Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

EXtremely Early-onset Type 1 Diabetes EXtremely Early-onset Type 1 Diabetes (A Musketeers' Memorandum Study) (EXE-T1D)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03369821
Recruitment Status : Recruiting
First Posted : December 12, 2017
Last Update Posted : March 29, 2019
Sponsor:
Collaborators:
Royal Devon and Exeter NHS Foundation Trust
King's College London
City of Hope National Medical Center
Benaroya Research Institute
Information provided by (Responsible Party):
University of Exeter

Brief Summary:

Type 1 diabetes (T1D) results from destruction of insulin-producing beta cells in the pancreas by the body's own immune system (autoimmunity). We do not fully understand what causes this type of diabetes and why there is variation in age of onset and severity between people who develop the disease. The aim of this work is to study very unusual people who develop T1D extremely young, as babies under 1 year of age. We think that, for the condition to have developed that early, they must have an unusual or extreme form of autoimmunity.

Studying people with very early-onset diabetes will enable us to look at exactly what goes wrong with the immune system because they have one of the most extreme forms of the disease. We may be able to learn a lot about the disease from a small number of rare individuals. We aim to confirm that they have autoimmune type 1 diabetes and then try to understand how it is possible that they have developed diabetes so young by studying their immune system genes, the function of their immune system, and environmental factors (such as maternal genetics) that may play a role in their development of the disease.

People with diabetes diagnosed under 12 months are very rare and they live all over the world. We will take advantage of the fact that they are usually referred to Exeter for genetic testing. As part of their wider clinical team, we will contact them via their clinician to ask for more information about their diabetes and their family history. We will collect samples to study whether they still make any of their own insulin and whether they make specific antibodies against their beta cells in the pancreas. Separately, we will study their immune system in depth using immune cells isolated from a blood sample. We will then study these cells using cutting edge techniques by Dr Tim Tree at King's College London, by Professor Bart Roep at the Diabetes Metabolism Research Institute Faculty, City of Hope National Medical Center, California (USA), and Dr Cate Speake, Benaroya Reseach Institute, Seattle (USA). Some of these tests have never been used in people of young ages around the world, so an aim of this project will be to develop methods that can be used to study people even if they live far away.


Condition or disease Intervention/treatment
Type1 Diabetes Mellitus Diagnostic Test: Beta Cell Loss and Immune Function Other: Immune Function with RNAseq

  Show Detailed Description

Layout table for study information
Study Type : Observational
Estimated Enrollment : 240 participants
Observational Model: Case-Control
Time Perspective: Cross-Sectional
Official Title: Understanding Beta-cell Destruction Through the Study of EXtremely Early-onset Type 1 Diabetes (A Musketeers' Memorandum Study)
Actual Study Start Date : September 1, 2017
Estimated Primary Completion Date : October 31, 2020
Estimated Study Completion Date : February 28, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

Group/Cohort Intervention/treatment
Study 1: Existing EET1D (Case)
  • Aged 0 to 70 years
  • Clinical diagnosis of diabetes <24 months (+ evidence of WHO diabetes criteria)
  • Negative genetic test for mutations causing non-autoimmune neonatal diabetes if diagnosed <12 months
  • Type 1 diabetes genetic risk score >50th centile of T1D reference group, or monogenic cause of T1D (e.g. STAT3 or FOXP3 mutation).
Diagnostic Test: Beta Cell Loss and Immune Function
Beta cell loss (measured by serum/urine C-peptide), islet-specific autoantibodies, T1D risk genes and autoreactive CD8 T cells.

Other: Immune Function with RNAseq
Immune function (measuring autoantibodies, autoreactive CD8 T cells and RNAseq of immune genes).

Study 1: T1D (Control)
  • Age 0-70 years (matched to above)
  • Clinical diagnosis of T1D (diagnosed age 1-20 years)
  • Insulin treated from diagnosis.
Diagnostic Test: Beta Cell Loss and Immune Function
Beta cell loss (measured by serum/urine C-peptide), islet-specific autoantibodies, T1D risk genes and autoreactive CD8 T cells.

Other: Immune Function with RNAseq
Immune function (measuring autoantibodies, autoreactive CD8 T cells and RNAseq of immune genes).

Study 2: Newly diagnosed EET1D (Case)
  • Aged 0 to 24 months at recruitment
  • Clinical diagnosis of diabetes <24 months (+ evidence of WHO diabetes criteria)
  • Negative genetic test for mutations causing non-autoimmune neonatal diabetes
  • Type 1 diabetes genetic risk score >50th centile of T1D reference group, or monogenic cause of T1D (e.g. STAT3 or FOXP3 mutation)
Diagnostic Test: Beta Cell Loss and Immune Function
Beta cell loss (measured by serum/urine C-peptide), islet-specific autoantibodies, T1D risk genes and autoreactive CD8 T cells.

Other: Immune Function with RNAseq
Immune function (measuring autoantibodies, autoreactive CD8 T cells and RNAseq of immune genes).

Study 2: NDM (Control)
  • Diagnosis of diabetes <24 months
  • Age 0 to 24 months at recruitment
  • Diagnosis of NDM (confirmed by Exeter Molecular Genetics Laboratory).
Diagnostic Test: Beta Cell Loss and Immune Function
Beta cell loss (measured by serum/urine C-peptide), islet-specific autoantibodies, T1D risk genes and autoreactive CD8 T cells.

Other: Immune Function with RNAseq
Immune function (measuring autoantibodies, autoreactive CD8 T cells and RNAseq of immune genes).




Primary Outcome Measures :
  1. Measure beta cell function in EET1D compared to T1D and NDM. [ Time Frame: Within 12 months of last participant's final visit. ]
    C-peptide and GAD, IA2, ZnT8 autoantibody measurement


Secondary Outcome Measures :
  1. Immune phenotyping in EET1D compared to T1D and NDM. [ Time Frame: Within 12 months of last participant's final visit. ]
    Presence/quantity of autoreactive CD8 and Treg; T cells; RNAseq; HLA alleles

  2. Difference in immune gene expression [ Time Frame: Within 12 months of last participant's final visit. ]
    Difference in immune gene expression, as measured by RNAseq in newly diagnosed EET1D v NDM

  3. Association of maternal and paternal non-inherited HLA alleles with EET1D [ Time Frame: Within 12 months of last participant's final visit. ]
    Association of maternal and paternal non-inherited HLA alleles with EET1D v older onset T1D and NDM


Biospecimen Retention:   Samples With DNA
A blood sample and optional urine sample will be collected. In addition to a clinical blood sample analysed locally, the following samples will be collected and sent (by courier) to the Exeter Clinical Laboratories: one EDTA tube for C-peptide and autoantibody analysis(12, 13) and, dependent on age and weight (http://www.who.int/bulletin/volumes/89/1/10-080010/en/), one Tempus tube with 0.5 ml minimum blood sample for RNAseq, and one to five 5 ml Sodium Heparin tubes for PBMC extraction and cryopreservation. An optional urine sample, if collected, will be provided in a 20 ml boric acid tube.


Information from the National Library of Medicine

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, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   up to 70 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Defining patients as EET1D:

Patients will be selected on the basis of:

i) diagnosis of diabetes <24 months ii) exclusion of mutation in all 23 monogenic non-autoimmune neonatal diabetes genes using targeted capture Next Generation Sequencing(NGS) iii) T1D GRS within distribution of T1D reference population. iv) Diagnosis of monogenic type 1 diabetes defined as a mutation in a gene known to cause type 1 diabetes or a Down's syndrome

Study 1: existing cases of any age meeting above criteria. Study 2: new cases referred to Exeter Genetics Service or Dr Oram within 12 months of diagnosis, meeting above criteria, and aged <24 months.

Comparison groups:

Study 1: duration-matched patients with T1D diagnosed at 1-20 years of age.

Study 2: Age- and duration-matched controls NDM. Eligible patients will include people with neonatal diabetes caused by mutations in the Kir6.2 and SUR1 genes.

Criteria

Inclusion Criteria:

Study 1:

EET1D

  • Aged 0 to 70 years
  • Clinical diagnosis of diabetes <24 months (+ evidence of WHO diabetes criteria)
  • Negative genetic test for mutations causing non-autoimmune neonatal diabetes if diagnosed <12 months
  • Type 1 diabetes genetic risk score >50th centile of T1D reference group, or monogenic cause of T1D.

T1D Controls

  • Age 0-70 years (matched to above)
  • Clinical diagnosis of T1D (diagnosed age 1-20 years)
  • Insulin treated from diagnosis.

Study 2:

EET1D

  • Aged 0 to 24 months at recruitment
  • Clinical diagnosis of diabetes <24 months (+ evidence of WHO diabetes criteria)
  • Negative genetic test for mutations causing non-autoimmune neonatal diabetes
  • Type 1 diabetes genetic risk score >50th centile of T1D reference group, or monogenic cause of T1D.

