Study of the Pharmacologic Action of a GPR119 Agonist on Glucagon Counter-regulation During Insulin-induced Hypoglycemia in Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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The purpose of this study is to test if a specific research medication could increase the response to low blood glucose in people with type 1 diabetes. The response of the body to low blood sugar will be measured in healthy people as a reference point.

Official Title
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A Randomized, Placebo-controlled, Double-blinded Cross-over Study of the Pharmacologic Action of a GPR119 Agonist on Glucagon Counter-regulation During Insulin-induced Hypoglycemia in Type 1 Diabetes Mellitus

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Placebo
* Drug: Study Medication (MBX-2982)
* Other: No medication for this group


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes cohort Age >20 years Diagnosis of T1DM according to American Diabetes Association (ADA) criteria continuously requiring insulin for survival Diabetes diagnosis performed more than 5 years before enrollment Fasting C-peptide levels < 0.7 ng/mL with a concurrent plasma glucose concentration > 90 mg/dL For female participants: agrees not to become pregnant during the study and for at least 2 weeks after the last dose of the study medication. For male participants: agrees not to donate sperm or not to get a woman pregnant during the study and for at least 2 weeks after the last dose of the study medication. Healthy subject cohort Age >20 years General good health Creatinine clearance >80 mL/min based on MDRD equation Fasting blood glucose (FBG) >70 mg/dL and <100 mg/dL No history of diabetes Exclusion Criteria: BMI >30 kg/m2 and <18.5 kg/m2 No evidence by history, EKG or exams of symptomatic cardiovascular disease (unstable angina, myocardial infarction or coronary revascularization within 6 months, clinically significant abnormalities on EKG, presence of cardiac pacemaker, implanted cardiac defibrillator) Evidence of autonomic neuropathy Liver disease (AST or ALT >2.5 times the upper limit of normal) Kidney disease (creatinine >1.6 mg/dl or estimated GFR <60 ml/min). Dyslipidemia, including triglycerides >500 mg/dl, LDL >200 mg/dl or unstable hyperlipidemia. Treatment with a single lipid lowering agents is allowed if stable within the previous 3 months. Anemia (hemoglobin <12 g/dl in men, <11 g/dl in women) Thyroid dysfunction (suppressed thyroid stimulating hormone (TSH), elevated TSH <10 µIU/ml if symptomatic or elevated TSH >10 µIU/ml if asymptomatic) Uncontrolled hypertension (BP >160 mmHg systolic or >100 mmHg diastolic) or treatment with more than 2 antihypertensive medications History of cancer within the last 5 years (skin cancers, with the exception of melanoma, may be acceptable). History of organ transplant History of HIV, active Hepatitis B or C, or Tuberculosis Pregnancy, lactation or 6 months postpartum from the scheduled date of collection Females of childbearing potential (any female except those with tubal ligation, hysterectomy, or absence of menses >2 years) unwilling to use an approved method of contraception (one medically accepted method of contraception with ≥99% effectiveness when used consistently and correctly: implantable uterine device (IUD), hormonal contraception). Male participants: unwilling to use appropriate contraception (e.g. condoms) and/or their partner uses a medically accepted form of contraception during the study. History of Major Depression in the last 5 years History of an eating disorder History of bariatric surgery History of drug or alcohol abuse (> 3 drinks per day) within the last 5 years Psychiatric disease prohibiting adherence to study protocol Use of oral or injectable anti-hyperglycemic agents: metformin, sulfonylureas, DPP IV inhibitors, SGLT-2 inhibitors, thiazolidinediones, acarbose, GLP-1 analogs Current use of beta-adrenergic blocking agents or their use was stopped less than one month before recruitment Initiation or change in hormone replacement therapy within the past 3 months (including, but not limited to thyroid hormone or estrogen replacement therapy) Use of any medications known to influence glucose, fat and/or energy metabolism within the last 3 months (e.g., growth hormone therapy, glucocorticoids [steroids], prescribed medications for weight loss, etc.) Current night shift worker Presence of any condition that, in the opinion of the Investigator, compromises participant safety or data integrity or the participant's ability to complete study visits Additional exclusion Criteria for type 1 diabetes cohort History of T2DM or any form of diabetes other than T1DM Hypoglycemia unawareness as assessed using the GOLD score Using a predictive low blood glucose suspend mode on an insulin pump or a hybrid closed loop algorithm for insulin delivery. For those applying these strategies for everyday management of blood glucose and willing to participate, the algorithm will be stopped at enrollment where possible. Two or more episode of severe hypoglycemia per month in the past six months. QTcF >450 ms for males and >470 ms for females Using non-insulin agents to control blood glucose levels. No evidence of moderate or severe end-organ diabetic complications of retinopathy, nephropathy or neuropathy. Non-proliferative retinopathy and microalbuminura will be allowed. Additional exclusion Criteria for the healthy cohort Insulin treatment

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MBX-2982 first then placebo- Volunteers with Type 1 diabetes<br>This will be followed by a second study period in which they will be crossed over to the other treatment. | Drug: Placebo<br>* Each group will receive either a pill that contains the study medication (MBX-2982) or a pill that does not contain the medication (placebo)<br>Drug: Study Medication (MBX-2982)<br>* Each group will receive either a pill that contains the study medication (MBX-2982) or a pill that does not contain the medication (placebo)<br>|
| Active Comparator: Healthy Volunteers<br>this group will not receive any medication. It will be studied to establish the norm of the measurement that will be performed to obtain the study outcomes. | Other: No medication for this group<br>* This group will be studied to establish the norm of the measurement that will be performed to obtain the study outcomes.<br>|
| Experimental: Placebo first then MBX-2982- Volunteers with Type 1 diabetes<br> | Drug: Placebo<br>* Each group will receive either a pill that contains the study medication (MBX-2982) or a pill that does not contain the medication (placebo)<br>Drug: Study Medication (MBX-2982)<br>* Each group will receive either a pill that contains the study medication (MBX-2982) or a pill that does not contain the medication (placebo)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal glucagon concentration during hypoglycemia |  | Day 14, Day 28, 6 hours | 
| Total area under the curve (AUC) for glucagon during hypoglycemia. |  | Day 14, Day 28, 6 hours | 
| Incremental AUC for glucagon during hypoglycemia (above baseline levels during euglycemia) |  | Day 14, Day 28, 6 hours |