Dulaglutide and Insulin MicrosecretiON in Type 1 Diabetes

Study Overview
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Brief Summary
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Some patients with type 1 diabetes (T1D) can still have some remaining insulin-positive cells in the pancreas and secrete little amounts of insulin. Despite the presence of residual beta cells, the HbA1C levels remain at high levels due to functional defects of insulin secretion associated with glucotoxicity. Previous trials have indicated that treatment with a Glucagon-like peptide 1 (GLP-1 )receptor agonist in T1D with some residual beta-cell function might improve glycemic control, reduce dose of insulin and risk of hypoglycemia. The general hypothesis of DIAMOND-GLP1 is that GLP1-R agonists will improve blood glucose After initial screening to select insulin microsecretors and a run-in period of one month, patients will be randomized into two arms and followed in parallel for 24 weeks : Experimental group receiving 1.5 mg Dulaglutide s.c weekly in addition to their usual insulin regimen Control group receiving placebo s.c weekly in addition to their usual insulin regimen. The primary endpoint is HbA1c value at 24 weeks

Official Title
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Dulaglutide and Insulin MicrosecretiON in Type 1 Diabetes : A Randomized Double-blind Placebo-controlled Trial

Conditions
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Adult Subjects With Type1Diabetes and Insulin Microsecretion

Intervention / Treatment
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* Drug: Dulaglutide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients with T1D> 4years, with age range 20-60years Diabetes onset after the age of 15years Duration of diabetes <15 years Treated with continuous sub-cutaneous insulin infusions (CSI) or multiple daily injections of insulin (MDI) Measuring their blood sugar at least four times daily Glycated hemoglobin (HbA1C) at screening >7 and <10% 16.0 kg/m2 <BMI<30.0kg/m2 Patients with childbearing potential should use effective contraception, defined as methods with a failure rate ≤ 2 % per year (OMS 2011) during the study. Patients who gave its written informed consent to participate to the study Patients affiliated to a social insurance regime Randomization criteria: Patients with fasting ultra-sensitive (us) C-peptide above 15pmol/l Exclusion Criteria: Patients are not eligible for this study if any of the following exclusion criteria apply: Patients with type 2 diabetes (T2D) Hypersensitivity to dulaglutide and/or any of its excipients Subjects with history of severe hypoglycemia or recent (< 6 months) history of diabetic ketoacidosis History of gastrointestinal disease with prolonged (> 3 months) nausea or vomiting, liver or kidney diseases, pancreatitis, thyroid medullary cancer or familial history of multiple endocrine neoplasia type 2 Estimated glomerular filtration rate<60ml/min/ 1.73m2 (CKD-EPI method) Congestive heart failure Any uncontrolled disease, cancers essentially Chronic use of paracetamol containing products, which may falsely raise sensor glucose readings Use of tricyclic antidepressant, selective serotonin reuptake inhibitor, triptans, neuroleptic drugs and glucocorticoid. Patient who participated in another clinical trial on experimental drug in the previous 30 days Patients of childbearing potential who are not using adequate contraception; Female patients who are pregnant or lactating. Gastric bypass surgery Patients under guardianship

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 60 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicentric, investigator-initiated, randomized, double-blinded, therapeutic clinical trial, placebo-controlled, two arm parallel group intervention trial during 24 weeks, phase II.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dulaglutide<br>Experimental group receiving 1.5 mg Dulaglutide subcutaneously weekly in addition to their usual insulin regimen during 24 weeks | Drug: Dulaglutide<br>* Dulaglutide 1.5mg : One injection per week during 24 weeks<br>|
| Placebo Comparator: placebo<br>Control group receiving placebo subcutaneously weekly in addition to their usual insulin regimen during 24 weeks | Drug: Placebo<br>* Placebo: one injection per week during 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HbA1c level | Blood level | after 24 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC us C-peptide following a MMT | Evaluation and comparison before and after 24wks of treatment with Dulaglutide vs placebo the area under curve (AUC) of ultrasensitive (us) C-peptide response from 6 values following a mixed meal test (MMT) | before and after 24 weeks of treatment | 
| Glucagon levels fasting and following a MMT | Evaluation and comparison before and after 24wks of treatment with Dulaglutide vs placebo AUC glucagon from 6 values on fasting and after MMT | before and after 24 weeks of treatment | 
| AUC us C-peptide over AUC blood glucose levels following a MMT | Evaluation and comparison the ratio of the area under curve (AUC) of us C-peptide over the glucose response following a mixed meal test (MMT) with before and after 24 weeks of treatment Dulaglutide vs placebo | before and after 24 weeks of treatment | 
| Daily percent times spent with continuous glucose measurements (CGM) readings between 4 and 10mmol/l, above and below this range | Evaluation and comparison the changes in the daily percent time spent with continuous glucose measurements (CGM) readings between 4 and 10mmol/l during the run-in period (1 month) and after 24 weeks with Dulaglutide vs placebo, coefficients of variation (CV) and standard deviation values (SD) as well as the average daily risk change (ADRR) of glucose values to assess blood glucose variability. | the run-in period (1 month) and after 24 weeks of treatment | 
| Daily insulin doses and basal/ prandial ratio | Evaluation and comparison before and after 24wks of treatment with Dulaglutide vs placebo the daily insulin doses and basal/ prandial ratio | : before and after 24weeks of treatment | 
| : Body weight |  | before and after 24weeks of treatment | 
| % carbohydrates | Evaluate and compare the changes in mean carbohydrate intake during the run-in period and after 24 weeks with Dulaglutide vs placebo | the run-in period (1 month) and after 24 weeks of treatment | 
| Number of symptomatic hypoglycemic episodes | Evaluation and comparison the number of symptomatic (both minor and severe) hypoglycemic episodes with Dulaglutide vs placebo during the study | 20 months | 
| Number of adverse events | Evaluation and comparison the number of adverse events with Dulaglutide vs placebo during the study | 20 months | 
| Autoantibodies to GAD65 | Evaluation and comparison before and after 24wks of treatment the levels and subtypes of autoantibodies associated with T1D with and without dulaglutide | : before and after 24wks of treatment | 
| insulin doses : basal/ prandial ratio | the insulin basal/ prandial ratio | before and after 24weeks of treatment | 
| Autoantibodies to IA-2 | Evaluation and comparison before and after 24wks of treatment the levels and subtypes of autoantibodies associated with T1D with and without dulaglutide | before and after 24wks of treatment | 
| Autoantibodies to ZnT8 | Evaluation and comparison before and after 24wks of treatment the levels and subtypes of autoantibodies associated with T1D with and without dulaglutide | before and after 24wks of treatment | 
| coefficients of variation (CV) | coefficients of variation (CV) of daily percent times spent with continuous glucose measurements (CGM) readings between 4 and 10mmol/l, above and below this range . | the run-in period (1 month) and after 24 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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type 1 diabetes, insulin microsecretion, dulaglutide, randomized, double-blind placebo-controlled trial