Safety, Tolerability and Pharmacokinetics of KBP-5074 in Healthy Subjects and Subjects With Renal Impairment

An Open-Label, Multiple Ascending Dose (MAD) Study to Evaluate the Safety, Tolerability and Pharmacokinetics of KBP-5074 in Healthy Subjects With a Separate Panel in Subjects With Mild to Moderate Renal Impairment

This multiple ascending dose (MAD) study in healthy subjects and subjects with mild to moderate renal impairment will evaluate the safety, tolerability and pharmacokinetics of KBP-5074. Safety/tolerability data and Pharmacokinetics (PK)/Pharmacodynamics (PD) (plasma aldosterone, serum potassium, UACR and Blood Pressure) relationships will be explored to support the selection of dosing regimens of KBP-5074 that are suitable for the Phase II/III study.

Study Overview

• Status: Completed
• Conditions: Healthy; Renal Insufficiency
• Intervention / Treatment: Drug: KBP-5074

Detailed Description

This study consists of two parts: Part 1 is an open-label, multiple ascending dose (MAD) study to evaluate the safety, tolerability and pharmacokinetics of KBP-5074 in healthy subjects. The safety and tolerability will be assessed at each dose level before progressing to the next higher dose. Part 2 is an open label, randomized, parallel study to assess the safety and tolerability, the effect of renal dysfunction on the pharmacokinetics of KBP-5074, as well as the PK/PD relationship in subjects with mild to moderate renal impairment.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Evergreen Park, Illinois, United States, 60805
      • Research by Design, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria for Part 1:

• Healthy male or female subject
• Are between the ages of 18 and 45 years (inclusive);
• Body mass index (BMI) of 19 to 30 kg/m2 inclusive and body weight not less than 50 kg.

Exclusion Criteria for Part 1:

• Clinically significant history of gastrointestinal, cardiovascular, musculoskeletal, endocrine, hematologic, psychiatric, renal, hepatic, bronchopulmonary, neurologic, immunologic, lipid metabolism disorders, or drug hypersensitivity;
• Known or suspected malignancy;
• Positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C (HCV) antibody;
• Positive pregnancy test result.

Inclusion Criteria for Part 2:

• Are between the ages of 18 and 75 years (inclusive);
• Mild to moderate chronic kidney disease (defined as estimated glomerular filtration rate (eGFR) > 30 and ≤89 mL/min/1.73 m2, using the modification of diet in renal disease (MDRD) formula, for > 3 months;
• Proteinuria (defined as urine albumin to creatinine ratio (UACR) ≥100 mg/g and ≤3,000 mg/g in two mid-morning urine specimens within a month interval);
• Subjects treated with an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)
• Serum potassium≥3.3 mmol/L and ≤4.8 mmol/L;
• Body mass index (BMI) of 19 to 40 kg/m2 inclusive and body weight not less than 50 kg.

Exclusion Criteria for Part 2:

• Severe uncontrolled hypertension (diastolic > 115 mmHg or systolic blood pressure > 180 mmHg) at either the Screening visit or the Study Check-in Visit;
• Type I diabetes mellitus or poorly controlled Type 2 diabetes mellitus (HbA1c > 10%) at the Screening visit;
• Prior kidney transplant, or anticipated need for transplant during study participation;
• Clinical diagnosis of heart failure and persistent symptoms (New York Heart Association [NYHA] Class II- IV) at either the Screening visit or the Study Check-in Visit;
• Known or suspected contraindications to study medications, including history of hypersensitivity or allergy to ACE inhibitors, ARBs, or aldosterone antagonists;
• Any clinically significant disorder, except for conditions associated with type 2 diabetes mellitus history, which in the investigators opinion could interfere with the results of the trial;
• Diabetic gastroparesis;
• Known bilateral clinically relevant renal artery stenosis (>75% reduction in artery diameter).

