Clinical Trials Register

Summary
EudraCT Number:	2014-002522-12
Sponsor's Protocol Code Number:	P121001
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-03-04
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2014-002522-12

A.3

Full title of the trial

European phase-II clinical trial evaluating efficacy of low dose rhIL-2 in patients with recently diagnosed type 1 diabetes

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study conducted on humans in Europe to test the importance of a small molecule normally produced by the body, called Interleukin 2 (IL-2) to treat a specific type of diabetes (called type 1 diabetes)

A.3.2

Name or abbreviated title of the trial where available

DIABIL-2

A.4.1

Sponsor's protocol code number

P121001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Assistance Publique - Hôpitaux de Paris (AP-HP)
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	FP7-Health-2012-innovation-1, European Commission
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AP-HP
B.5.2	Functional name of contact point	Clinical Research and Development
B.5.3	Address:
B.5.3.1	Street Address	avenue Claude Vellefaux
B.5.3.2	Town/ city	PARIS
B.5.3.3	Post code	75010
B.5.3.4	Country	France
B.5.4	Telephone number	003314484 1780
B.5.6	E-mail	jean-luc.joannic@aphp.fr

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ILT-101
D.3.4	Pharmaceutical form	Lyophilisate for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Aldesleukin
D.3.9.1	CAS number	8000048-25-1
D.3.9.3	Other descriptive name	INTERLEUKIN-2
D.3.9.4	EV Substance Code	SUB14225MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1.50 to 3.00
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Lyophilisate for solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

type -I diabetes

E.1.1.1

Medical condition in easily understood language

type-I diabetes

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10067584
E.1.2	Term	Type 1 diabetes mellitus
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. To evaluate efficacy of ILT-101 for the preservation of residual pancreatic β cells function
2. To select the optimal regimen of administration of ILT-101

E.2.2

Secondary objectives of the trial

To assess:
1. Tregs expansion after an induction period and during maintenance therapy,
2. Safety of low-dose rhIL-2 during the treatment period (1 year) and 1 year after its discontinuation
3. Relation between Tregs expansion and preservation of residual pancreatic β cells function
4. Clinical and biological responses according to (i) pubertal stage group, (i) time from diagnosis to treatment initiation, (iii) biomarkers of responses

Immunomonitoring:
5. Throrough evaluation of the effects of low dose rhIL-2 on disease-specific immune responses
6. identification of immune biomarkers for predicting/monitoring safety and efficacy of low dose rhIL- 2 treatment.

E.2.3

Trial contains a sub-study

E.3

Principal 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) 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
With a detectable peak C-peptide concentration during a standardised 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

E.4

Principal 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 severe or evolutive 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) only if 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
- 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).

E.5 End points

E.5.1

Primary end point(s)

AUC (T0-T120) of serum C-peptide, determined after a mixed meal tolerance test at month
12, compared to baseline

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months after baseline

E.5.2

Secondary end point(s)

· Serum concentrations of C-peptide after a 10 to 12-h fast, month 3, month 6, month 9,
month 12, compared to baseline; and then month 15 and 24 during discontinuation
period
· AUC (T0-T120) of serum C-peptide after a mixed meal tolerance test after treatment
discontinuation at month 15 (adults only) and at month 24 (V60)
· Diabetic monitoring will include assessment of daily insulin use at each visit
· HbA1c and IDAA1c score at month 3, month 6, month 9, month 12, compared to
baseline; and then month 15 and 24 during discontinuation period
· Number of hypoglycaemic episodes (< 0.5 g/L on capillary sample) over 15 days before
each visit compared to baseline; and after treatment discontinuation
· 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 Tregs Foxp3 gene methylation at day 5, month 1, month 3, month 6, month 9,
month 12 compared to baseline and then month 15 and month 24 after treatment
discontinuation
· Cytokines and chemokines assays at day 5, month 1, month 3, month 6, month 9, month
12 compared to baseline and then month 15 and month 24 after treatment
discontinuation
· Transcriptome analysis at day 5, month 1, month 3, month 6, month 9, month 12
compared to baseline and then month 15 and month 24 after treatment discontinuation
· Genotyping: only at baseline
· Treg phenotype and functionality in adults and adolescents only including pStat5 analysis
day 5, month 1, month 3, month 6, month 9, month 12 compared to baseline and then
month 15 and month 24 after treatment discontinuation

E.5.2.1

Timepoint(s) of evaluation of this end point

Please refer to E.5.2

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of the trial will be at the last visit (visit 59, month 24)

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

children age from 6

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

138

F.4.2.2

In the whole clinical trial

138

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

patients will revert to standard treatment of care

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-03-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-08-24

P. End of Trial
P.	End of Trial Status	Completed

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