NCT03369821 · University of Exeter
EXtremely Early-onset Type 1 Diabetes EXtremely Early-onset Type 1 Diabetes (A Musketeers' Memorandum Study)
(EXE-T1D)
What this study is about
Type 1 diabetes (T1D) results from destruction of insulin-producing beta cells in the pancreas by the body's own immune system (autoimmunity). It is not fully understood what causes this type of diabetes and why there is variation in age of onset and severity between people who develop the disease.
View original scientific description
Type 1 diabetes (T1D) results from destruction of insulin-producing beta cells in the pancreas by the body's own immune system (autoimmunity). It is not fully understood 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 2 years of age (EET1D). The investigators think that, for the condition to have developed that early, they must have an unusual or extreme form of autoimmunity. Studying people with EET1D 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. Much may be learned about the disease from a small number of rare individuals. The investigators aim to confirm that they have autoimmune type 1 diabetes and then try to understand how 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, live all over the world. and are usually referred to Exeter for genetic testing. Individuals will be contacted via their clinician to ask for more information about their diabetes and their family history. Samples will be collected 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, their immune system will be studied in depth using immune cells isolated from a blood sample. These cells will undergo cutting edge techniques by Dr Tim Tree at King's College London, by Professor Bart Roep at Leiden University Medical Center, Netherlands, and Dr Cate Speake, Benaroya Research 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. Additional funding extended the study for a further 3 years (Phase 2) to include recruitment of infants without diabetes, aged 0-6 years, as controls to enable assessment of how the abnormalities found in autoimmune and non-autoimmune diabetes compare to normal early life development of the immune system. An additional funding award extended the study (Phase 3) until November 2028, to advance the EXE-T1D program into its third phase, building on major discoveries from phases 1 and 2 to identify, validate, and target immune pathways that drive extremely early-onset type 1 diabetes (eeT1D) and are likely relevant to T1D across all ages. eeT1D cases, diagnosed within the first two years of life, represent particularly aggressive onset of beta-cell autoimmunity. They offer a unique lens to uncover mechanisms of immune dysregulation, informed by both polygenic and monogenic causes. The central aim is to move from pathway discovery to demonstration of novel druggable targets with potential to delay or prevent T1D onset across all ages.
Interventions
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
Measure beta cell function in EET1D compared to T1D, NDM and non-diabetic controls.
Time frame: Within 12 months of last participant's final visit.
C-peptide and GAD, IA2, ZnT8 autoantibody measurement
Who can participate
This study lists these criteria on ClinicalTrials.gov. A study coordinator reviews eligibility during screening — this page does not determine whether you qualify.
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. Monogenic / NDM controls
- Diagnosis of diabetes \<12 months
- Diagnosis of monogenic / NDM (confirmed by Exeter Molecular Genetics Laboratory). 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. Monogenic/NDM controls
- Diagnosis of diabetes \<24 months
- Age 0 to 18 months at recruitment
- Diagnosis of monogenic/NDM (confirmed by Exeter Molecular Genetics Laboratory). Non-diabetic controls
- Aged 0-6 years
- Attending specified participating hospital sites for elective surgery, including but not limited to: inguinal hernia repair, umbilical/midline hernia repair, orchidopexy, gastrostomy insertion/change, hypospadias repair, cleft palate repair, excision of accessory digit, laryngoscopy, adenoidectomy, tonsillectomy, MRI under general anaesthesia, eye surgery.
Exclusion criteria
- 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). Non-diabetic controls:
- Aged \>6 years
- Diagnosis of diabetes or other autoimmune condition
- Known immunological disorder
- On immunosuppressive medication
- Ongoing infections/sepsis
- Major congenital abnormality or significant systemic illness that may affect the immune system, e.g. metabolic disease, 22q deletion syndrome
- Recent (within two weeks) febrile illness
- Renal failure. 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).
Where
- Seattle, Washington
Collaborators
Royal Devon and Exeter NHS Foundation Trust, King's College London, Benaroya Research Institute
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Frequently asked questions
What is a clinical trial?
A clinical trial is a research study that tests new medical treatments, drugs, devices, or procedures to determine their safety and effectiveness. Trials are carefully designed and monitored to protect participants while advancing medical knowledge.
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Clinical trials follow strict safety guidelines and ethical standards. Trials must be reviewed and approved, and participants are closely monitored by medical professionals throughout the study. You can withdraw at any time if you choose.
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Will I receive a placebo instead of treatment?
When effective treatment exists, participants typically receive either the standard treatment plus the study intervention, or the standard treatment plus placebo. You would not be denied effective care. Placebos are primarily used when no proven treatment is available, or in addition to standard care. Your trial consent form will clearly explain what treatments you may receive.
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Data: ClinicalTrials.gov · synced Dec 19, 2025 · Source of record for eligibility and locations