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

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

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.

Study Overview

• Status: Terminated
• Conditions: Severe Renal Impairment
• Intervention / Treatment: Drug: RANEXA

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.

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33014
      • Clinical Pharmacology of Miami

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

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	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.

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Actual): August 1, 2012
• Study Completion (Actual): August 1, 2012

Study Registration Dates

• First Submitted: July 26, 2012
• First Submitted That Met QC Criteria: August 29, 2012
• First Posted (Estimate): August 30, 2012

Study Record Updates

• Last Update Posted (Estimate): December 6, 2012
• Last Update Submitted That Met QC Criteria: December 4, 2012
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Keywords: renal impairment; Ranolazine
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Sodium Channel Blockers; Ranolazine
• Other Study ID Numbers: GS-US-259-0112