Clinical trial NCT02653014: Safety, Tolerability and Pharmacokinetics of KBP-5074 in Healthy Subjects and Subjects With Renal Impairment
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Renal Insufficiency
Lead sponsor: KBP Biosciences
Sponsor class: INDUSTRY
First posted: 2016-01-12
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Safety and tolerability
timeFrame: Up to 69 days
Secondary outcomes:
measure: Area Under Curve (AUC) in healthy subjects
timeFrame: 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
measure: Area Under Curve (AUC) in subjects with mild to moderate renal impairment
timeFrame: 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
measure: The effect of mild to moderate renal impairment on the Area Under Curve (AUC)
timeFrame: Up to 15 days
measure: Plasma aldosterone levels in healthy subjects
timeFrame: 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
measure: Serum potassium levels in healthy subjects
timeFrame: 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
measure: Plasma aldosterone levels in subjects with mild to moderate renal impairment
timeFrame: 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
measure: Serum potassium levels in subjects with mild to moderate renal impairment
timeFrame: 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
measure: Urinary Albumin to Creatinine Ratio (UACR) in subjects with mild to moderate renal impairment
timeFrame: 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
measure: Blood Pressure in subjects with mild to moderate renal impairment
timeFrame: 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
Other outcomes:
Locations:
city: Evergreen Park
country: United States
facility: Research by Design, LLC
state: Illinois
Study officials:
References: