Effects of Sitagliptin in Relatives of T1D Patients

Study Overview
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Brief Summary
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Type 1 Diabetes (T1D) is a chronic autoimmune disease, with a genetic background, resulting from the immune-mediated destruction of beta cells of the pancreas. It can lead to fatal short-term and long-term complications, especially if it is diagnosed late. Three stages of the disease can be identified: Stage 1 is defined by the presence of two or more anti-islet autoantibodies (GAD65, ICA, IA-2, ZnT8) with normoglycemia, Stage 2 shows progression to dysglycemia (impaired glucose tolerance) in the setting of two or more anti-islet autoantibodies, Stage 3 occurs when a patient meets ADA criteria for the diagnosis of diabetes. It's been demonstrated that Teplizumab (an Fc receptor nonbinding anti-CD3 monoclonal antibody) delays the transition from pre-symptomatic T1D (stage 2) to overt T1D (stage 3). Also Sitagliptin, a DPP4 inhibitor, has been proved effective in inhibiting inflammation in T1D both in vitro in T1D mice, and in vivo in Latent autoimmune diabetes in adults (LADA) patients. Furthermore, it has been confirmed that Sitagliptin reduces the prevalence of worse forms of acute GVHD after myeloablative allogeneic hematopoietic stem-cell transplantation. The study aims to investigate if Sitagliptin can have a delaying effect on progression to overt T1D, on the account of its anti-inflammatory properties. The cohort is made of screened relatives of T1D patients, who are classified as high-risk of developing T1D. Screening relatives of T1D patients for dysglycemia and anti-islet autoantibodies. Selecting the patients in Stage 2 Pre-symptomatic T1D (dysglycemia and at least two types of autoantibodies) and then beginning therapy with Sitagliptin, while monitoring their glucose metabolism with a Continuous Glucose Monitoring (CGM) system.

Official Title
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Effects of Sitagliptin in Relatives of Patients With Type 1 Diabetes Mellitus, at High Risk of Developing the Disease

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Sitagliptin
* Device: Professional CGM


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of the subject between 10 and 45 years Subject (or legal guardian in the case of a minor) is able to provide informed consent If a first degree relative of the proband with T1D must be between 6 and 45 years old (brother, sister, parent, child) If a relative of the proband with T1D is second degree, he must be between 6 and 20 years old (nephew, uncle, aunt, grandfather, grandmother, cousin) Presence of at least two autoantibodies associated with diabetes Impaired glucose tolerance on the OGTT test (fasting glucose greater than 110 mg/dl but less than 126 mg/dl or 2-hour glucose greater than or equal to 140 mg/dl but less than 200 mg/dl or 'OGTT at 30', 60 ', 90' greater than or equal to 200 mg/dl) If the subject is a female with reproductive potential, she must have a negative pregnancy test at the enrollment visit and must agree not to seek pregnancy for at least one year from randomization If the subject is male, he must agree not to seek pregnancies with any partner for at least one year from the randomization The subject must agree to renounce other types of trials during this study Weight at the time of recruitment of at least 26 kg It must be favorable and clinically acceptable to postpone vaccinations with live and attenuated agents for at least one year after treatment Exclusion Criteria: Type 1 Diabetes Mellitus previously diagnosed or diagnosed during screening investigations Serological evidence of current or past HIV, Hepatitis C, Hepatitis B Changes in blood counts, INR or liver enzymes Being pregnant or breastfeeding Evidence of pancreatic changes in the laboratory Having undergone a previous experimental treatment for Type 1 Diabetes Mellitus Chronic Renal Failure stage IIIa onwards (eGFR <45 ml / min / 1.7 m2) History of previous pancreatitis Lymphopenia (<1000 lymphocytes / µL) Neutropenia (<1500 PMN / µL) Thrombocytopenia (<150,000 platelets / µL) Anemia (Hgb <10 grams / deciliter [g / dL]) AST or ALT> 1.5 x ULN Total bilirubin> 1.5 x upper limit of normal (ULN) with the exception of subjects diagnosed with Gilbert's syndrome who may be eligible provided they have no other cause leading to hyperbilirubinemia INR> 0.1 above the upper limit of the norm at the laboratory of the participating center Alterations of Amylase and Lipase due to the pancreas Chronic active infection other than localized skin infections A positive PPD test Vaccination with a live virus within 8 weeks of randomization Vaccination with a killed virus within 4 weeks of randomization Laboratory or clinical evidence of acute EBV or CMV infection Serological evidence of current or past HIV, hepatitis B or hepatitis C infection Being currently pregnant or breastfeeding, or planning to become pregnant Chronic use of steroids or other immunosuppressive agents A history of asthma or atopic disease that requires chronic treatment Untreated hypothyroidism or active Graves' disease at randomization Current use of non-insulin drugs that affect glycemic control Previous OKT®3 or other anti-CD3 treatment Administration of a monoclonal antibody within the year prior to randomization Participation in any type of clinical trial of therapeutic drugs or vaccines in the 12 weeks prior to randomization Any conditions that, in the opinion of the investigator, could interfere with the conduct of the study or with the safety of the subject.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A randomized controlled open label intervention study is proposed. Relatives of patients with type 1 diabetes in stage 2 will be included in the study and divided into two groups by randomization: sitagliptin add-on therapy vs placebo(group of control)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment group<br>Sitagliptin | Drug: Sitagliptin<br>* The dose of sitagliptin will be established on the basis of the estimated glomerular filtrate: 100 mg in single daily administration (estimated glomerular filtration rate less than or equal to 45 mL / min / 1.73 m2) or 50 mg (estimated glomerular filtration rate 30-45 mL / min / 1.73 m2)<br>Device: Professional CGM<br>* The sensor records the patient's glucose readings every 15 minutes for up to 14 days.<br>|
| Placebo Comparator: Control group<br>Placebo | Device: Professional CGM<br>* The sensor records the patient's glucose readings every 15 minutes for up to 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of new diagnoses of Type 1 Diabetes Mellitus per year |  | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse effects on Sitagliptin |  | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sitagliptin