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Study of Safety and Pharmacokinetics of MK-8242 in Participants With Advanced Solid Tumors (P07650)

Sponsor
Merck Sharp & Dohme LLC (Industry)
Overall Status
Terminated
CT.gov ID
NCT01463696
Collaborator
(none)
48
Enrollment
8
Arms
45.8
Actual Duration (Months)

Study Details

Study Description

Brief Summary

This study is being done to evaluate the safety and pharmacokinetic profile of MK-8242 and its active metabolite (M16) in participants with advanced solid tumors. In Part 1 of the study, the study drug dose will be escalated to determine the maximum tolerated dose (MTD). In Part 2 of the study, the MTD will be confirmed and the recommended Phase 2 dose (RPTD) established; the effect of MK-8242 on liposarcoma and other tumor types will also be evaluated.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

Participants are considered to have completed the study after Cycle 12. Amendment 4 (14 April 2015) was done to allow participants on active treatment at the time the study was closed to enrollment to continue study treatment beyond Cycle 12 if deriving clinical benefit, at the Investigator's discretion.

Study Design

Study Type:
Interventional
Actual Enrollment :
48 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I Study to Evaluate the Safety and Tolerability and Pharmacokinetic/Pharmacodynamics of MK-8242 in Patients With Advanced Solid Tumors
Actual Study Start Date :
Dec 21, 2011
Actual Primary Completion Date :
Sep 15, 2014
Actual Study Completion Date :
Oct 15, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: MK-8242 60 mg BID

In Cycle 1, participants received MK-8242 60 mg administered orally (PO) twice a day (BID) on Days 1-6 and PO once daily (QD) in the morning on Day 7 of the 21-day cycle to accommodate pharmacokinetic (PK) sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 60 mg PO BID on Days 1-7 of each 21-day cycle.

Drug: MK-8242
10 mg, 100 mg and 150 mg capsules
Other Names:
  • SCH 900242

    		•
    Experimental: MK-8242 120 mg BID

    In Cycle 1, participants received MK-8242 120 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 120 mg PO BID on Days 1-7 of each 21-day cycle.

    Drug: MK-8242
    10 mg, 100 mg and 150 mg capsules
    Other Names:
  • SCH 900242

    		•
    Experimental: MK-8242 170 mg BID

    In Cycle 1, participants received MK-8242 170 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 170 mg PO BID on Days 1-7 of each 21-day cycle.

    Drug: MK-8242
    10 mg, 100 mg and 150 mg capsules
    Other Names:
  • SCH 900242

    		•
    Experimental: MK-8242 250 mg BID

    In Cycle 1, participants received MK-8242 250 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 250 mg PO BID on Days 1-7 of each 21-day cycle.

    Drug: MK-8242
    10 mg, 100 mg and 150 mg capsules
    Other Names:
  • SCH 900242

    		•
    Experimental: MK-8242 300 mg BID

    In Cycle 1, participants received MK-8242 300 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 300 mg PO BID on Days 1-7 of each 21-day cycle.

    Drug: MK-8242
    10 mg, 100 mg and 150 mg capsules
    Other Names:
  • SCH 900242

    		•
    Experimental: MK-8242 350 mg BID

    In Cycle 1, participants received MK-8242 350 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 350 mg PO BID on Days 1-7 of each 21-day cycle.

    Drug: MK-8242
    10 mg, 100 mg and 150 mg capsules
    Other Names:
  • SCH 900242

    		•
    Experimental: MK-8242 400 mg BID

    In Cycle 1, participants received MK-8242 400 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 400 mg PO BID on Days 1-7 of each 21-day cycle.

    Drug: MK-8242
    10 mg, 100 mg and 150 mg capsules
    Other Names:
  • SCH 900242

    		•
    Experimental: MK-8242 500 mg BID

    In Cycle 1, participants received MK-8242 500 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 500 mg PO BID on Days 1-7 of each 21-day cycle.

