A Phase 1 Study to Assess the Effect of Severe Renal Impairment on the Pharmacokinetics, as Well as Safety/Tolerability, of Ranolazine

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to assess the effect of severe renal impairment on the steady-state PK, as well as safety and tolerability, of ranolazine, compared to subjects with normal renal function.

Detailed Description
-----------------
The primary objective of this study is to assess the effects of severe renal impairment (RI) on the steady-state pharmacokinetics (PK) of ranolazine and key metabolites. The secondary objective of this study is to assess the safety and tolerability of multiple oral doses of ranolazine in subjects with severe RI.

Official Title
-----------------
A Phase 1, Parallel-group, Open-label, Multiple-dose Study to Assess the Pharmacokinetics, Safety, and Tolerability of Ranolazine ER in Subjects With Severe Renal Impairment as Compared to Healthy Subjects With Normal Renal Function

Conditions
-----------------
Severe Renal Impairment

Intervention / Treatment
-----------------
* Drug: RANEXA


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria (All Cohorts): Males and females, 18 to 75 years old, inclusive Body mass index (BMI) 18 to 40 kg/m2, inclusive, at Screening Females of child-bearing potential must have a negative pregnancy test at Screening and on Day -1 (Cohort A) or Day -6 (Cohort B) 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 Inclusion criteria (Cohort A [Healthy subjects with normal renal function] only): Estimated creatinine clearance (CLCR), according to the Cockcroft-Gault (C-G) equation, ≥ 90 mL/min at Screening Age, BMI, and sex comparable to those of subjects of Cohort B Good health status as determined by no clinically significant deviation from normal in medical history, physical examination, ECGs, and clinical laboratory determinations Inclusion criteria (Cohort B, Severe RI): Diagnosis of CKD Estimated glomerular filtration rate (eGFR), according to the Modification of Diet in Renal Disease (MDRD) equation, < 30 mL/min/1.73 m2 (and not receiving dialysis) Stable medication dose and dosing regimen for treatment of the complications of renal disease or other concomitant chronic illnesses for at least 2 weeks prior to study drug administration Exclusion Criteria: Exclusion criteria (All Cohorts): History of uncontrolled or unstable cardiovascular, respiratory, hepatic, gastrointestinal, endocrine, hematopoietic, psychiatric, and/or neurological disease Current or recent (within 3 months) gastrointestinal (GI) disease or any GI surgery that could impact absorption of study drug Any major surgery within 4 weeks of dosing with study drug Donation of blood or plasma to a blood bank or in a clinical study (except a screening visit) within 4 weeks of dosing with study drug Blood transfusion within 4 weeks of dosing with study drug Consumption of > 14 alcoholic drinks per week, or more than 4 alcoholic drinks on any one day History of 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 Positive drug screen Positive alcohol test Clinically significant history of hepatic disease QTcF interval > 480 msec at Screening or Day -6 (for Cohort B) or Day -1 (for Cohort A) History of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmia, or torsade de pointes Known hypersensitivity or previous intolerance to ranolazine or any of its excipients Treatment with selected medications Pregnancy or lactation Other condition(s) that, in the opinion of the Investigator, would prevent compliance with the study protocol Exclusion criteria (Cohort A [Healthy subjects with normal renal function] only): Evidence of organ dysfunction or any clinically significant deviation from normal in physical examination, vital signs, ECG, or clinical laboratory determinations Hemoglobin < 12 g/dL for males, < 11 g/dL for females at Screening Any prescription and over-the-counter medications, including herbal products Exclusion criteria (Cohort B, Severe RI): Any clinical, ECG, and laboratory findings beyond those which are consistent with the degree of renal dysfunction History of or anticipated near-term need for renal transplant (within 3 months) History of hemodialysis or peritoneal dialysis within 1 year prior to Screening, or anticipated need for hemodialysis or peritoneal dialysis during the study History of acute renal failure or nephrotic syndrome within 1 year prior to Screening History of diabetic ketoacidosis History of severe hypoglycemia Other condition(s) that, in the opinion of the Investigator, would prevent compliance with the study protocol

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subjects with severe renal impairment<br>Cohort B (subjects with severe RI): Approximately 10 subjects will be enrolled to obtain approximately 8 evaluable subjects. | Drug: RANEXA<br>* 500mg BID up to 1000mg BID<br>|
| Experimental: Subjects with normal renal function<br>Cohort A (healthy subjects with normal renal function): Approximately 10 subjects will be enrolled to obtain approximately 8 evaluable subjects. | Drug: RANEXA<br>* 500mg BID up to 1000mg BID<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration vs time curve over the dosing interval at steady state (AUCtau) and Maximum observed plasma concentration at steady-state (Cmax) | Maximum observed plasma ranolazine concentration at steady-state (Cmax) [Time frame: 0, 1, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 7 for Cohort A and Days -1 and 7 for Cohort B] Area under the plasma ranolazine concentration versus time curve over the dosing interval at steady state (AUCtau) [Time frame: 0, 1, 2, 3, 4, 6, 8, 10, and 12 hours post-dose on Day 7 for Cohort A and Days -1 and 7 for Cohort B] | Day 7 for Cohorts A & B, and Day -1 for Cohort B only. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with AEs |  | From Day -5 for Cohort B or Day 1 for Cohort A through the 14-day follow-up. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Ranolazine, renal impairment