NDM controls

  • Diagnosis of diabetes <24 months
  • Age 0 to 18 months at recruitment
  • Diagnosis of NDM (confirmed by Exeter Molecular Genetics Laboratory).

Exclusion Criteria:

Study 1:

  • Aged >70 years
  • No diagnosis of diabetes
  • MODY (e.g. caused by HNF1A/HNF4A/HNF1B/GCK mutations), type 2 diabetes or diabetes related to pancreatic insufficiency or syndromic diabetes
  • Intercurrent illness at time of sampling for PBMCs (see below).

Study 2:

  • Aged >24 months
  • Clinical diagnosis of diabetes >24 months
  • Intercurrent illness at time of sampling for PBMCs or RNA (see below).

For PBMC and RNA sampling: Exclusion for factors that may alter T cell function and RNAseq

Review the following exclusion criteria carefully at time of appointment as some details may have changed since initial contact:

  • Recreational drug use (excluding cannabis use more than 1 week prior to blood sampling) - drug abuse may alter T cell function
  • Alcohol related illness (excessive alcohol consumption may alter T cell function)
  • Renal failure: Creatinine >200 (as may alter T cell function)
  • Any other medical condition which, in the opinion of the investigator, would affect the safety of the subject's participation.

Factors that if temporary would lead to rearrangement of study visit but if long duration, may lead to exclusion subject to the CI's discretion:

  • Pregnant or lactating (as this may limit blood sampling and affect T cell function)
  • Any infectious illness within the last 2 weeks if it was a febrile illness, or within 2-3 days if it was non-febrile (as this may activate T cells non-specifically)
  • Taking steroids or other immunosuppressive medications (as these may alter T cell function)
  • Received any immunoglobulin treatments or blood products in the last 3 months (as these may alter T cell function).

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): NCT03369821


Contacts
Layout table for location contacts
Contact: Richard Oram +44 (0) 1392 408538 r.oram@exeter.ac.uk
Contact: Michelle Hudson +44 (0) 1392 408180 m.hudson@exeter.ac.uk

Locations
Layout table for location information
United States, California
Diabetes and Metabolism Institute Not yet recruiting
Hope, California, United States, 91010
Contact: Bart Roep    626-256-4673    broep@crh.org   
United States, Washington
Benaroya Research Institute Not yet recruiting
Seattle, Washington, United States, 98101-2795
Contact: Cate Speake    206-342-6500    cspeake@benaroyaresearch.org   
United Kingdom
Royal Devon & Exeter NHS Foundation Trust Recruiting
Exeter, Devon, United Kingdom, EX2 5DW
Contact: Richard Oram    +44 (0) 1392 408538    r.oram@exeter.ac.uk   
Contact: Michelle Hudson    +44 (0) 1392 408183    m.hudson@exeter.ac.uk   
Sub-Investigator: Andrew T Hattersley         
Sub-Investigator: Timothy McDonald         
King's College London Active, not recruiting
London, United Kingdom, SE1 9RT
Sponsors and Collaborators
University of Exeter
Royal Devon and Exeter NHS Foundation Trust
King's College London
City of Hope National Medical Center
Benaroya Research Institute
Investigators
Layout table for investigator information
Principal Investigator: Richard Oram University of Exeter

Additional Information:
Publications:

Layout table for additonal information
Responsible Party: University of Exeter
ClinicalTrials.gov Identifier: NCT03369821     History of Changes
Other Study ID Numbers: CRF 228
17/EM/0255 ( Other Identifier: Research Ethics Committee )
1617/023 ( Other Identifier: Sponsor: University of Exeter )
1706443 ( Other Identifier: Co-Sponsor: Royal Devon & Exeter NHS Foundation Trust )
228082 ( Other Identifier: IRAS ref )
50793 ( Other Grant/Funding Number: Diabetes UK )
First Posted: December 12, 2017    Key Record Dates
Last Update Posted: March 29, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: The Exeter study team will have access to the final dataset. Of the multiple analyses done during the study, relevant co-investigators for each analysis (e.g. RNAseq for Cate Speake) will have access to the datasets they have contributed to. Other researchers are to contact Dr Richard Oram about the sharing of the study data.

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Exeter:
type 1 diabetes
monogenic diabetes
autoimmune diabetes
early-onset autoimmune diabetes
beta cell (β-cell) destruction
type 1 diabetes genetic risk
extremely early-onset Type 1 diabetes
neonatal diabetes

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