Clinical trial NCT03259087: Pharmacokinetics (PK) and Safety of a Single Intravenous (IV) Dose of MK-3866 in Participants With Impaired Renal Function and in Healthy Controls (MK-3866-005)
Official title: A 2-Part, Open-Label Trial to Evaluate the Pharmacokinetics of MK-3866 Following the Administration of a Single IV Dose to Subjects With Mild, Moderate, and Severe Renal Impairment and End Stage Renal Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Impairment
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2017-08-23
Enrollment: 42
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: The purpose of this study is to compare plasma and urine PK parameters of MK-3866 between participants with impaired renal function and healthy control participants, to investigate the extent to which MK-3866 is removed from the plasma by hemodialysis (HD), and evaluate the safety and tolerability of MK-3866 in participants with impaired renal function.

Detailed description: This is an open-label, 2-part single dose study: Part 1 will include participants with mild, moderate, and severe renal impairment (as well as healthy control participants), and Part 2 will include participants with end stage renal disease (ESRD) undergoing HD. Participants in Part 1 will receive a single IV dose of MK-3866, and plasma and urine samples will be collected over pre-specified time intervals. Participants in Part 2 will receive a single IV dose of MK-3866 on two separate occasions: in Period 1 immediately following their normally-scheduled HD, and in Period 2 approximately 30 minutes prior to their normally-scheduled HD. Plasma, urine, and dialysate samples will be collected over pre-specified time intervals for Part 2.

Eligibility criteria: Inclusion Criteria:

* Females of non-childbearing potential. Male participants with female partner(s) of child-bearing potential agree to use a medically acceptable method of contraception during the study and for 90 days after dosing. If partner is pregnant, males agree to use a condom; if partner is of child-bearing potential, partner must use additional birth control
* Male participants agree not to donate sperm from the first dose until 90 days after dosing
* Adequate venous access

Renal Impaired Participants

* Liver function tests (serum alanine aminotransferase \[ALT\] and aspartate aminotransferase \[AST\]) and serum bilirubin (total and direct) within upper limit of normal
* Panels A, B, and C: no clinically significant change in renal status at least 1 month prior to dosing and not currently or previously been on hemodialysis
* Panel E only: ESRD maintained on stable regimen of at least 3 times per week HD for at least 3 months prior to first dosing

Healthy Participants

* Age within ± 15 years of the mean age of participants with impaired renal function to which the healthy participant is matched
* Medically healthy as per medical history, physical examination, vital signs, 12-lead electrocardiograms (ECGs), and clinical laboratory safety tests
* Blood urea nitrogen, liver function tests (ALT, AST, alkaline phosphatase \[ALP\]), and serum bilirubin (total and direct) within upper limit of normal.

Exclusion Criteria:

* Mentally/legally incapacitated, or significant emotional problems or significant psychiatric disorder
* History of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, respiratory, genitourinary or major neurological abnormalities or diseases
* History of any illness that might confound the results of the study or poses an additional risk to the participant by their participation in the study
* Clinically significant history of cancer
* Smoker and/or has used nicotine or nicotine-containing products within 3 months prior to screening
* Female participants of childbearing potential, pregnant, or lactating
* Positive results for urine or saliva drug screen and/or urine or breath alcohol screen at screening or check-in
* Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV)
* Consumes more than 3 glasses of alcoholic beverages within 6 months of screening
* Consumes excessive amounts of coffee, tea, cola, energy-drinks, or other caffeinated beverages per day
* Major surgery, donated or lost 1 unit of blood within 4 weeks prior to screening, or donated plasma within 7 days prior to dosing in Part 1 or first dose in Part 2

Renal Impaired Participants

* Panels A, B, and C: Failed renal transplant or has had nephrectomy
* Panels A, B, and C: Rapidly fluctuating renal function, as determined by historical measurements; or demonstrated/suspected renal artery stenosis
* Panel E only: Has required frequent emergent HD (≥3) within a year prior to first dosing

Healthy Participants

* Renal transplant or nephrectomy

Primary outcomes:
measure: Part 1: Area Under the Plasma Concentration-time Curve of MK-3866 From Time Zero to Infinity (AUC0-inf)
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing on Day 1, and 60 and 72 hours after dosing for Severe Renal Impairment participants
measure: Part 1: Area Under the Plasma Concentration-time Curve of MK-3866 From Time Zero to the Time of the Last Quantifiable Sample (AUC0-last)
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing on Day 1, and 60 and 72 hours after dosing for Severe Renal Impairment participants
measure: Part 1: Area Under the Plasma Concentration-time Curve of MK-3866 From Time Zero to 24 Hours After Dosing (AUC0-24)
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, and 24 hours after dosing on Day 1
measure: Part 1: Plasma Concentration of MK-3866 at the End of the Infusion (Ceoi)
timeFrame: At the end of the infusion (0.5 hours after infusion start) on Day 1
measure: Part 1: Maximum Plasma Concentration of MK-3866 (Cmax)
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing on Day 1, and 60 and 72 hours after dosing for Severe Renal Impairment participants
measure: Part 1: Plasma Clearance of MK-3866 (CL)
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing on Day 1, and 60 and 72 hours after dosing for Severe Renal Impairment participants
measure: Part 1: Time to Maximum Plasma Concentration of MK-3866 (Tmax)
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing on Day 1, and 60 and 72 hours after dosing for Severe Renal Impairment participants
measure: Part 1: Elimination Terminal Half-life of Plasma MK-3866 (t1/2)
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing on Day 1, and 60 and 72 hours after dosing for Severe Renal Impairment participants
measure: Part 1: Volume of Distribution of Plasma MK-3866 (Vz)
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, and 48 hours after dosing on Day 1, and 60 and 72 hours after dosing for Severe Renal Impairment participants
measure: Part 2: AUC0-inf of Plasma MK-3866
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
measure: Part 2: AUC0-last of Plasma MK-3866
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
measure: Part 2: AUC0-24 of Plasma MK-3866
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, and 24 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
measure: Part 2: Ceoi of Plasma MK-3866
timeFrame: At the end of the infusion (0.5 hours after infusion start) on Day 1 of Period 1 and Period 2
measure: Part 2: Cmax of Plasma MK-3866
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
measure: Part 2: CL of Plasma MK-3866
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
measure: Part 2: Tmax of Plasma MK-3866
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
measure: Part 2: t1/2 of Plasma MK-3866
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
measure: Part 2: Vz of Plasma MK-3866
timeFrame: Predose and 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours after dosing on Day 1 of Period 1 and 2, and 2.5, 3.5, and 4 hours after dosing on Day 1 of Period 2
Secondary outcomes:
measure: Part 1: Total Amount of MK-3866 Excreted in the Urine Over 24 Hours (Ae0-24)
timeFrame: Predose and 0-4, 4-8, 8-12, and 12-24 hours after dosing on Day 1
measure: Part 1: Renal Clearance (CLr) of MK-3866
timeFrame: Predose and 0-4, 4-8, 8-12, and 12-24 hours after dosing on Day 1
measure: Part 1: Fraction of MK-3866 Excretion (Urine) During Each Collection Interval (Fe0-24)
timeFrame: Predose and 0-4, 4-8, 8-12, and 12-24 hours after dosing on Day 1
measure: Part 2: Total Amount of MK-3866 Excreted Unchanged in the Urine Over the Period of 24 Hours (Ae0-24)
timeFrame: Predose and 0-4, 4-8, 8-12, and 12-24 hours after dosing on Day 1 of Period 1 and Period 2
measure: Part 2: Renal Clearance (CLr) of MK-3866
timeFrame: Predose and 0-4, 4-8, 8-12, and 12-24 hours after dosing on Day 1 of Period 1 and Period 2
measure: Part 2: Fraction of MK-3866 Excretion (Urine) During Each Collection Interval (Fe0-24)
timeFrame: Predose and 0-4, 4-8, 8-12, and 12-24 hours after dosing on Day 1 of Period 1 and Period 2
measure: Part 2: Concentration of MK-3866 in Plasma Entering the Dialyzer Line (Ca)
timeFrame: 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
measure: Part 2: Concentration of MK-3866 in Plasma Exiting the Dialyzer Line (Cv)
timeFrame: 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
measure: Part 2: Area Under the Concentration-time Curve of MK-3866 in Plasma Entering the Dialyzer Line During the Dialysis Period (AUCD)
timeFrame: 0.5 (beginning of HD), 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
measure: Part 2: Area Under the Concentration-time Curve of MK-3866 in Plasma Entering the Dialyzer Line From 0.75 to 4.5 Hours During the Dialysis Period (AUC[0.75-4.5]Ca)
timeFrame: 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
measure: Part 2: Area Under the Concentration-time Curve of MK-3866 in Plasma Entering the Dialyzer Line From 0.75 to 4.5 Hours During the Dialysis Period (AUC[0.75-4.5]Cv)
timeFrame: 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
measure: Part 2: Dialysis Clearance of MK-3866 Based on Plasma (CLD,Plasma)
timeFrame: 0.5 (beginning of HD), 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
measure: Part 2: Concentration of MK-3866 in Dialysate Samples (CD)
timeFrame: 0.5 (beginning of HD), 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
measure: Part 2: Amount of MK-3866 Recovered From Each Dialysate Sample (AD)
timeFrame: 0.5 (beginning of HD), 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
measure: Part 2: Rate of Removal of MK-3866 From the Dialysate (rr)
timeFrame: 0.5 (beginning of HD), 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
measure: Part 2: Cumulative Amount of MK-3866 Recovered From the Dialysate (AD,Total)
timeFrame: 0.5 (beginning of HD), 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
measure: Part 2: Hemodialysis Clearance of MK-3866 Based on the Dialysate(CLD,Dialysate)
timeFrame: 0.5 (beginning of HD), 1, 1.5, 2, 2.5, 3, 3.5, 4, and 4.5 hours after dosing on Day 1 of Period 2
measure: Number of Participants With at Least One Adverse Event (AE)
timeFrame: Part 1: up to Day 14 after dosing; Part 2, Period 1: up to Day 14 after dosing (including ≥6 day washout period); Part 2, Period 2: up to Day 14 after dosing
measure: Number of Participants Discontinuing the Study Due to an Adverse Event
timeFrame: Part 1: up to Day 14 after dosing; Part 2, Period 1: up to Day 14 after dosing (including ≥6 day washout period); Part 2, Period 2: up to Day 14 after dosing
Other outcomes:
Locations:
city: Hialeah
country: United States
facility: Clinical Pharmacology of Miami ( Site 0001)
state: Florida
city: Orlando
country: United States
facility: Orlando Clinical Research Center ( Site 0002)
state: Florida
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: