Low-dose rhIL-2 in Patients With Recently-diagnosed Type 1 Diabetes
- Conditions
- Type 1 Diabetes
- Interventions
- Drug: rhIL-2Drug: Placebo
- Registration Number
- NCT02411253
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- Brief Summary
Type 1diabetes (T1D) is caused by autoimmune destruction of the pancreatic islet ß-cells, leading to an absolute deficiency in insulin.
In health, regulatory T cells (Tregs) suppress immune responses against normal tissues, and likewise prevent autoimmune diseases. Tregs are insufficient in T1D.
The investigators previously showed that administration of low doses of IL-2 induces selective expansion and activation of Tregs in mice and humans.
The investigators hypothesize that Tregs expansion and activation with low doses of IL2 could block the ongoing autoimmune destruction of insulin producing cells in patients with recently diagnosed T1D.
- Detailed Description
Scientific justification:
Clinical and preclinical studies, together with supportive mechanistic data showing that Tregs are activated by much lower IL-2 concentration than effector T cells (Teffs), provide a strong rationale for studying efficacy of low dose IL2 to stop the autoimmune destruction of insulin-secreting beta cells in patient with recently diagnosed with T1D.
Primary objective:
1. To evaluate efficacy of low dose IL-2 for the preservation of residual pancreatic β cells function
2. To select the optimal regimen of administration of IL-2
Primary assessment criterion:
AUC (T0-T120) of serum C-peptide, determined after a mixed meal tolerance test at month 12, compared to baseline.
Secondary objectives:
1. To assess Tregs expansion after an induction period and during maintenance therapy
2. To assess safety of IL-2 during the treatment period (1 year) and 1 year after its discontinuation
3. To assess the relation between Tregs expansion and preservation of residual pancreatic β cells function
4. To assess clinical and biological responses according to (i) pubertal stage group, (i) time from diagnosis to treatment initiation, (iii) biomarkers of responses
5. To assess effects of IL-2 on disease-specific immune responses
6. To identify biomarkers for predicting/monitoring safety and efficacy of IL-2.
Secondary assessment criteria:
* Serum concentrations of C-peptide
* AUC (T0-T120) of serum C-peptide after a mixed meal tolerance test after treatment discontinuation
* Diabetic monitoring (insulin use)
* HbA1c and IDAA1c score
* Number of hypoglycaemic episodes (\< 0.5 g/L on capillary sample) over 15 days before each visit.
* Number of clinically significant symptomatic episodes of hypoglycaemia between each visit.
* Change in Tregs (expressed as percentage of CD4 and absolute numbers) at day 5 compared to baseline.
* Change in trough level of Tregs (%CD4+ and absolute numbers) at month 1, month 3, month 6, month 9, month 12, compared to baseline; and then month 15 and 24 after treatment discontinuation.
* Change in Foxp3 gene methylation
* Cytokines and chemokines assays at day 5, month 1, month 3, month 6, month 9, and month 12 compared to baseline and then month 15 and month 24 after treatment discontinuation.
* Transcriptome analysis.
* Genotyping at baseline
* Treg phenotype and functionality in adults and adolescents only including pStat5 analysis
Pharmacokinetic of IL2 will be performed (in patients from regimen A only) on day 1 at T0, T60min (1h), T120min (2h), T240min (4h), T360min (6h), T600min (10h), T1440min (24h=day2) on day 4, V8 (D29±1day) and V54 (day 351±3 days) at the same time points in 27 patients of regimen A.
• Safety parameters will be evaluated by clinical examination (including height/weight and pubertal stage especially for children and adolescents), routine laboratory tests, ILT-101 auto-antibodies, ancillary investigations and adverse event.
Experimental design:
This is a multicenter European, sequential-group, randomized, double-blind trial evaluating IL-2 versus placebo
Population involved:
Male or female, aged between 6 and 35 years, with type 1 diabetes diagnosed for less than two months.
Number of subjects: 138
Inclusion period: 49 months
Duration of patient participation: 24 months (treatment period: 12 months, follow-up period: 12months)
Total duration of the study: 73 months
Statistical analysis:
The principal efficacy analysis will be drawn from the intention to treat group.
The per-protocol analysis will be used to confirm the intention to treat analysis.
For each regimen:
- MMTT: C-peptide concentrations will be summarized by the AUC from T0 to T+120 min. Before statistical analysis, log (x+1) normalizing transformation will be used, and IL-2 and placebo treated patients will be compared using a mixed model of ANCOVA including baseline value as covariate and factor pubertal stage group.
Quantitative endpoints will be analyzed using same methods as primary endpoint. Categorical endpoints will be analyzed using multivariate logistic regression models.
Subgroups analyses: Response to treatment will be analysed according to criteria such as:
* Pubertal stage, age, gender, BMI...
