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

A Pilot Trial of Adding Oral Hypoglycemic Therapy to Insulin Treatment in Monogenic Variant Carriers of the Joslin 50-Year Medalist Study

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Type 1 Diabetes; Monogenic Diabetes
• Intervention / Treatment: Drug: Metformin Extended Release Oral Tablet; Drug: Sitagliptin

• Study Type: Interventional
• Enrollment (Estimated): 21
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Joslin Diabetes Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 85 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: HLA+ Group; 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 (-)	Drug: Metformin Extended Release Oral Tablet; Initial oral hypoglycemic agent added to existing insulin treatment; Drug: Sitagliptin; Secondary oral hypoglycemic agent added to existing insulin treatment (for those who are intolerant to or unable to achieve glycemic targets with metformin)
Other: HLA- Group; 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	Drug: Metformin Extended Release Oral Tablet; Initial oral hypoglycemic agent added to existing insulin treatment; Drug: Sitagliptin; Secondary oral hypoglycemic agent added to existing insulin treatment (for those who are intolerant to or unable to achieve glycemic targets with metformin)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glycated hemoglobin (HbA1c)	Change in HbA1c (%) between the two study groups	3 months and 6 months

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Joslin Diabetes Center
• Investigators: Principal Investigator: George L. King, MD, Joslin Diabetes Center

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2021
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: November 14, 2019
• First Submitted That Met QC Criteria: May 28, 2020
• First Posted (Actual): June 1, 2020

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Metformin; Sitagliptin Phosphate
• Other Study ID Numbers: 2019-76

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes