Immune Biomarkers of Residual Beta-cell Mass in Type 1 Diabetes (IMMADIAB)

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Assistance Publique - Hôpitaux de Paris
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT01747967
First received: December 10, 2012
Last updated: June 13, 2014
Last verified: June 2014
  Purpose

There is currently no imaging technique allowing to directly visualize and measure pancreatic beta-cell mass. Consequently, the best parameter to estimate this mass is the insulin (and its C-peptide byproduct) that residual beta cells are able to produce. This insulin secretion is measured during a meal test, before and at different times after drinking a standardized quantity of nutrients. However, this test is cumbersome (lasting 3 h, with blood samples taken every 30 minutes) and it holds poor sensitivity, probably insufficient to detect very few residual beta cells. Nevertheless, these few residual cells can improve glycemic control and can be instrumental for the clinical efficacy of immune and/or regenerative therapies.

We hypothesize that residual beta cells may not only represent the remaining insulin secretory capacity, but also the antigenic load capable of stimulating beta-cell-reactive T lymphocytes. The disappearance of these T lymphocytes from circulating blood over time may thus be correlated with beta-cell loss. Measuring beta-cell-reactive T-cell responses may therefore provide simple and sensitive immune surrogate markers of residual insulin secretion. Other surrogate markers may be obtained by measuring urinary C peptide or residual secretion of the counter-regulatory hormone glucagon.

The main objectives of this study are:

  1. To evaluate the correlation between beta-cell-reactive T-cell responses and residual insulin secretion.
  2. To evaluate the correlation between the residual insulin secretion measured by serum C peptide and by urinary C peptide.
  3. To evaluate the correlation between the residual insulin and glucagon secretion.

Condition Intervention
Type 1 Diabetes
Other: Meal Test

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: Immune Biomarkers of Residual Beta-cell Mass in Type 1 Diabetes

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Correlation between residual insulin secretion and T-cell responses against beta-cell antigens. [ Time Frame: up to 18 months ] [ Designated as safety issue: No ]
    To evaluate the correlation between residual insulin secretion and T-cell responses against beta-cell antigens.

  • Correlation between residual insulin secretion and T-cell responses against beta-cell antigens. [ Time Frame: up to 30 months ] [ Designated as safety issue: No ]
    To evaluate the correlation between residual insulin secretion and T-cell responses against beta-cell antigens.


Secondary Outcome Measures:
  • Correlation between residual insulin secretion estimated by serum and urine C-peptide measurement. [ Time Frame: at Day 1 and at 18 months ] [ Designated as safety issue: No ]
    To evaluate the correlation between residual insulin secretion estimated by serum and urine C-peptide measurement.

  • Correlation between residual insulin and glucagon secretion. [ Time Frame: at Day 1 and at 18 months ] [ Designated as safety issue: No ]
    To evaluate the correlation between residual insulin and glucagon secretion.

  • Correlation between residual insulin secretion estimated by serum and urine C-peptide measurement. [ Time Frame: at Day 1 and at 30 months ] [ Designated as safety issue: No ]
    To evaluate the correlation between residual insulin secretion estimated by serum and urine C-peptide measurement.

  • Correlation between residual insulin and glucagon secretion. [ Time Frame: at Day 1 and at 30 months ] [ Designated as safety issue: No ]
    To evaluate the correlation between residual insulin and glucagon secretion.


Estimated Enrollment: 100
Study Start Date: November 2011
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Meal test
Both new-onset T1D children and adults will be recruited and followed up through 4 meal tests at 0, 6, 12 , 18, 24 and 30 months.
Other: Meal Test
Insulin secretion is stimulated by a standardized meal test. Blood and urine samples are collected in order to measure serum and urinary C peptide, glucagon and T-lymphocyte responses against selected beta-cell antigens. The meal test is performed at 0, 6, 12, 18, 24 and 30 months.

Detailed Description:

Type 1 Diabetes (T1D) displays an average 4% annual increase in incidence in most Western countries, particularly in children and young adults. As it requires life-long treatments and it carries significant risks of hypoglycemic and long-term micro- and macrovascular complications, it is a leading cause of disability and public health expenditure.

T1D is an autoimmune disease which comprises humoral responses (antibody-producing B lymphocytes) and cellular responses (T lymphocytes). However, antibodies are merely disease markers and do not play any major pathogenic role. Rather, T1D is caused by an abnormal recognition of beta-cell epitopes by T lymphocytes. This recognition leads to destruction of pancreatic insulin-secreting beta cells, hence the need for lifelong insulin treatment. However, beta-cell destruction is rarely complete at the time of T1D onset.

The hypothesis under testing is that the residual beta-cell mass may represent not only the endogenous insulin secretory capacity, but also the antigenic load capable of maintaining activation of autoreactive T lymphocytes. In other words, the disappearance of beta-cell-reactive T-cell responses over time may be correlated with beta-cell loss. Measurement of these T-cell responses may thus provide surrogate immune markers of residual beta cells.

The primary objective is to evaluate the correlation between residual insulin secretion and T-cell responses directed against beta-cell antigens.

The secondary objectives are to evaluate the correlation between residual insulin secretion estimated by serum and urine C-peptide measurement; and to evaluate the correlation between residual insulin and glucagon secretion.

The ImMaDiab study is a cohort-based investigation with blood sample collection. Both new-onset T1D children and adults will be recruited. Insulin secretion will be stimulated by a standardized meal test. Following T1D diagnosis, blood and urine samples will be collected every 6 months during 30 months in order to measure serum and urine C peptide, glucagon and T-lymphocyte responses against selected beta-cell antigens.

  Eligibility

Ages Eligible for Study:   6 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Pre-inclusion criteria :

  • children 6-18 years old;
  • adults 19-60 years old;
  • patients with a likely diagnosis of T1D, defined by an hyperglycaemia with ketonuria and/or weight loss ≥5% in the last 6 months, requiring insulin therapy.

Inclusion criteria:

  • presence of serum anti-GAD antibodies; and/or
  • presence of serum anti-IA-2 antibodies; and/or
  • for children, presence of serum IAA antibodies; and/or
  • presence of T-cell autoimmune responses;
  • meal test feasible within 10 weeks of diagnosis.

Exclusion Criteria:

  • recipients of solid organ or hematopoietic tissue transplantations ;
  • immunosuppressive therapies (anti-histamine agents are not included);
  • thyroid disease treated by methimazole;
  • known HIV, HBV or HCV infection;
  • known progressive cancer disease;
  • known primary immune deficiency
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01747967

Contacts
Contact: Roberto MALLONE, MD, PhD +33158414815 roberto.mallone@inserm.fr
Contact: Laurence Lecomte, PhD +33 1 71 19 64 94 laurence.lecomte@nck.aphp.fr

Locations
France
INSERM U1016 - DeAR Lab Avenir, Hôpital Cochin Recruiting
Paris, France, 75014
Contact: Roberto MALLONE, MD, PhD    +3317676535583    roberto.mallone@inserm.fr   
Contact: Laurence Lecomte, PhD    +331714196494    laurence.lecomte@nck.aphp.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Study Director: Etienne LARGER, MD, PhD Service de Diabétologie, Hôtel Dieu, AP-HP, Paris
  More Information

Additional Information:
Publications:
Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01747967     History of Changes
Other Study ID Numbers: K 091101
Study First Received: December 10, 2012
Last Updated: June 13, 2014
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Antibodies
Beta cells
C-peptide
GAD
Glucose
Glycemia
Insulin
Meal test
Pancreas
Proinsulin,
T lymphocytes

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Autoimmune Diseases
Endocrine System Diseases
Glucose Metabolism Disorders
Immune System Diseases
Metabolic Diseases

ClinicalTrials.gov processed this record on October 23, 2014