* Biomarkers (identified in previous studies as predictive of patients' response to treatment)
Funding source: European Commission under the Health Cooperation Programme of the Seventh Framework Programme (Grant Agreement n°305380-2).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 141
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description rhIL-2 rhIL-2 * 0.5 MIU/m²/day of IL2 with a maximum of 1MIU/day in a volume of 1 ml for children and adolescents, * 1MIU/day for adults. Subcutaneous injection every day (5 days) then: * Regimen A injection every two weeks between D15 and D351, * Regimen B injections every week between D15 and D351 Placebo Placebo Placebo with a identical formulation and regimen of injections i.e. Subcutaneous injection every day (5 days) then: * Regimen A injection every two weeks between D15 and D351 * Regimen B injections every week between D15 and D351
- Primary Outcome Measures
Name Time Method AUC (T0-T120) of serum C-peptide, determined after a mixed meal tolerance test at month 12, compared to baseline. Baseline, month12
- Secondary Outcome Measures
Name Time Method Change in Tregs (expressed as percentage of CD4 and absolute numbers) at day 5 compared to baseline. Baseline, Day 5. AUC (T0-T120) of serum C-peptide after a mixed meal tolerance test after treatment discontinuation month 15 Number of clinically significant symptomatic episodes of hypoglycaemia between each visit. baseline, Day 1, Day 5, month 1, month 3, month 6, month 9, month 12, month 15, month 18, month 21 HbA1c and IDAA1c score baseline, month 3, month 6, month 9, month 12, month 15 Change in trough level of Tregs (%CD4+ and absolute numbers) at month 1, month 3, month 6, month 9, month 12, compared to baseline; and then month 15 and 24 after treatment discontinuation. Baseline, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 24 Cytokines and chemokines assays at day 5, month 1, month 3, month 6, month 9, and month 12 compared to baseline and then month 15 and month 24 after treatment discontinuation. Baseline, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 24 Transcriptome analysis. Baseline, Month 6, Month 12 Transcriptome analysis on whole PBMCs will allow analysis of changes in inflammation-related signatures, as already described in Saadoun et al. NEJM, 2011.
Genotyping at baseline baseline Genotyping will be used to assess genetic variation (polymorphisms) associated with T1D, such as those linked to IL2RA, PTPN22, CTLA-4...
Serum concentrations of C-peptide month 3, month 6, month 9, month 15 Diabetic monitoring (insulin use) baseline, Day 1, Day 5, month 1, month 3, month 6, month 9, month 12, month 15, month 18, month 21. Number of hypoglycaemic episodes (< 0.5 g/L on capillary sample) over 15 days before each visit. baseline, Day 1, Day 5, month 1, month 3, month 6, month 9, month 12, month 15, month 18, month 21 Change in Foxp3 gene methylation Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15 Treg phenotype and functionality in adults and adolescents only including pStat5 analysis Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15 Clinical examination. Baseline Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24 Height/weight and pubertal stage especially for children and adolescents. Baseline, Month 12, Month 24 Based on Tanner staging (Tanner J. M. 1986).
Routine laboratory tests Baseline Day 1, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24 Biochemistry, Liver function
Haematology Baseline Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24 Detection of IL-2 auto-antibodies Day1, Month 6, Month 12 T cells repertory Day 1, Day 5, Month 6, Month 12 Intestinal microbiota. Baseline, Month 6, Month 12 Adverse event. Baseline, Day 1, 2, 3, 4, 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24 Throughout the study.
Trial Locations
- Locations (34)
Pediatric Department, Centre Hospitalier Régional de la Citadelle
🇧🇪Liège, Province De Liège, Belgium
UZ - Diabetes voor Kinderen en Adolescenten-Leuven
🇧🇪Leuven, Belgium
CHU UCL Namur - site Godinne
🇧🇪Yvoir, Belgium
Centre d'Investigations Cliniques, CHU-HOPITAL HAUTEPIERRE
🇫🇷Strasbourg, Alsace, France
Centre d'Investigations Cliniques, HÔPITAL CIVIL
🇫🇷Strasbourg, Alsace, France
Service de pédiatrie 1CHU de HAUTEPIERRE
🇫🇷Strasbourg, Alsace, France
Structure d'Endocrinologie-Diabète-Nutrition et Addictologie HOPITAUX UNIVERSITAIRES NHC
🇫🇷Strasbourg, Alsace, France
Service d'endocrinologie, diabétologie, maladies métaboliques, et nutrition, CHU de Bordeaux, Hôpital Haut Levêque
🇫🇷Pessac, Aquitaine, France
Service d' Endocrinologie HOPITAL CAVALE BLANCHE
🇫🇷Brest, Brittany, France
Service de Pédiatrie, HOPITAL MORVAN
🇫🇷Brest, Brittany, France
Scroll for more (24 remaining)Pediatric Department, Centre Hospitalier Régional de la Citadelle🇧🇪Liège, Province De Liège, Belgium