A Study to Evaluate the Effect of Ranolazine on Postprandial Glucagon in Subjects With Type 2 Diabetes.

Study Overview
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Brief Summary
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To explore the mechanism of action of ranolazine as a potential treatment for type 2 diabetes mellitus (T2DM).

Official Title
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A Phase 1, Randomized, Single-blind, Placebo-controlled, Multiple-dose, Two-sequence, Cross-over Study to Evaluate the Effect of Ranolazine on Glucagon Secretion in Subjects With Type 2 Diabetes Mellitus, Followed by An Open-label, Single Dose, Exenatide Active-control Period

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Ranolazine
* Drug: Placebo
* Drug: Exenatide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females, 18 to 65 years old, inclusive Documented history of T2DM for ≥5 years Body mass index (BMI) 20.0 to 40.0 kg/m2, inclusive, at Screening Stable treatment (≥ 12 weeks) with metformin alone, a sulfonylurea alone, a meglitinide alone, or a combination of metformin with either a sulfonylurea or a meglitinide HbA1c ≥ 7.0% and ≤ 10.5%, inclusive, at Screening Fasting glucose within specific ranges, at Screening and after 14 +/-2 days of wash-out from prior oral anti-diabetic agents Fasting serum C-peptide ≥0.8 ng/mL, at Screening Estimated glomerular filtration rate (eGFR)≥60 mL/min/1.73 m2 Ability and willingness to comply with all study procedures during the course of the study, including washout from oral anti-diabetic (OAD) agents approximately 2 weeks prior to Day -2 admission Females of childbearing potential must have a negative pregnancy test at Screening and on Day -2 admission and must agree to use highly effective contraception methods from Screening throughout study participation and for 14 days following the last dose of study drug. Exclusion Criteria: History of type 1 diabetes mellitus or secondary forms of diabetes History of acute diabetes complications Recent or significant heart conditions Uncontrolled hypertension QTc interval > 500 msec by ECG at Screening or on Day -2 admission, a personal or family history of QTc prolongation, congenital long QT syndrome, or use of drugs that prolong the QTc interval, such as Class Ia or Class III antiarrhythmic agents, erythromycin, and certain antipsychotics (eg, ziprasidone) History of severe GI disease (e.g., gastroparesis) History of pancreatitis (acute or chronic) Current consumption of > 14 alcoholic drinks per week, or more than 4 alcoholic drinks on any one day Current regular use of tobacco- or nicotine-containing products in excess of 10 cigarettes per day or equivalent History of substance abuse within 12 months prior to Screening Significant hepatic disease, including, but not limited to, chronic active hepatitis and liver cirrhosis (Child-Pugh Class A, B, or C) History of malignancy within 5 years prior to Screening Significant thyroid disease Treatment with selected medications, as indicated in the protocol Prior treatment with open-label ranolazine or known hypersensitivity or intolerance to ranolazine or its excipients Known hypersensitivity or intolerance to GLP-1 mimetics Known hypersensitivity or intolerance to acetaminophen Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2.5 X upper limit of normal (ULN) Total Bilirubin (TB) > 2 mg/dL Hemoglobin < 12 g/dL (for males) or < 11 g/dL (for females) Positive for hepatitis B surface antigen Positive for anti-hepatitis C virus antibody Positive for human immunodeficiency virus-1 (HIV-1) antibody Positive urine drug screen Positive alcohol test Donation of blood or blood products to a blood bank, blood transfusion, or participation in a clinical study requiring withdrawal of > 500 mL of blood during the 6 weeks prior to Screening Females who are pregnant or breastfeeding Other condition(s) that, in the opinion of the investigator, would compromise the safety of the subject, would prevent compliance with the study protocol, or would compromise the quality of the clinical study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Placebo, Ranolazine, Exenatide<br> | Drug: Ranolazine<br> <br> Drug: Placebo<br> <br> Drug: Exenatide<br> <br> |
| Active Comparator: Ranolazine, Placebo, Exenatide<br> | Drug: Ranolazine<br> <br> Drug: Placebo<br> <br> Drug: Exenatide<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the concentration-time curve (AUC) of plasma glucagon during the standard meal test (SMT) |  | Days 5, 10, and 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma glucose, serum insulin, and serum C-peptide AUCs during the SMT |  | Days 5, 10, and 14 | 
| Collapse under Acetaminophen PK |  | Days 5 and 10 | 
| Area under the plasma acetaminophen concentration-time curve from time 0 to 240 min (AUC0-240 min) |  | Days 5 and 10 | 
| Collapse all under ranolazine pharmacokinetics (PK) |  | Days 5 and 10 | 
| Trough plasma ranolazine concentrations (Ctrough) |  | Days 5 and 10 | 
| Average plasma ranolazine concentration during a dosing interval at steady state (Css,ave) |  | Days 5 and 10 | 
| Area under the plasma ranolazine concentration-time curve over dosing interval (AUCtau) |  | Days 5 and 10 | 
| Apparent elimination half-life (t1/2) of ranolazine |  | Days 5 and 10 | 
| Adverse events, physical examinations, clinical laboratory determinations, electrocardiograms (ECG), and vital sign assessments. |  | From Screening to 7 days after the final dose |