Dose-effect Relationship of Low-dose IL-2 in Type 1 Diabetes (DF-IL2)
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| ClinicalTrials.gov Identifier: NCT01353833 |
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Recruitment Status :
Completed
First Posted : May 16, 2011
Last Update Posted : April 23, 2012
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Type 1 Diabetes | Drug: Aldesleukin | Phase 1 Phase 2 |
Rationale:
Type 1 diabetes (T1D) results from an autoimmune destruction of beta-pancreatic cells that regulatory T cells (Treg) fail to control. This is in part due to a deficit in production of, or response to, interleukin 2 (IL-2). This cytokine is essential to Treg development, survival and function. Importantly, while IL-2 also contributes to the activation of effector T cells (Teff), IL-2/IL-2 receptor signal transduction threshold is much lower for Treg than Teff. Thus low-dose IL-2 could be a specific Treg inducer/stimulator.
The investigators then recently showed that low-dose IL-2 could cure recent onset diabetes in NOD mice that develop spontaneous diabetes considered as the best model of human T1D. A 5-day treatment with IL-2 could cure over 30% of the mice versus 0% for controls.
With these premises, the investigators propose to explore if Treg induction could be obtained in patients who may have a deficit in production of, or response to, IL-2. Defining the dose effect relationship of low dose IL-2 for Treg induction will optimize the risk benefit ratio for IL-2 in T1D.
Principal objective:
To define the dose-effect relationship of low dose IL-2 for Treg induction in patient with recent onset diabetes
Evaluation Criteria:
- Efficacy Kinetic variation of Treg proportions within CD4+ T cells in peripheral blood from Day+0 to Day+60.
- Tolerance Evaluation by clinical exams, laboratory tests and monitoring of side effects. The criterion for terminating the study will be the occurrence of one serious unexpected side effect in the month following IL-2 first administration in at least 2 patients.
Study plan:
After inclusion (Day0), the patient receives a 5-day course of IL-2 or placebo. Patients are randomized in 4 arms receiving either a placebo, or IL-2 doses of 0,33 - 1 or 3 millions UI/day. Laboratory follow-up of peripheral blood T cell subsets will be performed at D0 to D6 (daily), D15, D22 and D60 by immunophenotyping and transcriptomics.
Tolerance will be evaluated at D0-6, D15, D22 and D60.
Methodology:
Double blind placebo controlled randomized study, with 4 parallel groups. Patients will have T1D of autoimmune origin attested by the presence of auto-antibodies (at least one of: anti-islet, anti-GAD, anti-IA2 or anti-ZnT8), with a diagnostic inferior or equal to 24 months.
Study length:
Study length = 9 months Patient participation = 2 months Inclusion period = 6 months
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 25 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Double (Participant, Care Provider) |
| Primary Purpose: | Treatment |
| Official Title: | Dose-effect Relationship of Repeated Administration of Low-dose IL-2 Versus Placebo on the Kinetic of Regulatory T Cells in Patients With Type 1 Diabetes |
| Study Start Date : | May 2011 |
| Actual Primary Completion Date : | October 2011 |
| Actual Study Completion Date : | April 2012 |
| Arm | Intervention/treatment |
|---|---|
| Placebo Comparator: IL2-4 |
Drug: Aldesleukin
0.33 ; 1 ; 3 ; 0 millions IU of IL-2 per day for arm 1 to 4, respectively. 1 s.c. injection per day for 5 days.
Other Name: IL2 |
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Experimental: IL2-2
1 millions IU of IL-2 per day
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Drug: Aldesleukin
0.33 ; 1 ; 3 ; 0 millions IU of IL-2 per day for arm 1 to 4, respectively. 1 s.c. injection per day for 5 days.
Other Name: IL2 |
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Experimental: IL2-3
3 millions IU of IL-2 per day
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Drug: Aldesleukin
0.33 ; 1 ; 3 ; 0 millions IU of IL-2 per day for arm 1 to 4, respectively. 1 s.c. injection per day for 5 days.
Other Name: IL2 |
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Experimental: IL2-1
0.33 millions IU of IL-2 per day
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Drug: Aldesleukin
0.33 ; 1 ; 3 ; 0 millions IU of IL-2 per day for arm 1 to 4, respectively. 1 s.c. injection per day for 5 days.
Other Name: IL2 |
- Kinetic parameters of Treg proportions variation within CD4+ T cells in peripheral blood [ Time Frame: from Day+0 to Day+60 ]
- Improvement of residual secretion of insulin assessed by the AUC of peptide C during a standardized test meal in IL-2 vs placebo treated patients [ Time Frame: at Day+0 and Day+60 ]
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| Ages Eligible for Study: | 18 Years to 50 Years (Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Age [18-50] years;
- With a T1D:
- Treated with insulin for ≤ 2 years,
- With at least one auto-antibody among: anti-islet, anti-GAD, anti-IA2, anti-ZnT8 ;
- No clinically relevant abnormal value for hematology, biochemistry, liver and kidney function
- Lymphocyte [1000-4000]/ mm3
- Informed consent signed by the patient and the investigator before any intervention necessary for the trial.
Exclusion Criteria:
- Contra-indications to IL2 :
- Hypersensibility to IL-2 or its excipients,
- Severe cardiopathy
- Ongoing infection requiring antibiotherapy,
- O2 Saturation ≤ 90 %
- Severe impairment of a vital organ
- Previous organ allograft
- Non authorized concomitant treatment : i.e. immuno-modulators, cytotoxic, drug modifying glycemia
- Cancer progressing or cured for less than 5 years except for primary basal cell carcinoma or carcinoma in situ of the uterine cervix.
- Participation to another clinical investigation in < 3 months
- Pregnant or lactating women
- Male or female in age of procreation without efficient contraception during the study
- No affiliation to National Health Insurance
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01353833
| France | |
| Hôpital Pitié-Salpêtrière | |
| Paris, France, 75013 | |
| Principal Investigator: | Davis Klatzmann, MD, PhD | Assistance Publique - Hôpitaux de Paris |
| Responsible Party: | Assistance Publique - Hôpitaux de Paris |
| ClinicalTrials.gov Identifier: | NCT01353833 |
| Other Study ID Numbers: |
P101101 2010-024499-24 ( EudraCT Number ) |
| First Posted: | May 16, 2011 Key Record Dates |
| Last Update Posted: | April 23, 2012 |
| Last Verified: | May 2011 |
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Diabetes Mellitus Diabetes Mellitus, Type 1 Glucose Metabolism Disorders Metabolic Diseases Endocrine System Diseases Autoimmune Diseases Immune System Diseases |
Aldesleukin Antineoplastic Agents Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents |