Ciclosporin Followed by Low-dose IL-2 in Patients With Recently Diagnosed Type 1 Diabetes

Study Overview
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Brief Summary
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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.

Detailed Description
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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

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

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Cyclosporin
* Drug: ILT101
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single group during ciclosporin treatment and parallel group during ILT-101 treatment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ciclosporin/ILT-101<br>Ciclosporin during 2 months (for all patients) followed by ILT-101 during 10 months | Drug: Cyclosporin<br>* • Ciclosporin: 3.5mg/kg, twice a day, oral, between Day 1 and Day 60<br>Drug: ILT101<br>* • 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.<br>|
| Placebo Comparator: Ciclosporin/placebo<br>Ciclosporin during 2 months (for all patients) followed by placebo during 10 months | Drug: Cyclosporin<br>* • Ciclosporin: 3.5mg/kg, twice a day, oral, between Day 1 and Day 60<br>Drug: Placebo<br>* • 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.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Interleukin 2, Ciclosporin, Auto-immune disease, Diabetes, Regulatory T cells, Immune tolerance, Immunotherapy