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

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Healthy Volunteers will receive 2.5mg of KBP-5074, QD, 14 days	Drug: KBP-5074; Other Names: mineralocorticoid receptor antagonist
Experimental: Cohort 2; Healthy Volunteers will receive 5.0mg of KBP-5074, QD, 14 days	Drug: KBP-5074; Other Names: mineralocorticoid receptor antagonist
Experimental: Cohort 3; Subjects with mild to moderate renal impairment will receive 0.5mg of KBP-5074, QD, 56 days	Drug: KBP-5074; Other Names: mineralocorticoid receptor antagonist
Experimental: Cohort 4; Subjects with mild to moderate renal impairment will receive 2.5mg of KBP-5074, QD, 56 days	Drug: KBP-5074; Other Names: mineralocorticoid receptor antagonist

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability	Rate of adverse events	Up to 69 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under Curve (AUC) in healthy subjects	AUC 0-24 hours	pre-dose and 2, 4, 6, 8, 10, 12, 18, and 24 hours post dose on Day 1; pre-dose on Days 8, 11, 12, and 13; and pre-dose and 2, 4, 6, 8, 10, 12, 18, 24, 48, 72, 96, 120, 168, 216, 264, and 312 hours post dose on Day 14
Area Under Curve (AUC) in subjects with mild to moderate renal impairment	AUC 0-24 hours	pre-dose and 2, 4, 6, 8, 10, 12, 18, and 24 hours post dose on Day 1; pre-dose on Days 8, 11, 12, and 13; pre-dose and 2, 4, 6, 8, 10, 12, 18, and 24 hours post dose on Day 14; pre-dose on Days 29 and 43; and pre-dose and 6, 12, and 24 hours on Day 56
The effect of mild to moderate renal impairment on the Area Under Curve (AUC)	AUC 0-24 hours	Up to 15 days
Plasma aldosterone levels in healthy subjects	Plasma aldosterone level	Pre-dose, 6, and 24 hours post dose on Day 1; pre-dose on Day 8; and 24 hours post last dose on Day 15
Serum potassium levels in healthy subjects	Serum potassium level	Pre-dose, 6, and 24 hours post dose on Day 1; pre-dose on Day 8; and 24 hours post last dose on Day 15
Plasma aldosterone levels in subjects with mild to moderate renal impairment	Plasma aldosterone level	Pre-dose, 6, and 24 hours post dose on Day 1; pre-dose on Days 8, 15, 29, and 43; and 24 hours post last dose on Day 57
Serum potassium levels in subjects with mild to moderate renal impairment	Serum potassium level	Pre-dose, 6, and 24 hours post dose on Day 1; pre-dose on Days 8, 15, 29, and 43; and 24 hours post last dose on Day 57
Urinary Albumin to Creatinine Ratio (UACR) in subjects with mild to moderate renal impairment	Ratio of urinary albumin level to creatinine level	Pre-dose, 6, and 24 hours post dose on Day 1; pre-dose on Days 8, 15, 29, and 43; and 24 hours post last dose on Day 57
Blood Pressure in subjects with mild to moderate renal impairment	Systolic and diastolic seated blood pressure	Pre-dose, 6, and 24 hours post dose on Day 1; pre-dose on Days 8, 15, 29, and 43; and 24 hours post last dose on Day 57

Collaborators and Investigators

• Sponsor: KBP Biosciences
• Investigators: Study Chair: Fred Yang, PhD, KBP Biosciences USA Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 29, 2015
• Primary Completion (Actual): May 26, 2016
• Study Completion (Actual): March 28, 2017

Study Registration Dates

• First Submitted: December 29, 2015
• First Submitted That Met QC Criteria: January 8, 2016
• First Posted (Estimated): January 12, 2016

Study Record Updates

• Last Update Posted (Estimated): April 15, 2024
• Last Update Submitted That Met QC Criteria: April 12, 2024
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Renal Insufficiency; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Natriuretic Agents; Diuretics; Hormone Antagonists; Diuretics, Potassium Sparing; Mineralocorticoid Receptor Antagonists; Mineralocorticoids
• Other Study ID Numbers: KBP5074-1-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No