value (in %) 3. Variation in IDAA1c score (IDAA1c score = HbA1c (in %) + [4 × insulin dose (in international units per kilogram per 24 h)]. 4. Change in Insulin requirement (insulin dose in international units per kilogram per 24 h 5. Change in Tregs values (in %/CD4+) at month 3, month 6, month 9, month 12 and after treatment interruption at month 18 and month 24 compared to baseline and post-cyclosporin values (Day 63)	up to month 24
Variation in HbA1c value (in %) during the treatment period and during the 1-year follow-up period compared to Baseline at day 63,	Variation in HbA1c value (in %) during the treatment period and during the 1-year follow-up period compared to baseline	up to day 63
Variation in HbA1c value (in %) during the treatment period and during the 1-year follow-up period compared to Baseline at month 3	Variation in HbA1c value (in %) during the treatment period and during the 1-year follow-up period compared to baseline	up to month 3
Variation in HbA1c value (in %) during the treatment period and during the 1-year follow-up period compared to Baseline at month 6	Variation in HbA1c value (in %) during the treatment period and during the 1-year follow-up period compared to baseline	up to month 6
Variation in HbA1c value (in %) during the treatment period and during the 1-year follow-up period compared to Baseline at month 9	Variation in HbA1c value (in %) during the treatment period and during the 1-year follow-up period compared to baseline	up to month 9
Variation in HbA1c value (in %) during the treatment period and during the 1-year follow-up period compared to Baseline at month 12	Variation in HbA1c value (in %) during the treatment period and during the 1-year follow-up period compared to baseline	up to month 12
Variation in HbA1c value (in %) during the treatment period and during the 1-year follow-up period compared to Baseline at month 18	Variation in HbA1c value (in %) during the treatment period and during the 1-year follow-up period compared to baseline	up to month 18
Variation in HbA1c value (in %) during the treatment period and during the 1-year follow-up period compared to Baseline at month 24	Variation in HbA1c value (in %) during the treatment period and during the 1-year follow-up period compared to baseline	up to month 24
Variation in IDAA1c scoreduring the treatment period and during the 1 year follow-up period at day 63	Variation in IDAA1c score (IDAA1c score = HbA1c (in %) + [4 × insulin dose (in international units per kilogram per 24 h)] during the treatment period and during the 1 year follow-up period compared to baseline	up to day 63
Variation in IDAA1c scoreduring the treatment period and during the 1 year follow-up period up to month 3	Variation in IDAA1c score (IDAA1c score = HbA1c (in %) + [4 × insulin dose (in international units per kilogram per 24 h)] during the treatment period and during the 1 year follow-up period compared to baseline	up to month 3
Variation in IDAA1c scoreduring the treatment period and during the 1 year follow-up period at month 6	Variation in IDAA1c score (IDAA1c score = HbA1c (in %) + [4 × insulin dose (in international units per kilogram per 24 h)] during the treatment period and during the 1 year follow-up period compared to baseline	up to month 6
Variation in IDAA1c scoreduring the treatment period and during the 1 year follow-up period at month 9	Variation in IDAA1c score (IDAA1c score = HbA1c (in %) + [4 × insulin dose (in international units per kilogram per 24 h)] during the treatment period and during the 1 year follow-up period compared to baseline	up to month 9
Variation in IDAA1c scoreduring the treatment period and during the 1 year follow-up period at month 12	Variation in IDAA1c score (IDAA1c score = HbA1c (in %) + [4 × insulin dose (in international units per kilogram per 24 h)] during the treatment period and during the 1 year follow-up period compared to baseline	up to month 12
Variation in IDAA1c scoreduring the treatment period and during the 1 year follow-up period at day month 18	Variation in IDAA1c score (IDAA1c score = HbA1c (in %) + [4 × insulin dose (in international units per kilogram per 24 h)] during the treatment period and during the 1 year follow-up period compared to baseline	up to month 18
Variation in IDAA1c scoreduring the treatment period and during the 1 year follow-up period at month 24	Variation in IDAA1c score (IDAA1c score = HbA1c (in %) + [4 × insulin dose (in international units per kilogram per 24 h)] during the treatment period and during the 1 year follow-up period compared to baseline	up to month 24
Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period at day 30	Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period compared to baseline	up to day 30
Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period at day 63	Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period compared to baseline	up to day 63
Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period at month 3	Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period compared to baseline	up to month 3
Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period at month 6	Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period compared to baseline	up to month 6
Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period at month 9	Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period compared to baseline	up to month 9
Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period at month 12	Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period compared to baseline	up to month 12
Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period at month 18	Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period compared to baseline	up to month 18
Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period at month 24	Change in Insulin requirement (insulin dose in international units per kilogram per 24 h) during the treatment period and during the 1 year follow-up period compared to baseline	up to month 24
Change in Tregs values (in %/CD4+) after treatment interruption and post-cyclosporin values at day 30	Change in Tregs values (in %/CD4+) after treatment interruption compared to baseline and post-cyclosporin values	up to day 30
Change in Tregs values (in %/CD4+) after treatment interruption and post-cyclosporin values at day 63	Change in Tregs values (in %/CD4+) after treatment interruption compared to baseline and post-cyclosporin values	up to day 63
Change in Tregs values (in %/CD4+) after treatment interruption and post-cyclosporin values at month 3	Change in Tregs values (in %/CD4+) after treatment interruption compared to baseline and post-cyclosporin values	up to month 3
Change in Tregs values (in %/CD4+) after treatment interruption and post-cyclosporin values at month 6	Change in Tregs values (in %/CD4+) after treatment interruption compared to baseline and post-cyclosporin values	up to month 6
Change in Tregs values (in %/CD4+) after treatment interruption and post-cyclosporin values at month 9	Change in Tregs values (in %/CD4+) after treatment interruption compared to baseline and post-cyclosporin values	up to month 9
Change in Tregs values (in %/CD4+) after treatment interruption and post-cyclosporin values at month 12	Change in Tregs values (in %/CD4+) after treatment interruption compared to baseline and post-cyclosporin values	up to month 12
Change in Tregs values (in %/CD4+) after treatment interruption and post-cyclosporin values at month 18	Change in Tregs values (in %/CD4+) after treatment interruption compared to baseline and post-cyclosporin values	up to month 18
Change in Tregs values (in %/CD4+) after treatment interruption and post-cyclosporin values at month 24	Change in Tregs values (in %/CD4+) after treatment interruption compared to baseline and post-cyclosporin values	up to month 24
incidence of adverse events at day 30	incidence of adverse events throughout the study (according to NCI-CTC AE classification) to the Baseline to month 24	up to day 30
incidence of adverse events at day 63	incidence of adverse events throughout the study (according to NCI-CTC AE classification) to the Baseline to month 24	up to day 63
incidence of adverse events at month 3	incidence of adverse events throughout the study (according to NCI-CTC AE classification) to the Baseline to month 24	up to month 3
incidence of adverse events at month 6	incidence of adverse events throughout the study (according to NCI-CTC AE classification) to the Baseline to month 24	up to month 6
incidence of adverse events at month 9	incidence of adverse events throughout the study (according to NCI-CTC AE classification) to the Baseline to month 24	up to month 9
incidence of adverse events at month 12	incidence of adverse events throughout the study (according to NCI-CTC AE classification) to the Baseline to month 24	up to month 12
incidence of adverse events at month 18	incidence of adverse events throughout the study (according to NCI-CTC AE classification) to the Baseline to month 24	up to month 18
incidence of adverse events at month 24	incidence of adverse events throughout the study (according to NCI-CTC AE classification) to the Baseline to month 24	up to month 24

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Iltoo Pharma
• Investigators: Study Director: David Klatzmann, MD, Ph.D, APHP(ASSISTANCE PUBLIQUE DES HOPITAUX DE PARIS; Principal Investigator: Agnès Hartmann, MD, Ph.D, APHP(ASSISTANCE PUBLIQUE DES HOPITAUX DE PARIS

Study record dates

Study Major Dates

• Study Start (Actual): September 21, 2022
• Primary Completion (Estimated): April 21, 2026
• Study Completion (Estimated): April 21, 2028

Study Registration Dates

• First Submitted: April 16, 2021
• First Submitted That Met QC Criteria: December 9, 2021
• First Posted (Actual): December 10, 2021

Study Record Updates

• Last Update Posted (Actual): June 27, 2025
• Last Update Submitted That Met QC Criteria: June 24, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Diabetes; Immunotherapy; Auto-immune disease; Interleukin 2; Regulatory T cells; Immune tolerance; Ciclosporin
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Autoimmune Diseases; Immune System Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Diabetes Mellitus, Type 1; Anti-Infective Agents; Antifungal Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Dermatologic Agents; Calcineurin Inhibitors; Cyclosporine; Cyclosporins
• Other Study ID Numbers: P120142

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No