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

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

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

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Placebo; Drug: Ranolazine; Drug: Exenatide

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Chula Vista, California, United States, 91911
      • Profil Institute for Clinical Research, Inc.
  • Florida
    • Miami, Florida, United States, 33126
      • SeaView Research, Inc
    • Orlando, Florida, United States, 32804
      • Translational Research Institute-Florida Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Placebo, Ranolazine, Exenatide	Drug: Placebo; Drug: Ranolazine; Drug: Exenatide
Active Comparator: Ranolazine, Placebo, Exenatide	Drug: Placebo; Drug: Ranolazine; Drug: Exenatide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: April 17, 2013
• First Submitted That Met QC Criteria: April 29, 2013
• First Posted (Estimate): April 30, 2013

Study Record Updates

• Last Update Posted (Estimate): March 31, 2014
• Last Update Submitted That Met QC Criteria: March 28, 2014
• Last Verified: March 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Membrane Transport Modulators; Sodium Channel Blockers; Anti-Obesity Agents; Incretins; Exenatide; Ranolazine
• Other Study ID Numbers: GS-US-259-0165