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An Open-Label Study Investigating MK-8931 in Participants With Mild and Moderate Hepatic Insufficiency (MK-8931-016)

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified September 2016 by Merck Sharp & Dohme Corp.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT02910739
First received: September 20, 2016
Last updated: NA
Last verified: September 2016
History: No changes posted
  Purpose
This study consists of Part I and Part II. The purpose of Part I is to compare the plasma pharmacokinetics of verubecestat (MK-8931) following administration of a single oral dose of 40 mg MK-8931 to participants with moderate hepatic insufficiency (HI) to that of healthy matched controls. A safety and pharmacokinetic analysis will be performed in order to support the decision to continue with part II. If a decision to continue with part II is made, participants with mild HI will be enrolled to receive a single oral dose of MK-8931 40mg. If any healthy participants from Part I do not meet the matching criteria for Part II additional healthy participants will be enrolled.

Condition Intervention Phase
Amnestic Mild Cognitive Impairment
Alzheimer's Disease
Prodromal Alzheimer's Disease
Drug: MK-8931
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Two-Part, Open-Label Study to Investigate the Single-Dose Pharmacokinetics of MK-8931 When Administered to Subjects With Mild and Moderate Hepatic Insufficiency

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Area under the concentration versus time curve of MK-8931 from 0 to infinity (AUC0-∞) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after dosing ] [ Designated as safety issue: No ]
  • Maximum observed plasma concentration of MK-8931 (Cmax) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after dosing ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Area under the concentration versus time curve of MK-8931 from 0 to the time of the last quantifiable (above LLOQ) sample (AUCO-last) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after dosing ] [ Designated as safety issue: No ]
  • Area under the concentration versus time curve of MK-8931 from 0 to 24 hours (AUC0-24) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours after dosing ] [ Designated as safety issue: No ]
  • Plasma concentration of MK-8931 at 24 hours(C24hr) [ Time Frame: 24 hours after dosing ] [ Designated as safety issue: No ]
  • Apparent clearance of MK-8931 after extravascular administration (CL/F) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after dosing ] [ Designated as safety issue: No ]
  • Time to maximum observed MK-8931 plasma drug concentration (Tmax) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after dosing ] [ Designated as safety issue: No ]
  • Apparent terminal half-life of MK-8931 (t1/2) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after dosing ] [ Designated as safety issue: No ]
  • Apparent volume of distribution of MK-8931 during the terminal phase after extravascular administration (Vz/F) [ Time Frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after dosing ] [ Designated as safety issue: No ]

Estimated Enrollment: 32
Study Start Date: October 2016
Estimated Study Completion Date: May 2017
Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part I: MK-8931 40 mg in Moderate HI Participants
Single oral dose of MK-8931 40 mg tablet in participants with moderate HI in fasted state (Part I)
Drug: MK-8931
MK-8931 40 mg
Other Name: Verubecestat
Active Comparator: Part I: MK-8931 40 mg in Healthy Participants
Single oral dose of MK-8931 40 mg tablet in healthy matched participants in fasted state (Part I)
Drug: MK-8931
MK-8931 40 mg
Other Name: Verubecestat
Experimental: Part II: MK-8931 40 mg in Mild HI Participants
Single oral dose of MK-8931 40 mg tablet in participants with mild HI in fasted state (Part II)
Drug: MK-8931
MK-8931 40 mg
Other Name: Verubecestat
Active Comparator: Part II: MK-8931 40 mg in Healthy Participants
Single oral dose of MK-8931 40 mg tablet in healthy matched participants in fasted state (Part II)
Drug: MK-8931
MK-8931 40 mg
Other Name: Verubecestat

  Eligibility

Ages Eligible for Study:   55 Years to 85 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Hepatic Insufficiency Participants Inclusion Criteria

  1. Adult male or female participants, 55-85 years of age, inclusive, at screening.
  2. Body Mass Index (BMI) ≥ 19 and ≤ 40 kg/m2, at screening.
  3. Continuous non-smokers or light smokers (< 10 cigarettes/day or the equivalent).
  4. Baseline health is judged to be stable based on medical history (except for the hepatic insufficiency condition).
  5. Participant has a 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 due to any etiology.
  6. Part 1 only: Participant's score on the Child-Pugh scale must range from 7 to 9 (moderate HI) at screening.
  7. Part 2 only: Participant's score on the Child-Pugh scale must range from 5 to 6 (mild HI) at screening.
  8. Participants must be completely informed of the unknown risks of pregnancy and agree not to become pregnant or father a child during the time they are participating in this study.
  9. For a female of childbearing potential: either be sexually inactive (abstinent) for 14 days prior to dosing and throughout the study or be using an acceptable birth control method.
  10. Females of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first dose:

    • hysteroscopic sterilization;
    • bilateral tubal ligation or bilateral salpingectomy;
    • hysterectomy;
    • bilateral oophorectomy; or be postmenopausal with amenorrhea for at least 1 year prior to dosing and have follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status as per Investigator or designee's judgment.
  11. Non-vasectomized male participants must agree to use a condom with spermicide or abstain from sexual intercourse from dosing until 90 days after dosing.
  12. Male participants must agree not to donate sperm from dosing until 90 days after dosing.
  13. Understands the study procedures in informed consent forms (ICFs), be willing and able to comply with the protocol, and provides written informed consent for the trial, including for Future Biomedical Research. Future Biomedical Research participation is voluntary and is not required in order to participate in the trial.