    Drug: MK-8242
    10 mg, 100 mg and 150 mg capsules
    Other Names:
  • SCH 900242

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Dose Limiting Toxicities (DLTs) [Cycle 1 (21 days)]

      DLT was defined as: any drug-related hematologic toxicity ≥ Grade 3 lasting ≥1 week, ≥ Grade 3 thrombocytopenia with bleeding, ≥ Grade 3 neutropenia with infection OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions/clarifications: 1) Grade 3 nausea, vomiting, diarrhea, and dehydration were excluded from the determination of DLT if, in the opinion of the investigator and sponsor, they occurred in a setting of inadequate treatment, 2) Grade 3 nausea, vomiting, diarrhea, and dehydration were each considered a DLT if they persisted despite 72 hours of maximal supportive care measures or 3) Any abnormal non-hematological laboratory value ≥ Grade 3 (that is not attributable to any other causes) was considered a DLT only if medical intervention was required to treat the participant, the abnormality led to hospitalization, or the abnormality persisted for ≥1 week.

    Secondary Outcome Measures

    1. Maximum Observed Plasma Concentration (Cmax) of MK-8242 [Cycle 1, Day 1 pre-dose and through 24 hours post dose; Cycle 1 Day 7 pre-dose and through 48 hours post dose]

      PK plasma samples were to be collected at the following time points: 0, 0.5, 1, 2, 4, 6, 8,and 12 hours after the first dose on Day 1; and 0, 0.5, 1, 2, 4, 6, 8, 12, 24 (Day 8) and 48 (Day 9) hours post-dose on Day 7.

    2. Time to Maximum Plasma Concentration (Tmax) of MK-8242 [Cycle 1, Day 1 pre-dose and through 12 hours postdose; Cycle 1 Day 7 pre-dose and through 48 hours post dose]

      PK plasma samples were to be collected at the following time points: 0, 0.5, 1, 2, 4, 6, 8 and 12 hours after the first dose on Day 1; and 0, 0.5, 1, 2, 4, 6, 8, 12, 24 (Day 8) and 48 (Day 9) hours post-dose on Day 7.

    3. Area Under the Concentration Time Curve From Hour 0 to Hour 12 (AUC0-12) for MK-8242 [Cycle 1, Day 1 and Day 7, Hour 0 through Hour 12]

      PK plasma samples were to be collected at the following time points: 0, 0.5, 1, 2, 4, 6, 8 and 12 hours after the first dose on Day 1; and 0, 0.5, 1, 2, 4, 6, 8, 12, 24 (Day 8) and 48 (Day 9) hours post-dose on Day 7.

    4. AUC at Time of Last Sample (AUClast) for MK-8242 [Cycle 1, Day 1 pre-dose and through 12 hours post dose; Cycle 1 Day 7 pre-dose and through 48 hours post dose]

      PK plasma samples were to be collected at the following time points: 0, 0.5, 1, 2, 4, 6, 8 and 12 hours after the first dose on Day 1; and 0, 0.5, 1, 2, 4, 6, 8, 12, 24 (Day 8) and 48 (Day 9) hours post-dose on Day 7.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion criteria:

    • Histologically confirmed advanced solid tumor for which there are no effective standard therapy options

    • Willing to provide tumor tissue for p53 wild type gene analysis

    • Eastern Cooperative Oncology Group (ECOG) performance status of ≤1

    • Adequate organ function

    • Female participants and male participants and their partners who are of childbearing potential must agree to abstain from sexual intercourse or to use an acceptable method of contraception during the study and for 90 days following the last dose of study drug

    • At least one measurable lesion

    • In Part 2, participants with liposarcoma must have a confirmed well-differentiated or de-differentiated histology

    Exclusion criteria:

    • Known treated or untreated leptomeningeal metastases, or metastatic central nervous system disease

    • History of recent myocardial infarction (within the past year); or with unstable or uncontrolled angina, New York Heart Association (NYHA) Class III or IV congestive heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or clinically significant electrocardiogram (ECG) abnormality

    • Uncontrolled active infection on optimal systemic treatment

    • Clinically significant hepatitis or hepatitis C antibody positive, hepatitis B surface antigen positive, or human immunodeficiency virus (HIV) seropositive

    • Persistent, unresolved common terminology criteria for adverse events (CTCAE v4.0) ≥Grade 2 drug-related toxicity associated with previous treatment except for alopecia

    • Radiation therapy or other loco-regional therapy within 2 weeks prior to study

    • Use of moderate and strong cytochrome P450 inhibitors or inducers within 1 week prior to study

