Ignite Creation Date:
2024-05-06 @ 3:56 AM
Last Modification Date:
2024-10-26 @ 11:41 AM
Study NCT ID:
NCT02411253
Status:
COMPLETED
Last Update Posted:
2023-08-14
First Post:
2015-03-23
Brief Title:
Low-dose rhIL-2 in Patients With Recently-diagnosed Type 1 Diabetes
Sponsor:
Assistance Publique - Hôpitaux de Paris
Organization:
Assistance Publique - Hôpitaux de Paris
Study Overview
Official Title:
European Phase-IIb Clinical Trial Evaluating Efficacy of Low Dose rhIL-2 in Patients With Recently-diagnosed Type 1 Diabetes DIABIL-2
Status:
COMPLETED
Status Verified Date:
2023-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
DIABIL-2
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
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 predictingmonitoring 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 05 gL 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 24hday2 on day 4 V8 D291day and V54 day 3513 days at the same time points in 27 patients of regimen A
Safety parameters will be evaluated by clinical examination including heightweight 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 T120 min Before statistical analysis log x1 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 n305380-2
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 predictingmonitoring 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 05 gL 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 24hday2 on day 4 V8 D291day and V54 day 3513 days at the same time points in 27 patients of regimen A
Safety parameters will be evaluated by clinical examination including heightweight 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 T120 min Before statistical analysis log x1 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 n305380-2
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None