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Low-dose rhIL-2 in Patients With Recently-diagnosed Type 1 Diabetes (DIABIL-2)

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ClinicalTrials.gov Identifier: NCT02411253
Recruitment Status : Completed
First Posted : April 8, 2015
Last Update Posted : August 14, 2023
Sponsor:
Collaborator:
Iltoo Pharma
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Study Description
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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.


Condition or disease Intervention/treatment Phase
Type 1 Diabetes Drug: rhIL-2 Drug: Placebo Phase 2

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Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 141 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: European Phase-IIb Clinical Trial Evaluating Efficacy of Low Dose rhIL-2 in Patients With Recently-diagnosed Type 1 Diabetes DIABIL-2
Actual Study Start Date : June 2015
Actual Primary Completion Date : November 2020
Actual Study Completion Date : November 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

Arms and Interventions
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Arm Intervention/treatment
Experimental: 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
 Drug: rhIL-2
Subcutaneous injections of IL2 according to regimen A Subcutaneous injections of IL2 according to regimen B
Placebo Comparator: 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
 Drug: Placebo
Subcutaneous injections of Placebo according to regimen A Subcutaneous injections of Placebo according to regimen B


Outcome Measures
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Primary Outcome Measures :
  1. AUC (T0-T120) of serum C-peptide, determined after a mixed meal tolerance test at month 12, compared to baseline. [ Time Frame: Baseline, month12 ]

Secondary Outcome Measures :
  1. Serum concentrations of C-peptide [ Time Frame: month 3, month 6, month 9, month 15 ]
  2. AUC (T0-T120) of serum C-peptide after a mixed meal tolerance test after treatment discontinuation [ Time Frame: month 15 ]
  3. Diabetic monitoring (insulin use) [ Time Frame: baseline, Day 1, Day 5, month 1, month 3, month 6, month 9, month 12, month 15, month 18, month 21. ]
  4. HbA1c and IDAA1c score [ Time Frame: baseline, month 3, month 6, month 9, month 12, month 15 ]
  5. Number of hypoglycaemic episodes (< 0.5 g/L on capillary sample) over 15 days before each visit. [ Time Frame: baseline, Day 1, Day 5, month 1, month 3, month 6, month 9, month 12, month 15, month 18, month 21 ]
  6. Number of clinically significant symptomatic episodes of hypoglycaemia between each visit. [ Time Frame: baseline, Day 1, Day 5, month 1, month 3, month 6, month 9, month 12, month 15, month 18, month 21 ]
  7. Change in Tregs (expressed as percentage of CD4 and absolute numbers) at day 5 compared to baseline. [ Time Frame: Baseline, Day 5. ]
  8. 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. [ Time Frame: Baseline, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 24 ]
  9. Change in Foxp3 gene methylation [ Time Frame: Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15 ]
  10. 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. [ Time Frame: Baseline, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 24 ]
  11. Transcriptome analysis. [ Time Frame: 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.

  12. Genotyping at baseline [ Time Frame: baseline ]
    Genotyping will be used to assess genetic variation (polymorphisms) associated with T1D, such as those linked to IL2RA, PTPN22, CTLA-4...

  13. Treg phenotype and functionality in adults and adolescents only including pStat5 analysis [ Time Frame: Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15 ]
  14. Clinical examination. [ Time Frame: Baseline Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24 ]
  15. Height/weight and pubertal stage especially for children and adolescents. [ Time Frame: Baseline, Month 12, Month 24 ]
    Based on Tanner staging (Tanner J. M. 1986).

  16. Routine laboratory tests [ Time Frame: Baseline Day 1, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24 ]
    Biochemistry, Liver function

  17. Haematology [ Time Frame: Baseline Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24 ]
  18. Detection of IL-2 auto-antibodies [ Time Frame: Day1, Month 6, Month 12 ]
  19. T cells repertory [ Time Frame: Day 1, Day 5, Month 6, Month 12 ]
  20. Intestinal microbiota. [ Time Frame: Baseline, Month 6, Month 12 ]
  21. Adverse event. [ Time Frame: 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.