    • Chemotherapy or any investigational drug(s) within 4 weeks prior to study

    • Known hypersensitivity to MK-8242 or its components

    • Nursing, pregnant, or intention to become pregnant during the study

    • Initiating bisphosphonate therapy or adjusting the bisphosphonate dose or regimen within 30 days of Cycle 1 Day 1

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Merck Sharp & Dohme LLC

    Investigators

    • Study Director: Medical Director, Merck Sharp & Dohme LLC

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Merck Sharp & Dohme LLC
    ClinicalTrials.gov Identifier:
    NCT01463696
    Other Study ID Numbers:
    • P07650
    • 2011-001346-15
    • MK-8242-006
    First Posted:
    Nov 2, 2011
    Last Update Posted:
    Aug 27, 2018
    Last Verified:
    Jul 1, 2018
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Additional relevant MeSH terms:
    Neoplasms

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title MK-8242 60 mg BID MK-8242 120 mg BID MK-8242 170 mg BID MK-8242 250 mg BID MK-8242 300 mg BID MK-8242 350 mg BID MK-8242 400 mg BID MK-8242 500 mg BID
    Arm/Group Description In Cycle 1, participants received MK-8242 60 mg administered orally (PO) twice a day (BID) on Days 1-6 and PO once daily (QD) in the morning on Day 7 of the 21-day cycle to accommodate pharmacokinetic (PK) sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 60 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 120 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 120 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 170 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 170 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 250 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 250 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 300 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 300 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 350 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 350 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 400 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 400 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 500 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 500 mg PO BID on Days 1-7 of each 21-day cycle.
    Period Title: Overall Study
    STARTED 1 6 3 7 3 6 16 6
    Treated 1 6 3 7 3 6 15 6
    COMPLETED 1 4 2 3 2 3 6 2
    NOT COMPLETED 0 2 1 4 1 3 10 4

    Baseline Characteristics

    Arm/Group Title MK-8242 60 mg BID MK-8242 120 mg BID MK-8242 170 mg BID MK-8242 250 mg BID MK-8242 300 mg BID MK-8242 350 mg BID MK-8242 400 mg BID MK-8242 500 mg BID Total
    Arm/Group Description In Cycle 1, participants received MK-8242 60 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 60 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 120 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 120 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 170 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 170 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 250 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 250 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 300 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 300 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 350 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 350 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 400 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 400 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 500 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 500 mg PO BID on Days 1-7 of each 21-day cycle. Total of all reporting groups
    Overall Participants 1 6 3 7 3 6 16 6 48
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    47.0
    (NA)
    60.0
    (11.0)
    68.3
    (7.4)
    60.3
    (11.4)
    53.3
    (12.3)
    58.2
    (10.2)
    63.9
    (10.4)
    62.5
    (12.8)
    61.3
    (10.8)
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    2
    33.3%
    2
    66.7%
    3
    42.9%
    1
    33.3%
    2
    33.3%
    6
    37.5%
    3
    50%
    19
    39.6%
    Male
    1
    100%
    4
    66.7%
    1
    33.3%
    4
    57.1%
    2
    66.7%
    4
    66.7%
    10
    62.5%
    3
    50%
    29
    60.4%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Dose Limiting Toxicities (DLTs)
    Description DLT was defined as: any drug-related hematologic toxicity ≥ Grade 3 lasting ≥1 week, ≥ Grade 3 thrombocytopenia with bleeding, ≥ Grade 3 neutropenia with infection OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions/clarifications: 1) Grade 3 nausea, vomiting, diarrhea, and dehydration were excluded from the determination of DLT if, in the opinion of the investigator and sponsor, they occurred in a setting of inadequate treatment, 2) Grade 3 nausea, vomiting, diarrhea, and dehydration were each considered a DLT if they persisted despite 72 hours of maximal supportive care measures or 3) Any abnormal non-hematological laboratory value ≥ Grade 3 (that is not attributable to any other causes) was considered a DLT only if medical intervention was required to treat the participant, the abnormality led to hospitalization, or the abnormality persisted for ≥1 week.
    Time Frame Cycle 1 (21 days)

    Outcome Measure Data

    Analysis Population Description
    The DLT-evaluable population consisted of participants who received at least one dose of MK-8242 and completed Cycle 1 of Part 1 (dose escalation) or the dose confirmation portion of Part 2, or discontinued due to toxicity.
    Arm/Group Title MK-8242 60 mg BID MK-8242 120 mg BID MK-8242 170 mg BID MK-8242 250 mg BID MK-8242 300 mg BID MK-8242 350 mg BID MK-8242 400 mg BID MK-8242 500 mg BID
    Arm/Group Description In Cycle 1, participants received MK-8242 60 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 60 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 120 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 120 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 170 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 170 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 250 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 250 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 300 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 300 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 350 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 350 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 400 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 400 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 500 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 500 mg PO BID on Days 1-7 of each 21-day cycle.
    Measure Participants 1 6 3 7 3 6 15 6
    Number [Participants]
    0
    0%
    1
    16.7%
    0
    0%
    1
    14.3%
    0
    0%
    2
    33.3%
    2
    12.5%
    4
    66.7%
    2. Secondary Outcome
    Title Maximum Observed Plasma Concentration (Cmax) of MK-8242
    Description PK plasma samples were to be collected at the following time points: 0, 0.5, 1, 2, 4, 6, 8,and 12 hours after the first dose on Day 1; and 0, 0.5, 1, 2, 4, 6, 8, 12, 24 (Day 8) and 48 (Day 9) hours post-dose on Day 7.
    Time Frame Cycle 1, Day 1 pre-dose and through 24 hours post dose; Cycle 1 Day 7 pre-dose and through 48 hours post dose

    Outcome Measure Data

    Analysis Population Description
    The All Participants as Treated (APaT) population consisted of all participants who received at least one dose of study drug.
    Arm/Group Title MK-8242 60 mg BID MK-8242 120 mg BID MK-8242 170 mg BID MK-8242 250 mg BID MK-8242 300 mg BID MK-8242 350 mg BID MK-8242 400 mg BID MK-8242 500 mg BID
    Arm/Group Description In Cycle 1, participants received MK-8242 60 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 60 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 120 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 120 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 170 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 170 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 250 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 250 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 300 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 300 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 350 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 350 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 400 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 400 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 500 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 500 mg PO BID on Days 1-7 of each 21-day cycle.
    Measure Participants 1 5 3 6 3 6 14 6
    Day 1 (n=1, 5, 3, 6, 3, 6, 14, 6)
    162
    (NA)
    402
    (101.2)
    813
    (208.7)
    1210
    (80.4)
    1320
    (33.4)
    1510
    (166.2)
    3820
    (39.4)
    4240
    (45.5)
    Day 7 (n=1, 5, 3, 6, 3, 5, 12, 3)
    150
    (NA)
    551
    (90.1)
    1680
    (30.2)
    1030
    (133.7)
    1720
    (89.7)
    1930
    (52.4)
    3070
    (38.7)
    1800
    (63.0)
    3. Secondary Outcome
    Title Time to Maximum Plasma Concentration (Tmax) of MK-8242
    Description PK plasma samples were to be collected at the following time points: 0, 0.5, 1, 2, 4, 6, 8 and 12 hours after the first dose on Day 1; and 0, 0.5, 1, 2, 4, 6, 8, 12, 24 (Day 8) and 48 (Day 9) hours post-dose on Day 7.
    Time Frame Cycle 1, Day 1 pre-dose and through 12 hours postdose; Cycle 1 Day 7 pre-dose and through 48 hours post dose

    Outcome Measure Data

    Analysis Population Description
    The APaT population consisted of all participants who received at least one dose of study drug.
    Arm/Group Title MK-8242 60 mg BID MK-8242 120 mg BID MK-8242 170 mg BID MK-8242 250 mg BID MK-8242 300 mg BID MK-8242 350 mg BID MK-8242 400 mg BID MK-8242 500 mg BID
    Arm/Group Description In Cycle 1, participants received MK-8242 60 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 60 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 120 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 120 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 170 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 170 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 250 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 250 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 300 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 300 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 350 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 350 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 400 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 400 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 500 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 500 mg PO BID on Days 1-7 of each 21-day cycle.
    Measure Participants 1 5 3 6 3 6 14 6
    Day 1 (n=1, 5, 3, 6, 3, 6, 14, 6)
    2.03
    2.07
    4.30
    4.00
    2.18
    4.04
    2.00
    3.04
    Day 7 (n=1, 5, 3, 6, 3, 5, 12, 3)
    1.98
    4.00
    2.00
    3.23
    2.00
    4.00
    3.03
    2.08
    4. Secondary Outcome
    Title Area Under the Concentration Time Curve From Hour 0 to Hour 12 (AUC0-12) for MK-8242
    Description PK plasma samples were to be collected at the following time points: 0, 0.5, 1, 2, 4, 6, 8 and 12 hours after the first dose on Day 1; and 0, 0.5, 1, 2, 4, 6, 8, 12, 24 (Day 8) and 48 (Day 9) hours post-dose on Day 7.
    Time Frame Cycle 1, Day 1 and Day 7, Hour 0 through Hour 12

    Outcome Measure Data

    Analysis Population Description
    The APaT population consisted of all participants who received at least one dose of study drug.
    Arm/Group Title MK-8242 60 mg BID MK-8242 120 mg BID MK-8242 170 mg BID MK-8242 250 mg BID MK-8242 300 mg BID MK-8242 350 mg BID MK-8242 400 mg BID MK-8242 500 mg BID
    Arm/Group Description In Cycle 1, participants received MK-8242 60 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 60 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 120 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 120 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 170 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 170 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 250 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 250 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 300 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 300 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 350 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 350 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 400 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 400 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 500 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 500 mg PO BID on Days 1-7 of each 21-day cycle.
    Measure Participants 1 5 3 6 3 6 14 6
    Day 1 (n=1, 4, 1, 3, 3, 2, 12, 4)
    548
    (NA)
    1820
    (51.2)
    11000
    (NA)
    5550
    (100.1)
    5020
    (45.4)
    6940
    (110.7)
    16800
    (45.3)
    24100
    (46.0)
    Day 7 (n=1, 5, 3, 6, 3, 4, 12, 3)
    706
    (NA)
    2450
    (57.9)
    7190
    (24.7)
    6710
    (130.9)
    8720
    (65.1)
    13100
    (70.2)
    16500
    (41.2)
    13400
    (77.8)
    5. Secondary Outcome
    Title AUC at Time of Last Sample (AUClast) for MK-8242
    Description PK plasma samples were to be collected at the following time points: 0, 0.5, 1, 2, 4, 6, 8 and 12 hours after the first dose on Day 1; and 0, 0.5, 1, 2, 4, 6, 8, 12, 24 (Day 8) and 48 (Day 9) hours post-dose on Day 7.
    Time Frame Cycle 1, Day 1 pre-dose and through 12 hours post dose; Cycle 1 Day 7 pre-dose and through 48 hours post dose

    Outcome Measure Data

    Analysis Population Description
    The APaT population consisted of all participants who received at least one dose of study drug.
    Arm/Group Title MK-8242 60 mg BID MK-8242 120 mg BID MK-8242 170 mg BID MK-8242 250 mg BID MK-8242 300 mg BID MK-8242 350 mg BID MK-8242 400 mg BID MK-8242 500 mg BID
    Arm/Group Description In Cycle 1, participants received MK-8242 60 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 60 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 120 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 120 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 170 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 170 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 250 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 250 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 300 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 300 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 350 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 350 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 400 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 400 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 500 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 500 mg PO BID on Days 1-7 of each 21-day cycle.
    Measure Participants 1 5 3 6 3 6 14 6
    Day 1 (n=1, 5, 3, 6, 3, 6, 14, 6)
    509
    (NA)
    1380
    (72.0)
    3240
    (131)
    5410
    (69.0)
    4830
    (49.7)
    6350
    (152)
    16700
    (41.9)
    17400
    (84.7)
    Day 7 (n=1, 5, 3, 6, 3, 5, 12, 3)
    677
    (NA)
    2260
    (65.0)
    8290
    (25.1)
    7590
    (103)
    11300
    (75.0)
    15100
    (81.1)
    21400
    (48.2)
    17300
    (90.4)

    Adverse Events

    Time Frame Up to approximately 10 months (Up to 30 days after last dose of study drug)
    Adverse Event Reporting Description The All Participants as Treated (APaT) population consisted of all participants who received at least one dose of study drug.
    Arm/Group Title MK-8242 60 mg BID MK-8242 120 mg BID MK-8242 170 mg BID MK-8242 250 mg BID MK-8242 300 mg BID MK-8242 350 mg BID MK-8242 400 mg BID MK-8242 500 mg BID
    Arm/Group Description In Cycle 1, participants received MK-8242 60 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 60 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 120 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 120 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 170 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 170 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 250 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 250 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 300 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 300 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 350 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 350 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 400 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 400 mg PO BID on Days 1-7 of each 21-day cycle. In Cycle 1, participants received MK-8242 500 mg administered PO BID on Days 1-6 and PO QD in the morning on Day 7 of the 21-day cycle to accommodate PK sampling. In Cycle 2 and subsequent cycles, participants received MK-8242 500 mg PO BID on Days 1-7 of each 21-day cycle.
    All Cause Mortality
    MK-8242 60 mg BID MK-8242 120 mg BID MK-8242 170 mg BID MK-8242 250 mg BID MK-8242 300 mg BID MK-8242 350 mg BID MK-8242 400 mg BID MK-8242 500 mg BID
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    MK-8242 60 mg BID MK-8242 120 mg BID MK-8242 170 mg BID MK-8242 250 mg BID MK-8242 300 mg BID MK-8242 350 mg BID MK-8242 400 mg BID MK-8242 500 mg BID
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/1 (0%) 1/6 (16.7%) 0/3 (0%) 2/7 (28.6%) 1/3 (33.3%) 3/6 (50%) 5/15 (33.3%) 4/6 (66.7%)
    Blood and lymphatic system disorders
    Anaemia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Febrile neutropenia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 1/6 (16.7%) 1
    Gastrointestinal disorders
    Anal fissure 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Diarrhoea 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 2
    Nausea 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Vomiting 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 2/6 (33.3%) 2
    General disorders
    Chest pain 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Fatigue 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Oedema peripheral 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Hepatobiliary disorders
    Hyperbilirubinaemia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Infections and infestations
    Pneumonia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 1/15 (6.7%) 1 0/6 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Dehydration 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 2
    Musculoskeletal and connective tissue disorders
    Back pain 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Renal and urinary disorders
    Hydronephrosis 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Renal failure acute 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 2
    Pulmonary embolism 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 2 0/15 (0%) 0 1/6 (16.7%) 1
    Other (Not Including Serious) Adverse Events
    MK-8242 60 mg BID MK-8242 120 mg BID MK-8242 170 mg BID MK-8242 250 mg BID MK-8242 300 mg BID MK-8242 350 mg BID MK-8242 400 mg BID MK-8242 500 mg BID
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/1 (100%) 6/6 (100%) 3/3 (100%) 7/7 (100%) 3/3 (100%) 6/6 (100%) 15/15 (100%) 6/6 (100%)
    Blood and lymphatic system disorders
    Anaemia 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 5/15 (33.3%) 5 0/6 (0%) 0
    Leukopenia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/15 (13.3%) 2 0/6 (0%) 0
    Neutropenia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 1/3 (33.3%) 1 1/6 (16.7%) 2 10/15 (66.7%) 22 3/6 (50%) 4
    Pancytopenia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 1/6 (16.7%) 1
    Thrombocytopenia 0/1 (0%) 0 1/6 (16.7%) 1 1/3 (33.3%) 2 2/7 (28.6%) 6 0/3 (0%) 0 2/6 (33.3%) 7 9/15 (60%) 23 2/6 (33.3%) 6
    Cardiac disorders
    Angina pectoris 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Endocrine disorders
    Hypothyroidism 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Eye disorders
    Conjunctival haemorrhage 1/1 (100%) 1 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Photopsia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Presbyopia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Vision blurred 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 1/6 (16.7%) 1
    Vitreous floaters 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Gastrointestinal disorders
    Abdominal discomfort 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Abdominal pain 0/1 (0%) 0 1/6 (16.7%) 2 1/3 (33.3%) 1 1/7 (14.3%) 1 0/3 (0%) 0 1/6 (16.7%) 1 0/15 (0%) 0 1/6 (16.7%) 1
    Abdominal pain lower 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 2
    Abdominal pain upper 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Coeliac artery stenosis 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Constipation 1/1 (100%) 1 3/6 (50%) 3 1/3 (33.3%) 1 3/7 (42.9%) 4 1/3 (33.3%) 2 0/6 (0%) 0 2/15 (13.3%) 2 1/6 (16.7%) 1
    Diarrhoea 0/1 (0%) 0 1/6 (16.7%) 2 1/3 (33.3%) 3 3/7 (42.9%) 3 2/3 (66.7%) 4 3/6 (50%) 4 13/15 (86.7%) 23 5/6 (83.3%) 15
    Dry mouth 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/15 (20%) 3 0/6 (0%) 0
    Dyspepsia 0/1 (0%) 0 1/6 (16.7%) 2 1/3 (33.3%) 2 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Dysphagia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Flatulence 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 2 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Gastritis 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Gastrooesophageal reflux disease 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Haemorrhoids 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Nausea 0/1 (0%) 0 5/6 (83.3%) 10 3/3 (100%) 10 5/7 (71.4%) 11 3/3 (100%) 10 5/6 (83.3%) 15 12/15 (80%) 21 5/6 (83.3%) 11
    Oral pain 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Retching 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Stomatitis 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Tongue coated 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Tongue dry 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Toothache 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Vomiting 0/1 (0%) 0 2/6 (33.3%) 2 1/3 (33.3%) 4 4/7 (57.1%) 10 1/3 (33.3%) 2 4/6 (66.7%) 7 7/15 (46.7%) 11 3/6 (50%) 3
    General disorders
    Asthenia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Chest pain 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Chills 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Facial pain 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Fatigue 1/1 (100%) 1 4/6 (66.7%) 7 3/3 (100%) 6 6/7 (85.7%) 7 2/3 (66.7%) 5 4/6 (66.7%) 10 12/15 (80%) 17 6/6 (100%) 14
    Generalised oedema 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Influenza like illness 0/1 (0%) 0 2/6 (33.3%) 2 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Malaise 0/1 (0%) 0 2/6 (33.3%) 2 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Mucosal inflammation 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Oedema peripheral 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/15 (13.3%) 2 1/6 (16.7%) 1
    Pain 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 1/6 (16.7%) 1
    Peripheral swelling 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/15 (0%) 0 0/6 (0%) 0
    Pyrexia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 2/6 (33.3%) 2
    Hepatobiliary disorders
    Hyperbilirubinaemia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/15 (13.3%) 4 0/6 (0%) 0
    Immune system disorders
    Hypersensitivity 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Infections and infestations
    Candida infection 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/7 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 1/15 (6.7%) 1 0/6 (0%) 0
    Cellulitis 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Lung infection 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Oral candidiasis 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Otitis media 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Pneumonia 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Respiratory tract infection 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Sinusitis 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Small intestinal bacterial overgrowth 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Urinary tract infection 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Injury, poisoning and procedural complications
    Accidental overdose 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/15 (0%) 0 0/6 (0%) 0
    Sunburn 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Investigations
    Blood alkaline phosphatase increased 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Blood bilirubin increased 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 2/6 (33.3%) 3
    Blood cholesterol increased 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Blood creatinine increased 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Blood glucose increased 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 2
    Blood phosphorus decreased 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 3 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Blood uric acid increased 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Coagulation time prolonged 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/15 (0%) 0 0/6 (0%) 0
    Gamma-glutamyltransferase increased 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    International normalised ratio increased 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/15 (20%) 3 0/6 (0%) 0
    Neutrophil count decreased 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 4
    Platelet count decreased 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 2/6 (33.3%) 5
    Weight decreased 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    White blood cell count decreased 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 2/15 (13.3%) 2 2/6 (33.3%) 7
    Metabolism and nutrition disorders
    Decreased appetite 0/1 (0%) 0 3/6 (50%) 5 1/3 (33.3%) 1 5/7 (71.4%) 6 1/3 (33.3%) 2 3/6 (50%) 6 11/15 (73.3%) 17 3/6 (50%) 6
    Dehydration 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 4/15 (26.7%) 7 1/6 (16.7%) 1
    Hypercalcaemia 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Hypercholesterolaemia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Hyperglycaemia 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 2/15 (13.3%) 4 1/6 (16.7%) 1
    Hyperkalaemia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Hyperuricaemia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Hypocalcaemia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 1/6 (16.7%) 1
    Hypochloraemia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Hypoglycaemia 0/1 (0%) 0 2/6 (33.3%) 2 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Hypokalaemia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 1/6 (16.7%) 1
    Hypomagnesaemia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 5/15 (33.3%) 5 0/6 (0%) 0
    Hyponatraemia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 1/6 (16.7%) 1
    Hypophosphataemia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 3
    Musculoskeletal and connective tissue disorders
    Back pain 0/1 (0%) 0 0/6 (0%) 0 2/3 (66.7%) 2 0/7 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 3/15 (20%) 3 0/6 (0%) 0
    Bone pain 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Flank pain 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Muscle spasms 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Musculoskeletal chest pain 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Musculoskeletal pain 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/15 (13.3%) 2 0/6 (0%) 0
    Myalgia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Pain in extremity 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Pain in jaw 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Nervous system disorders
    Allodynia 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Dizziness 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 1/7 (14.3%) 1 1/3 (33.3%) 1 0/6 (0%) 0 1/15 (6.7%) 1 1/6 (16.7%) 1
    Dysaesthesia 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Dysgeusia 0/1 (0%) 0 2/6 (33.3%) 4 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 1/6 (16.7%) 1 2/15 (13.3%) 2 0/6 (0%) 0
    Headache 0/1 (0%) 0 2/6 (33.3%) 6 2/3 (66.7%) 2 1/7 (14.3%) 1 1/3 (33.3%) 1 1/6 (16.7%) 1 3/15 (20%) 3 1/6 (16.7%) 1
    Hypoaesthesia 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Memory impairment 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Migraine 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Neuropathy peripheral 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 2 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 1/6 (16.7%) 1
    Paraesthesia 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Parosmia 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Syncope 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Tremor 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Psychiatric disorders
    Anxiety 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Depressed mood 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Depression 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Insomnia 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 1/7 (14.3%) 2 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Libido decreased 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Mood altered 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Panic attack 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Renal and urinary disorders
    Pollakiuria 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Proteinuria 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Renal impairment 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 1/6 (16.7%) 1
    Urinary hesitation 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Urinary retention 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Urine abnormality 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Reproductive system and breast disorders
    Erectile dysfunction 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Oedema genital 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Cough 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 2/15 (13.3%) 2 0/6 (0%) 0
    Dyspnoea 1/1 (100%) 1 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 2/6 (33.3%) 2
    Dyspnoea exertional 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 2/15 (13.3%) 2 0/6 (0%) 0
    Haemoptysis 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Hiccups 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Oropharyngeal pain 0/1 (0%) 0 1/6 (16.7%) 2 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Rales 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Upper-airway cough syndrome 0/1 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Skin and subcutaneous tissue disorders
    Alopecia 0/1 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/7 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 4/15 (26.7%) 5 1/6 (16.7%) 1
    Dry skin 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Erythema 1/1 (100%) 1 0/6 (0%) 0 0/3 (0%) 0 1/7 (14.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Palmar-plantar erythrodysaesthesia syndrome 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Photosensitivity reaction 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Rash 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 2
    Rash macular 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Rash pruritic 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/15 (6.7%) 1 0/6 (0%) 0
    Skin fissures 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 1/6 (16.7%) 1
    Vascular disorders
    Hot flush 0/1 (0%) 0 1/6 (16.7%) 2 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/15 (0%) 0 0/6 (0%) 0
    Hypotension 0/1 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/7 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/15 (20%) 3 1/6 (16.7%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The investigator agrees to provide to the sponsor 45 days prior to submission for publication or presentation, review copies of abstracts or manuscripts for publication that report any results of the study.

    Results Point of Contact

    Name/Title Senior Vice President, Global Clinical Development
    Organization Merck Sharp & Dohme Corp.
    Phone 1-800-672-6372
    Email ClinicalTrialsDisclosure@merck.com
    Responsible Party:
    Merck Sharp & Dohme LLC
    ClinicalTrials.gov Identifier:
    NCT01463696
    Other Study ID Numbers:
    • P07650
    • 2011-001346-15
    • MK-8242-006
    First Posted:
    Nov 2, 2011
    Last Update Posted:
    Aug 27, 2018
    Last Verified:
    Jul 1, 2018