Clinical trial NCT02411253: Low-dose rhIL-2 in Patients With Recently-diagnosed Type 1 Diabetes
Official title: European Phase-IIb Clinical Trial Evaluating Efficacy of Low Dose rhIL-2 in Patients With Recently-diagnosed Type 1 Diabetes DIABIL-2
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Type 1 Diabetes
Keywords: IL2
Interleukin 2
IL-2
Auto-immune disease
Insulin
Diabetes
Regulatory T cells
Treg
Immunoregulation
Immune tolerance
Immunotherapy
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Iltoo Pharma
First posted: 2015-04-08
Enrollment: 141
Sex: ALL
Minimum age (years): 6
Maximum age (years): 35
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Eligibility 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).

Primary outcomes:
measure: AUC (T0-T120) of serum C-peptide, determined after a mixed meal tolerance test at month 12, compared to baseline.
timeFrame: Baseline, month12
Secondary outcomes:
measure: Serum concentrations of C-peptide
timeFrame: month 3, month 6, month 9, month 15
measure: AUC (T0-T120) of serum C-peptide after a mixed meal tolerance test after treatment discontinuation
timeFrame: month 15
measure: Diabetic monitoring (insulin use)
timeFrame: baseline, Day 1, Day 5, month 1, month 3, month 6, month 9, month 12, month 15, month 18, month 21.
measure: HbA1c and IDAA1c score
timeFrame: baseline, month 3, month 6, month 9, month 12, month 15
measure: Number of hypoglycaemic episodes (< 0.5 g/L on capillary sample) over 15 days before each visit.
timeFrame: baseline, Day 1, Day 5, month 1, month 3, month 6, month 9, month 12, month 15, month 18, month 21
measure: Number of clinically significant symptomatic episodes of hypoglycaemia between each visit.
timeFrame: baseline, Day 1, Day 5, month 1, month 3, month 6, month 9, month 12, month 15, month 18, month 21
measure: Change in Tregs (expressed as percentage of CD4 and absolute numbers) at day 5 compared to baseline.
timeFrame: Baseline, Day 5.
measure: 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.
timeFrame: Baseline, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 24
measure: Change in Foxp3 gene methylation
timeFrame: Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15
measure: 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.
timeFrame: Baseline, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 24
measure: Transcriptome analysis.
timeFrame: Baseline, Month 6, Month 12
measure: Genotyping at baseline
timeFrame: baseline
measure: Treg phenotype and functionality in adults and adolescents only including pStat5 analysis
timeFrame: Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15
measure: Clinical examination.
timeFrame: Baseline Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
measure: Height/weight and pubertal stage especially for children and adolescents.
timeFrame: Baseline, Month 12, Month 24
measure: Routine laboratory tests
timeFrame: Baseline Day 1, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
measure: Haematology
timeFrame: Baseline Day 1, Day 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
measure: Detection of IL-2 auto-antibodies
timeFrame: Day1, Month 6, Month 12
measure: T cells repertory
timeFrame: Day 1, Day 5, Month 6, Month 12
measure: Intestinal microbiota.
timeFrame: Baseline, Month 6, Month 12
measure: Adverse event.
