Single Cohort 4-period Study to Assess Pharmacokinetics of Metformin Alone and in Combination With Ranolazine

A Phase 1, Open-Label, Single Cohort, Four-period Sequential Study to Assess the Pharmacokinetics of Metformin Alone and in Combination With Ranolazine in Subjects With Type 2 Diabetes Mellitus

The purpose of this study is to evaluate the effect of steady-state ranolazine on the steady state PK of metformin in subjects with type 2 diabetes mellitus (T2DM).

Study Overview

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

Detailed Description

The primary objective of this study is as follows:

• To evaluate the effect of steady-state ranolazine on the steady state PK of metformin in subjects with T2DM.

The secondary objectives of this study are as follows:

• To examine the safety and tolerability of metformin when co administered with ranolazine at steady-state in subjects with T2DM.
• To determine the steady-state PK of ranolazine in subjects with T2DM receiving metformin.

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

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • Cetero Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Males and females, 30 to 65 years old, inclusive
• Documented history of T2DM
• HbA1c = 6.5%-10%, inclusive
• Fasting serum glucose ≤ 270 mg/dL at Screening
• Fasting C-peptide ≥ 1 ng/mL at Screening
• Stable metformin monotherapy (metformin 1000 to 2000 mg total daily dose for at least 4 weeks prior to Screening)
• Body mass index (BMI) = 25 to 40 kg/m2, inclusive, at Screening
• Creatinine Clearance > 80 mL/min at Screening
• Females of child-bearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day -1 and must agree to use highly effective contraception methods from Screening throughout the duration of the Treatment Period and for 14 days following the last dose of study drug

Exclusion Criteria:

• Type 1 Diabetes Mellitus (T1DM)
• Use of insulin therapy < 3 months prior to Screening
• History of ketoacidosis, ketosis-prone diabetes, or lactic acidosis
• Clinically significant complications of diabetes
• History of hypoglycemia
• Any non-insulin antidiabetic therapy (other than metformin) < 2 months prior to Screening
• Any clinically significant cardiovascular event < 2 months prior to Screening
• Clinically significant, inadequately controlled, or unstable hypertension
• Hospitalization < 2 months prior to Screening or major surgery < 3 months prior to Screening
• History of gastrointestinal disease or surgery that could impact drug absorption
• History of substance of alcohol or substance abuse
• Positive urine drug screen for drugs of abuse
• Positive alcohol breath test
• Any other clinically significant existing medical or psychiatric condition or one requiring further evaluation
• Treatment with selected medications
• Hemoglobin < 12 g/dL for males; or < 11 g/dL for females at Screening
• Active thyroid disease (hypo- or hyperthyroidism)
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5x upper limits of normal
• QTc interval > 500 msec at Screening
• Females who are pregnant or are breastfeeding

Study Plan

How is the study designed?

Design Details

• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metformin, Ranolazine; Single cohort, 4-period study: Period 1, metformin 500 mg bid on Days 1-5; Period 2, metformin 850 mg bid on Days 6-10; Period 3, metformin 500 mg bid + ranolazine 1000 mg bid on Days 11-15; Period 4, metformin 850 mg bid + ranolazine 1000 mg bid on Days 16-20	Drug: Metformin; Metformin 500 mg bid on Days 1-5; Metformin 850 mg bid on Days 6-10; Metformin 500 mg bid on Days 11-15; Metformin 850 mg bid on Days 16-20; Other Names: Glucophase; Drug: Ranolazine; Ranolazine 1000 mg bid on Days 11-15; Ranolazine 1000 mg bid on Days 16-20; Other Names: Ranexa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum observed plasma concentration (Cmax) of metformin	0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Days 5, 10, 15 and 20
Time to reach maximum observed plasma concentration (Cmax) of metformin	0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Days 5, 10, 15 and 20
Area under the plasma concentration versus time curve over the dosing interval, at steady state (AUCtau) of metformin	0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Days 5, 10, 15 and 20

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of participants with adverse events	participants will be followed upon signing informed consent until the follow-up phone call, an expected average of 7 weeks
Maximum observed plasma concentration (Cmax) of ranolazine and metabolites	0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Days 15 and 20
Time to reach maximum observed plasma concentration (Cmax) of ranolazine and metabolites	0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Days 15 and 20
Area under the plasma concentration versus time curve over the dosing interval, at steady state (AUCtau) of ranolazine and metabolites	0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hours post-dose on Days 15 and 20

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: February 14, 2012
• First Submitted That Met QC Criteria: March 2, 2012
• First Posted (Estimate): March 7, 2012

Study Record Updates

• Last Update Posted (Estimate): July 11, 2012
• Last Update Submitted That Met QC Criteria: July 9, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: Metformin; Type 2 Diabetes Mellitus; Ranolazine
• 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; Membrane Transport Modulators; Sodium Channel Blockers; Metformin; Ranolazine
• Other Study ID Numbers: GS-US-259-0137