Healthy Control Participants Inclusion Criteria

  1. Healthy adult male or female participants, 55-85 years of age, inclusive, at screening.
  2. BMI ≥ 19 and ≤ 40 kg/m2 at screening.
  3. Continuous non-smokers or light smokers (< 10 cigarettes/day or the equivalent).
  4. Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs, or ECGs, as deemed by the Investigator.
  5. Participants must be completely informed of the unknown risks of pregnancy and agree not to become pregnant or father a child during the time they are participating in this study.
  6. For a female of childbearing potential: either be sexually inactive (abstinent) for 14 days prior to dosing and throughout the study or be using an acceptable birth control method.
  7. Females of non-childbearing potential must have undergone one of the following sterilization procedures at least 6 months prior to the first dose:

    • hysteroscopic sterilization;
    • bilateral tubal ligation or bilateral salpingectomy;
    • hysterectomy;
    • bilateral oophorectomy; or be postmenopausal with amenorrhea for at least 1 year prior to dosing and have FSH serum levels consistent with postmenopausal status as per Investigator or designee's judgment.
  8. Non-vasectomized male participants must agree to use a condom with spermicide or abstain from sexual intercourse from dosing until 90 days after dosing.
  9. Male participants must agree not to donate sperm from dosing until 90 days after dosing.
  10. Understands the study procedures in ICFs, be willing and able to comply with the protocol, and provides written informed consent for the trial, including for Future Biomedical Research. Future Biomedical Research participation is voluntary and is not required in order to participate in the trial.

Hepatic Insufficiency Participants Exclusion Criteria

  1. Participant is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study.
  2. History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the Investigator.
  3. History of any illness that, in the opinion of the Investigator, might confound the results of the study or poses an additional risk to the participant by their participation in the study.
  4. History or presence of alcoholism or drug abuse within the past 2 years prior to dosing.
  5. History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related compounds.
  6. Female participants who are pregnant or lactating.
  7. Positive results for the urine drug and/or alcohol screen at screening or check-in, unless the positive drug screen is due to prescription drug use and is approved by the Investigator and the Sponsor Medical Monitor.
  8. Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV).
  9. Seated blood pressure is less than 90/40 mmHg or greater than 180/105 mmHg at screening.
  10. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
  11. QTcF interval is > 460 msec (males) or > 480 msec (females) or has ECG findings deemed abnormal with clinical significance by the Investigator or designee at screening.
  12. Abnormal hemoglobin level deemed clinically significant by the Investigator at screening.
  13. Unable to refrain from or anticipates the use of any medication or substance (including prescription or over-the-counter, vitamin supplements, natural or herbal supplements).
  14. Has been on a diet incompatible with the Clinical Research Unit (CRU) -provided standard meals/snacks, in the opinion of the Investigator, within the 28 days prior to dosing of study drug, and throughout the study.
  15. Donation of blood or had significant blood loss within 56 days prior to dosing of study drug.
  16. Plasma donation within 28 days prior to dosing of study drug.
  17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this study.
  18. Participation in another clinical trial within 28 days prior to dosing.
  19. Participant who dosed in one part (e.g., Part 1) will not be enrolled in the other part (e.g., Part 2).

Healthy Control Participants Exclusion Criteria

  1. Participant is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study.
  2. History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the Investigator.
  3. History of any illness that, in the opinion of the Investigator, might confound the results of the study or poses an additional risk to the participant by their participation in the study.
  4. History or presence of alcoholism or drug abuse within the past 2 years prior to dosing.
  5. History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related compounds.
  6. Female participants who are pregnant or lactating.
  7. Positive results for the urine drug and/or urine or breath alcohol screen at screening or check-in.
  8. Positive results at screening for HIV, HBsAg, or HCV (i.e., HCV antibody positive, HCV RNA positive).
  9. Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg at screening.
  10. Seated heart rate is lower than 40 bpm or higher than 99 bpm at screening.
  11. QTcF interval is > 460 msec (males) or > 480 msec (females) or has ECG findings deemed abnormal with clinical significance by the Investigator or designee at screening.
  12. Abnormal hemoglobin level deemed clinically significant by the Investigator at screening.
  13. Unable to refrain from or anticipates the use of any medication or substance (including prescription or over-the-counter, vitamin supplements, natural or herbal supplements).
  14. Has been on a diet incompatible with the CRU-provided standard meals/snacks, in the opinion of the Investigator, within the 28 days prior to dosing of study drug, and throughout the study.
  15. Donation of blood or had significant blood loss within 56 days prior to dosing of study drug.
  16. Plasma donation within 28 days prior to dosing of study drug.
  17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this study.
  18. Participation in another clinical trial within 28 days prior to dosing.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02910739

Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT02910739     History of Changes
Other Study ID Numbers: P08593  Celerion Project No. 
Study First Received: September 20, 2016
Last Updated: September 20, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Alzheimer Disease
Cognition Disorders
Mild Cognitive Impairment
Hepatic Insufficiency
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Liver Diseases
Digestive System Diseases

ClinicalTrials.gov processed this record on September 26, 2016