timeFrame: Baseline, Day 1, 2, 3, 4, 5, Month 1, Month 3, Month 6, Month 9, Month 12, Month 15, Month 18, Month 24
Other outcomes:
Locations:
city: Liège
country: Belgium
facility: Pediatric Department, Centre Hospitalier Régional de la Citadelle
state: Province De Liège
city: Leuven
country: Belgium
facility: UZ - Diabetes voor Kinderen en Adolescenten-Leuven
city: Yvoir
country: Belgium
facility: CHU UCL Namur - site Godinne
city: Strasbourg
country: France
facility: Centre d'Investigations Cliniques, CHU-HOPITAL HAUTEPIERRE
state: Alsace
city: Strasbourg
country: France
facility: Centre d'Investigations Cliniques, HÔPITAL CIVIL
state: Alsace
city: Strasbourg
country: France
facility: Service de pédiatrie 1CHU de HAUTEPIERRE
state: Alsace
city: Strasbourg
country: France
facility: Structure d'Endocrinologie-Diabète-Nutrition et Addictologie HOPITAUX UNIVERSITAIRES NHC
state: Alsace
city: Pessac
country: France
facility: Service d'endocrinologie, diabétologie, maladies métaboliques, et nutrition, CHU de Bordeaux, Hôpital Haut Levêque
state: Aquitaine
city: Brest
country: France
facility: Service d' Endocrinologie HOPITAL CAVALE BLANCHE
state: Brittany
city: Brest
country: France
facility: Service de Pédiatrie, HOPITAL MORVAN
state: Brittany
city: Nantes
country: France
facility: Service de Pédiatrie CHRU DE NANTES
state: Brittany
city: Rennes
country: France
facility: Service d' Endocrinologie Diabétologie CHRU DE RENNES
state: Brittany
city: Besançon
country: France
facility: Médecine pédiatrique, CHU Jean Minjoz
state: Franche-Compté
city: Besançon
country: France
facility: Service Diabétologie -Endocrinologie, CHU Jean Minjoz
state: Franche-Comté
city: Paris
country: France
facility: CIC Paris-Est (Adultes), Hôpitaux Universitaires Pitié-Salpêtrière, Charles Foix
state: Ile De France
city: Paris
country: France
facility: CIC pédiatrique Hôpital Necker Enfants Malades
state: Ile De France
city: Paris
country: France
facility: Endocrinologie gynécologie diabétologie pédiatriques, Hôpital Universitaire Necker Enfants Malades.
state: Ile De France
city: Paris
country: France
facility: CIC Pédiatrique, Hôpital d'enfants Robert Debré
state: Ile De France
city: Paris
country: France
facility: Institut E3M, Hôpital Pitié-Salpêtrière
state: Ile-de France
city: Paris
country: France
facility: Service d'Endocrinologie Pédiatrique, Hôpital d'enfants Robert Debré
state: Ile-de France
city: Toulouse
country: France
facility: Service Pédiatrie - Gastro-entérologie, Hépatologie, Nutrition, Diabétologie, Hôpital des Enfants Pôle Enfants
state: Midi Pyrénnées
city: Lille
country: France
facility: CHRU de Lille, Hôpital Claude Huriez Service d'endocrinologie
state: Nord-Pas-de-Calais
city: Marseille
country: France
facility: Service d' Endocrinologie, maladies métaboliques HOPITAL NORD
state: Paca
city: Marseille
country: France
facility: Service de Nutrition - Maladies Métaboliques - Endocrinologie HOPITAL DE LA CONCEPTION
state: Paca
city: Saint Herblain
country: France
facility: Hopital G&R Laënnec , Endocrinologie, Maladies Métaboliques et Nutrition
state: Pays De La Loire
city: Marseille
country: France
facility: Unité d'Endocrinologie et Diabétologie Pédiatriques, CHU de Marseille, Hôpital La Timone Enfants
state: Provence-Alpes-Côte-d'Azur
city: Lyon
country: France
facility: Endocrinologie-Diabétologie-Maladies de la nutrition, Centre Hospitalier Lyon-Sud
state: Rhones-Alpes
city: Bron
country: France
facility: Service d'Endocrinologie pédiatrique - HFME
city: Freiburg
country: Germany
facility: Division of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg
state: Baden-Württemberg
city: Freiburg
country: Germany
facility: Division of Endocrinology, Diabetology and Metabolic Diseases, University Hospital of Freiburg, Department for children and adolescents
state: Baden-Württemberg
city: München
country: Germany
facility: Institute of Diabetes Research, Helmholtz Zentrum München
state: Bayern
city: Rotterdam
country: Netherlands
facility: Center for Pediatric and Adolescent Diabetes Care and Research
state: Randstad Holland
city: Malmö
country: Sweden
facility: Dept. of Clinical Sciences Lund University, Skåne University Hospital.
state: Öresund Region
city: Basel
country: Switzerland
facility: Endocrinology and Diabetes department, University Hospital of Basel
state: Bâle-Ville
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: David Klatzmann, MD, Ph.D.
role: STUDY_DIRECTOR
References: