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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Metformin
* Drug: Ranolazine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 30 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

Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin, Ranolazine<br>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<br>* 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<br>* Other names: Glucophase;Drug: Ranolazine<br>* Ranolazine 1000 mg bid on Days 11-15 Ranolazine 1000 mg bid on Days 16-20<br>* Other names: Ranexa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metformin, Ranolazine, Type 2 Diabetes Mellitus