Oral Hypoglycemic Therapy for Monogenic Variant Carriers of the Joslin Medalist Study

Phase 2

Completed

• Conditions: Type 1 Diabetes; Monogenic Diabetes
• Interventions: Drug: Metformin Extended Release Oral Tablet; Drug: Sitagliptin

• Registration Number: NCT04409795
• Lead Sponsor: Joslin Diabetes Center

Brief Summary

The purpose of this study is to evaluate the efficacy of adding oral hypoglycemic agents (OHA) to existing insulin treatment in monogenic variant carriers of the Joslin 50-Year Medalist Study ("Medalists"), who are characterized by ≥50 years of insulin-dependent diabetes. Our primary objective is to evaluate whether the presence of human leukocyte antigen (HLA) high-risk alleles for diabetes (DR3 and/or DR4) can affect the effectiveness of OHA in these subjects.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-11-14
• Study First Submitted QC: 2020-05-28
• Study First Posted: 2020-06-01
• Study Start: 2021-08-26
• Primary Completion: 2024-12-31
• Study Completion: 2024-12-31
• Status Verified: 2025-02
• Last Update Submitted: 2025-02-21
• Last Update Posted: 2025-02-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 3

Inclusion Criteria

• Existing participants in the Joslin 50-Year Medalist Study
• Residing in the United States
• Capable of giving informed consent
• Known detectable C-peptide >0.05 ng/mL

Exclusion Criteria

• Known diagnosis of cancer or active inflammatory disease such as rheumatoid arthritis, lupus, and inflammatory bowel disease
• Recent history of myocardial infarction, angioplasty, bypass surgery, heart failure, angina, stroke, or uncontrolled hypertension>160/100 during the past 3 months
• Known diagnosis of cognitive dysfunction, dementia or Alzheimer's disease
• Pre-existing liver disease or liver function tests (AST or ALT)>3x the upper limit of normal
• Pre-existing kidney disease (Chronic Kidney Disease Stage IV and below, or estimated glomerular filtration rate<45 mL/min/1.73 m2)
• Active use of immunosuppressants
• Recipients of prior islet cell or pancreas transplantation
• Inability to travel due to frailty or health reasons
• Donated blood within the previous two (2) months

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
HLA+ Group	Metformin Extended Release Oral Tablet	Participants who are high-risk HLA-DR3 and/or DR4 (+); monogenic variant (+) with rare exome variant ensemble learner (REVEL) score\>0.75; and both glutamic acid decarboxylase (GAD65) and islet antigen (IA2) autoantibody (-)
HLA- Group	Metformin Extended Release Oral Tablet	Participants who are high-risk HLA-DR3 and DR4 (-); with known or yet unknown monogenic variants with REVEL score\>0.75; and either GAD65 and IA2 autoantibody (-), or autoantibody (+) with titers close to the cutoff
HLA+ Group	Sitagliptin	Participants who are high-risk HLA-DR3 and/or DR4 (+); monogenic variant (+) with rare exome variant ensemble learner (REVEL) score\>0.75; and both glutamic acid decarboxylase (GAD65) and islet antigen (IA2) autoantibody (-)
HLA- Group	Sitagliptin	Participants who are high-risk HLA-DR3 and DR4 (-); with known or yet unknown monogenic variants with REVEL score\>0.75; and either GAD65 and IA2 autoantibody (-), or autoantibody (+) with titers close to the cutoff

Primary Outcome Measures

Name	Time	Method
Glycated hemoglobin (HbA1c)	3 months and 6 months	Change in HbA1c (%) between the two study groups

Secondary Outcome Measures

Name	Time	Method
Daily insulin dose	3 months and 6 months	Change in daily insulin dose (units/kg body weight) between the two study groups
Total cholesterol	3 months and 6 months	Change in total cholesterol (mg/dL) between the two study groups
Triglycerides	3 months and 6 months	Change in triglycerides (mg/dL) between the two study groups
Area under the plasma concentration versus time curve (AUC) of C-peptide	6 months	Change in AUC of C-peptide between the two study groups, as measured by the hyperglycemic/arginine clamp, at the end of the study
Body mass index (BMI)	3 months and 6 months	Change in BMI between the two study groups. Weight and height will be combined to report BMI in kg/m\^2.
High density lipoprotein (HDL)-cholesterol	3 months and 6 months	Change in HDL-cholesterol (mg/dL) between the two study groups
C-peptide	3 months and 6 months	Change in C-peptide (ng/mL) between the two study groups
Low density lipoprotein (LDL)-cholesterol	3 months and 6 months	Change in LDL-cholesterol (mg/dL) between the two study groups

Trial Locations

Locations (1)

Joslin Diabetes Center; 🇺🇸 Boston, Massachusetts, United States