Eligibility Criteria
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Ages Eligible for Study:   6 Years to 35 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria

  • Age 6-35 years old.
  • Male or female both using effective methods of contraception during treatment if sexually active.
  • Specifically; Females (if sexually active) with childbearing potential must use contraceptive methods that are considered as highly-effective (pearl index < 1). The following methods are acceptable: Oral , injectable, or implanted hormonal contraceptives (with the exception of oral minipills ie low-dose gestagens which are not acceptable (lynestrenol and norestisteron), Intrauterine device, Intrauterine system (for example, progestin-releasing toit),
  • beta HCG negative at inclusion;
  • With type-1 diabetes:
  • Newly diagnosed (ADA criteria, see annexe 19.6) at most three months between insulin initiation and anticipated start of experimental treatment.
  • Positive for one or more of the autoantibodies typically associated with T1D (anti-islet, -insulin, -GAD, -IA2, -ZnT8)
  • With a detectable peak C-peptide concentration during a standardised MMTT at Visit MMTT (≥0.2pmol/ml);
  • patients with a stable blood glucose level and seric glycaemia between 60 mg/dL and 250 mg/dL verified at MMTT visit
  • Absence of clinically significant abnormal laboratory values (out of range and associated with clinical symptoms or signs) in haematology, biochemistry, thyroid, liver and kidney function;
  • Normal cardiac function: no documented history of heart disease and absence of family history of sudden death, normal ECG especially QTc duration within normal value (<480ms);
  • Free, informed and written consent, signed by the patient and investigator before any Study examination. If the patient is a minor by child and both parents or child and the legal representative in case only one parent is alive. (Journal officiel des communautés européennes (1.5.2001)
  • NB: patient with history of thyroidism on treatment at the inclusion and with normal thyroid hormone values (TSH+T4) can be included.

Exclusion criteria

  • Children under the age of 6 years old cannot be included
  • Patient who, before inclusion, have been treated with other anti-diabetic medication than Insulin for more than 3 months consecutively
  • Chronic adrenal insufficiency known or fasting ACTH ≥2.5 ULN normal at inclusion after control;
  • Anti TPO present at inclusion and abnormal TSH and T4
  • Anti-transglutaminase positive at inclusion
  • Hypersensitivity to the active substance or to any of the excipients
  • Any major health problem including: any major auto-immune/auto-inflammatory disease (other than type 1 diabetes) present at inclusion, any significant respiratory disease (such as moderate or severe COPD or asthma) requiring the chronic use of corticosteroids (whatever route of administration) and serious digestive malfunctions.
  • Patient with existing malignancy or history of malignancy
  • Major psychosocial instability with expected lack of compliance with insulin treatment, psychiatric pathology of patient or parents, or major problems of family dynamics;
  • Signs of active infection;
  • Any patient with obesity defined as BMI ≥ 35
  • Existence of a serious malfunction of a vital organ;
  • History of organ allograft;
  • Use of treatments not allowed in the Study (see Section 8.4.2);
  • Vaccination with alive attenuated virus within 4 weeks of the first injection of the induction period and during the whole maintenance period
  • Pregnant female (confirmed by laboratory testing) or lactating
  • Participation in another clinical trial in the previous 3 months;
  • Lack of affiliation to a social security scheme (as a beneficiary or assignee).
Contacts and Locations
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Information from the National Library of Medicine

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): NCT02411253


Locations
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Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Iltoo Pharma
Investigators
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Study Director: David Klatzmann, MD, Ph.D. Assistance Publique - Hôpitaux de Paris
More Information
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02411253    
Other Study ID Numbers: P121001
First Posted: April 8, 2015    Key Record Dates
Last Update Posted: August 14, 2023
Last Verified: August 2023
Keywords provided by Assistance Publique - Hôpitaux de Paris:
IL2
Interleukin 2
IL-2
Auto-immune disease
Insulin
Diabetes
 Regulatory T cells
Treg
Immunoregulation
Immune tolerance
Immunotherapy
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
 Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases