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Single-Dose Pharmacokinetics of MK-3866 in Participants With Hepatic Impairment (MK-3866-006)

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ClinicalTrials.gov Identifier: NCT03295266
Recruitment Status : Terminated (Business and program changes)
First Posted : September 27, 2017
Results First Posted : November 13, 2019
Last Update Posted : November 13, 2019
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:
This is an open-label, single-dose, Phase 1 study to evaluate the pharmacokinetics (PK) of intravenous (IV) MK-3866 in participants with moderate and severe hepatic impairment (HI) compared to that of matched healthy participants. The primary purpose of this study is to understand the effect of HI on the plasma PK of MK-3866 in order to guide dosing recommendations for participants with HI. This study will also evaluate the safety and tolerability of MK-3866 in participants with moderate and severe HI.

Condition or disease Intervention/treatment Phase
Hepatic Insufficiency Antibacterial Agents Drug: MK-3866 Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label Study to Investigate the Single-Dose Pharmacokinetics of MK-3866 When Administered to Subjects With Moderate and Severe Hepatic Impairment
Actual Study Start Date : December 19, 2017
Actual Primary Completion Date : March 15, 2018
Actual Study Completion Date : March 15, 2018

Arm Intervention/treatment
Experimental: Moderate Hepatic Impairment (Panel A)
Participants with moderate HI (estimated glomerular filtration rate [eGFR] of ≤60mL/min/1.73m^2) receive a single IV dose of MK-3866 (150 mg) on Day 1.
Drug: MK-3866
Single IV infusion of MK-3866 150 mg administered over 30 minutes at Hour 0 on Day 1 of treatment period.

Experimental: Severe Hepatic Impairment (Panel B)
Participants with severe HI (eGFR of ≤50 mL/min/1.73m^2) receive a single IV dose of MK-3866 (150 mg) on Day 1.
Drug: MK-3866
Single IV infusion of MK-3866 150 mg administered over 30 minutes at Hour 0 on Day 1 of treatment period.

Experimental: Healthy Matched Controls (Panel C)
Healthy participants receive a single IV dose of MK-3866 (150 mg) on Day 1.
Drug: MK-3866
Single IV infusion of MK-3866 150 mg administered over 30 minutes at Hour 0 on Day 1 of treatment period.




Primary Outcome Measures :
  1. Area Under the Concentration-time Curve of MK-3866 From Time 0 to Infinity (AUC0-∞) [ Time Frame: Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 48, and 72 hours postdose ]
    AUC0-∞ is determined for the period up to 72 hours post-single dose. AUC0-∞ is an estimate of total plasma exposure from dosing to (extrapolated) infinity.

  2. Area Under the Concentration-time Curve of MK-3866 From Time 0 to Last Quantifiable Concentration (AUC0-last) [ Time Frame: Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 48, and 72 hours postdose ]
    AUC0-last is determined for the period up to 72 hours post-single dose. AUC0-last is an estimate of total plasma exposure from dosing to the time of last measurable sample.

  3. Area Under the Concentration-time Curve of MK-3866 From Time 0 to 24 Hours (AUC0-24hr) [ Time Frame: Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, and 24 hours postdose ]
    AUC0-24 is determined for the period up to 24 hours post-single dose. AUC0-24 is an estimate of total daily plasma exposure from dosing to 24 hours postdose.

  4. Concentration at the End of Infusion (Ceoi) of MK-3866 [ Time Frame: 0.5 (end of infusion) hours postdose ]
    The plasma sample collected at end-of-infusion (0.5 hours postdose) was used to determine Ceoi.

  5. Time to Maximum Concentration (Tmax) of MK-3866 [ Time Frame: Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 48, and 72 hours postdose ]
    Tmax is the time at which the maximum plasma drug concentration is detected.

  6. Apparent Terminal Half-life (t1/2) of MK-3866 [ Time Frame: Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 48, and 72 hours postdose ]
    Apparent t1/2 is the elimination half-life of MK-3866 from plasma.

  7. Clearance (CL) of MK-3866 [ Time Frame: Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 48, and 72 hours postdose ]
    CL is the volume of plasma from which the study drug is completely removed per unit time.

  8. Volume of Distribution (Vz) of MK-3866 [ Time Frame: Predose, 0.5 (end of infusion), 0.75, 1, 1.5, 2, 3, 4.5, 6, 8, 10, 12, 24, 48, and 72 hours postdose ]
    Vz is the apparent volume of distribution during the terminal phase.


Secondary Outcome Measures :
  1. Fraction of Dose of MK-3866 Excreted Unchanged in Urine (Fe) [ Time Frame: Predose, then pooled in the following increments: 0-4, 4-8, 8-12, 12-24 hours postdose ]
    Fe is the amount of drug excreted unchanged in urine. Urine samples were collected in 4-hour intervals up to 24 hours post-dose. The study terminated prior to analysis of urine samples and therefore no data are available.

  2. Renal Clearance (CLr) of MK-3866 [ Time Frame: Predose, then pooled in the following increments: 0-4, 4-8, 8-12, 12-24 hours postdose ]
    CLr is the volume of plasma from which the study drug is completely removed per unit time by the kidney (i.e., excreted into the urine). Urine samples are collected in 4-hour intervals up to 24 hours post-dose. The study terminated prior to analysis of urine samples and therefore no data are available.

  3. Number of Participants With at Least One Adverse Event (AE) [ Time Frame: Up to 14 days ]
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

  4. Number of Participants Who Discontinued the Study Due to an AE [ Time Frame: Up to 14 days ]
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Body mass index ≥19 & ≤40 kg/m^2
  • Continuous non-smoker prior to screening & enrollment
  • HI Participants: Baseline health judged to be stable based on medical history (except for the HI condition), physical examination, vital signs, electrocardiograms, & laboratory safety tests
  • Healthy control participants: Is medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs, or electrocardiograms
  • HI Participants: Diagnosis of chronic (>6 months), stable (no acute episodes of illness within the previous 2 months due to deterioration in hepatic function) HI with features of cirrhosis
  • HI Participants - Panel A (moderate HI) only: score on the Child-Pugh scale from 7 to 9 (moderate HI). At least 3 participants must have a score of 2 or higher on at least one of the laboratory parameters (i.e., albumin, international normalized ratio, and/or bilirubin) on the Child-Pugh scale
  • HI Participants - Panel B (severe HI) only: Score on the Child-Pugh scale from 10 to 15 (severe HI)
  • Is completely informed of the unknown risks of pregnancy & agrees not to become pregnant or father a child during time in study
  • For a female of childbearing potential: is either sexually inactive (abstinent) for 14 days prior to dosing & throughout the study or is using an acceptable birth control method
  • Non-vasectomized male: Participants must agree to use a condom with spermicide or abstain from sexual intercourse from dosing until 90 days after dosing

Exclusion Criteria:

  • Mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study
  • Has a history or presence of clinically significant medical or psychiatric condition or disease (other than HI - Panels A & B) that might confound the results of the study or poses an additional risk to the participant. Remote history of cholecystectomy that is not an active issue may be included.
  • Panels A & B: Has a clinically significant history of cancer. Remote history with full cure or limited disease with complete resection (cure) may be included
  • Has a history of drug/alcohol abuse within the past 6 months prior to dosing (Panels A & B) or within the past 2 years prior to dosing (Panel C [Healthy controls])
  • Panels A & B: Consumes more than 3 glasses of alcoholic beverages (1 glass approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day, within 6 months of screening. Participants that consume 4 glasses of alcoholic beverages/day may be enrolled
  • Panels A & B: Consumes excessive amounts, defined as more than 6 servings (1 serving approximately equivalent to 120 mg of caffeine), of coffee, tea, cola, energy-drinks, or other caffeinated beverages/day
  • Panels A & B: Has a history of a liver transplant
  • Has a history or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds
  • Has moderate or severe renal insufficiency (estimated glomerular filtration rate of ≤60 mL/min/1.73 m2 for moderate HI or healthy control participants or ≤50 mL/min/1.73 m2 for severe HI participants)
  • Panel C: Has positive macroscopic urine protein at screening (trace protein by dipstick allowed)
  • Is a female participant who is pregnant or lactating
  • Has positive results for the urine or breath alcohol screen and/or urine drug screen at screening
  • Has positive results at screening for human immunodeficiency virus (HIV) (Panels A & B) or for HIV, HBsAg, or hepatitis C virus (HCV) (Panel C)
  • Panels A & B: Participants with active HCV infection or hepatitis B virus (HBV) infection. Participants with prior/inactive HCV infection or past HBV infection may be enrolled.
  • Is unable to refrain from or anticipates use of any medication or substance prohibited in study
  • Has taken amiodarone at any time in their life

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03295266


Locations
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United States, Florida
Clinical Pharmacology of Miami ( Site 0001)
Hialeah, Florida, United States, 33014
Orlando Clinical Research Center ( Site 0002)
Orlando, Florida, United States, 32809
Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.
  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme Corp.:
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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT03295266    
Other Study ID Numbers: 3866-006
MK-3866-006 ( Other Identifier: Merck Protocol Number )
First Posted: September 27, 2017    Key Record Dates
Results First Posted: November 13, 2019
Last Update Posted: November 13, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hepatic Insufficiency
Liver Failure
Liver Diseases
Digestive System Diseases