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A Combination Therapy Study of MK-2206 and AZD6244 in Participants With Advanced Solid Tumors (MK-2206-010)

Sponsor
Merck Sharp & Dohme LLC (Industry)
Overall Status
Completed
CT.gov ID
NCT01021748
Collaborator
AstraZeneca (Industry)
63
Enrollment
9
Arms
55.7
Actual Duration (Months)

Study Details

Study Description

Brief Summary

This study will investigate the safety and tolerability of combination therapy with MK-2206 and AZD6244 (selumetinib) and determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RPTD) for this drug combination in the treatment of participants with locally advanced or metastatic solid tumors. Preliminary efficacy data will also be collected.

The primary hypotheses for this study are that: 1) the Dose-limiting Toxicities (DLTs) observed in participants with locally advanced or metastatic solid tumors after administration of combination therapy with MK-2206 and AZD6244 will be dose-dependent and allow for identification of the MTD, and 2) oral administration of combination therapy with MK-2206 and AZD6244 to participants with advanced solid tumors will be generally well-tolerated.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
63 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I Study of Oral MK-2206 in Combination With Oral AZD6244 in Patients With Locally Advanced or Metastatic Solid Tumors
Actual Study Start Date :
Nov 23, 2009
Actual Primary Completion Date :
Nov 26, 2012
Actual Study Completion Date :
Jul 16, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: MK-2206 45 mg QOD + AZD6244 75 mg QD

Participants receive MK-2206 45 mg oral tablets once every other day (QOD) PLUS AZD6244 75 mg oral capsules once daily (QD) starting on Day 1 of each 28-day cycle.

Drug: MK-2206
Oral tablets

Drug: AZD6244
Oral capsules
Other Names:
  • selumetinib

    		•
    Experimental: MK-2206 45 mg QOD + AZD6244 75 mg BID

    Participants receive MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules twice daily (BID) starting on Day 1 of each 28-day cycle.

    Drug: MK-2206
    Oral tablets

    Drug: AZD6244
    Oral capsules
    Other Names:
  • selumetinib

    		•
    Experimental: MK-2206 90 mg QW + AZD6244 50 mg BID

    Participants receive MK-2206 90 mg oral tablets once weekly (QW) PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle.

    Drug: MK-2206
    Oral tablets

    Drug: AZD6244
    Oral capsules
    Other Names:
  • selumetinib

    		•
    Experimental: MK-2206 90 mg QW + AZD6244 75 mg QD

    Participants receive MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle.

    Drug: MK-2206
    Oral tablets

    Drug: AZD6244
    Oral capsules
    Other Names:
  • selumetinib

    		•
    Experimental: MK-2206 90 mg QW + AZD6244 75 mg BID

    Participants receive MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle.

    Drug: MK-2206
    Oral tablets

    Drug: AZD6244
    Oral capsules
    Other Names:
  • selumetinib

    		•
    Experimental: MK-2206 90 mg QW + AZD6244 100 mg QD

    Participants receive MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.

    Drug: MK-2206
    Oral tablets

    Drug: AZD6244
    Oral capsules
    Other Names:
  • selumetinib

    		•
    Experimental: MK-2206 90 mg QW + AZD6244 150 mg QD

    Participants receive MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle.

    Drug: MK-2206
    Oral tablets

    Drug: AZD6244
    Oral capsules
    Other Names:
  • selumetinib

    		•
    Experimental: MK-2206 100 mg QW + AZD6244 100 mg QD

    Participants receive MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.

    Drug: MK-2206
    Oral tablets

    Drug: AZD6244
    Oral capsules
    Other Names:
  • selumetinib

    		•
    Experimental: MK-2206 135 mg QW + AZD6244 100 mg QD

    Participants receive MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.

    Drug: MK-2206
    Oral tablets

    Drug: AZD6244
    Oral capsules
    Other Names:
  • selumetinib

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With a Dose-limiting Toxicity (DLT) [Cycle 1 (Up to 28 days)]

      Adverse events (AEs) were graded using Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. DLTs included: Grade 4 neutropenia lasting for ≥7 days; Grade 3 or Grade 4 neutropenia with fever >38.5ºC and/or infection requiring antibiotic or anti-fungal treatment; Grade 4 thrombocytopenia (≤25.0 x 10^9/L); Grade ≥3 non-hematologic toxicity with exceptions; Any drug-related AE, regardless of CTCAE Grade, leading to a dose modification of MK-2206 or AZD6244; Unresolved CTCAE Grade ≥3 drug-related toxicity requiring drug interruption for >14 days; ≥ Grade 3 signs or symptoms of glucose intolerance and accompanied by ≥ Grade 2 hyperglycemia (glucose >160 dL or 8.9 mmol/L); ≥ Grade 3 electrolyte abnormalities due to glucose intolerance and not attributable to another cause; Diagnosis of lactoacidosis or ketoacidosis; Persistent increases in corrected QT (QTc) interval (>60 msec from baseline and/or >500 msec); Clinically significant bradycardia.

    2. Number of Participants Who Experienced at Least One Adverse Event (AE) [Up to approximately 23 months]

      An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening of a pre-existing condition which was temporally associated with the use of study drug was also an AE. The number of participants who experienced at least one AE is presented.

    3. Number of Participants Who Discontinued Study Treatment Due to an AE [Up to approximately 20 months]

      An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening of a pre-existing condition which was temporally associated with the use of study drug was also an AE. The number of participants who discontinued study treatment due to an AE is presented.

    Secondary Outcome Measures

    1. Number of Participants With a Tumor Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [Baseline and after every 8 weeks of treatment until documentation of objective response or disease progression (Up to 2 years)]

      Radiological evaluation (via computed tomography [CT] or magnetic resonance imaging [MRI]) of tumor response was assessed every 8 weeks post-treatment during Cycles 1-6, and per institutional standard of care in Cycle 7 and beyond. The best overall tumor response was the best response based on RECIST 1.1 recorded from the start of the study treatment until the end of treatment. Response categories included: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Participants whose tumor was not evaluable (NE) were missing a valid RECIST1.1 measurement at baseline. The best overall tumor response for participants is presented.

    Eligibility Criteria

    Criteria

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

    • Participant has confirmed metastatic or locally advanced solid tumor that has failed to respond to standard therapy, progressed despite standard therapy, or therapies known to provide clinical benefit, or for whom efficacious standard therapy or any other therapy known to provide clinical benefit does not exist

    • Participant has no history of prior cancer, except certain cervical, skin, or prostate cancers, or has undergone potentially curative therapy with no evidence of disease for 5 years

    • At least 18 years of age

    • Participant is able to swallow oral medications

    • For participants enrolled in the MTD expansion cohorts, must have a diagnosis of Kirsten rat sarcoma viral oncogene homolog (KRAS) tumor-type non small-cell lung cancer (NSCLC). Additional tumor types (with specific mutations) may be added to the MTD expansion cohorts after discussion between Sponsor and Investigator

    Exclusion Criteria:

    • Participant has had chemotherapy, radiotherapy or biological therapy within 4 weeks of entering the study

    • Participant is currently participating in or has participated in a study of an investigational compound or device within 30 days or 5x the compound's half-life of Cycle 1, Day 1

    • Participant has known central nervous system metastases and/or carcinomatous meningitis

    • Participant has a primary central nervous system tumor or spinal cord compression

    • Participant is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of drug or alcohol abuse

    • Participant is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study

    • Participant is human immunodeficiency virus (HIV) positive

    • Participant is has history of hepatitis B or C or active hepatitis A

    • Participant has a history or current evidence of heart disease

    • Participant has uncontrolled high blood pressure

    • Participant has poorly controlled diabetes

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Merck Sharp & Dohme LLC
    • AstraZeneca

    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:
    NCT01021748
    Other Study ID Numbers:
    • 2206-010
    • 2009_698
    First Posted:
    Nov 30, 2009
    Last Update Posted:
    Aug 7, 2018
    Last Verified:
    Nov 1, 2017
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Neoplasms

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
    Arm/Group Description Participants received MK-2206 45 mg oral tablets once every other day (QOD) PLUS AZD6244 75 mg oral capsules once daily (QD) starting on Day 1 of each 28-day cycle. Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules twice daily (BID) starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets once weekly (QW) PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
    Period Title: Overall Study
    STARTED 6 5 7 7 9 3 3 6 17
    Treated 6 4 7 7 9 3 3 6 17
    COMPLETED 0 0 0 0 0 0 0 0 1
    NOT COMPLETED 6 5 7 7 9 3 3 6 16

    Baseline Characteristics

    Arm/Group Title MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD Total
    Arm/Group Description Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Total of all reporting groups
    Overall Participants 6 4 7 7 9 3 3 6 17 62
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    55.0
    (8.0)
    50.0
    (5.9)
    48.9
    (8.6)
    56.6
    (7.3)
    56.1
    (12.5)
    44.3
    (8.0)
    63.0
    (6.2)
    54.3
    (15.3)
    64.7
    (9.4)
    56.8
    (11.1)
    Sex: Female, Male (Count of Participants)
    Female
    4
    66.7%
    3
    75%
    4
    57.1%
    2
    28.6%
    5
    55.6%
    2
    66.7%
    2
    66.7%
    2
    33.3%
    12
    70.6%
    36
    58.1%
    Male
    2
    33.3%
    1
    25%
    3
    42.9%
    5
    71.4%
    4
    44.4%
    1
    33.3%
    1
    33.3%
    4
    66.7%
    5
    29.4%
    26
    41.9%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With a Dose-limiting Toxicity (DLT)
    Description Adverse events (AEs) were graded using Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. DLTs included: Grade 4 neutropenia lasting for ≥7 days; Grade 3 or Grade 4 neutropenia with fever >38.5ºC and/or infection requiring antibiotic or anti-fungal treatment; Grade 4 thrombocytopenia (≤25.0 x 10^9/L); Grade ≥3 non-hematologic toxicity with exceptions; Any drug-related AE, regardless of CTCAE Grade, leading to a dose modification of MK-2206 or AZD6244; Unresolved CTCAE Grade ≥3 drug-related toxicity requiring drug interruption for >14 days; ≥ Grade 3 signs or symptoms of glucose intolerance and accompanied by ≥ Grade 2 hyperglycemia (glucose >160 dL or 8.9 mmol/L); ≥ Grade 3 electrolyte abnormalities due to glucose intolerance and not attributable to another cause; Diagnosis of lactoacidosis or ketoacidosis; Persistent increases in corrected QT (QTc) interval (>60 msec from baseline and/or >500 msec); Clinically significant bradycardia.
    Time Frame Cycle 1 (Up to 28 days)

    Outcome Measure Data

    Analysis Population Description
    The population consisted of all participants who completed ≥ 80% of the first cycle of combination therapy unless interruption of study medication was due to toxicity (e.g. DLT).
    Arm/Group Title MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
    Arm/Group Description Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
    Measure Participants 6 4 7 7 9 3 3 6 17
    Number [Participants]
    0
    0%
    2
    50%
    2
    28.6%
    1
    14.3%
    3
    33.3%
    0
    0%
    2
    66.7%
    0
    0%
    3
    17.6%
    2. Secondary Outcome
    Title Number of Participants With a Tumor Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
    Description Radiological evaluation (via computed tomography [CT] or magnetic resonance imaging [MRI]) of tumor response was assessed every 8 weeks post-treatment during Cycles 1-6, and per institutional standard of care in Cycle 7 and beyond. The best overall tumor response was the best response based on RECIST 1.1 recorded from the start of the study treatment until the end of treatment. Response categories included: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Participants whose tumor was not evaluable (NE) were missing a valid RECIST1.1 measurement at baseline. The best overall tumor response for participants is presented.
    Time Frame Baseline and after every 8 weeks of treatment until documentation of objective response or disease progression (Up to 2 years)

    Outcome Measure Data

    Analysis Population Description
    The analysis population consisted of all participants with assessable disease at baseline or measureable disease at baseline per RECIST1.1.
    Arm/Group Title MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
    Arm/Group Description Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
    Measure Participants 6 3 7 7 9 3 2 6 13
    Complete Response
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Partial Response
    0
    0%
    0
    0%
    2
    28.6%
    0
    0%
    1
    11.1%
    0
    0%
    0
    0%
    0
    0%
    2
    11.8%
    Stable Disease
    4
    66.7%
    0
    0%
    1
    14.3%
    3
    42.9%
    3
    33.3%
    3
    100%
    2
    66.7%
    4
    66.7%
    10
    58.8%
    Progressive Disease
    2
    33.3%
    3
    75%
    4
    57.1%
    4
    57.1%
    5
    55.6%
    0
    0%
    0
    0%
    2
    33.3%
    1
    5.9%
    3. Primary Outcome
    Title Number of Participants Who Experienced at Least One Adverse Event (AE)
    Description An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening of a pre-existing condition which was temporally associated with the use of study drug was also an AE. The number of participants who experienced at least one AE is presented.
    Time Frame Up to approximately 23 months

    Outcome Measure Data

    Analysis Population Description
    The population consisted of all participants who received at least one dose of study treatment.
    Arm/Group Title MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
    Arm/Group Description Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
    Measure Participants 6 4 7 7 9 3 3 6 17
    Number [Participants]
    6
    100%
    4
    100%
    7
    100%
    7
    100%
    9
    100%
    3
    100%
    3
    100%
    6
    100%
    17
    100%
    4. Primary Outcome
    Title Number of Participants Who Discontinued Study Treatment Due to an AE
    Description An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening of a pre-existing condition which was temporally associated with the use of study drug was also an AE. The number of participants who discontinued study treatment due to an AE is presented.
    Time Frame Up to approximately 20 months

    Outcome Measure Data

    Analysis Population Description
    The population consisted of all participants who received at least one dose of study treatment.
    Arm/Group Title MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
    Arm/Group Description Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
    Measure Participants 6 4 7 7 9 3 3 6 17
    Number [Participants]
    2
    33.3%
    1
    25%
    2
    28.6%
    0
    0%
    2
    22.2%
    0
    0%
    1
    33.3%
    0
    0%
    7
    41.2%

    Adverse Events

    Time Frame Up to approximately 23 months
    Adverse Event Reporting Description The population consisted of all participants who received at least one dose of study treatment.
    Arm/Group Title MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
    Arm/Group Description Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
    All Cause Mortality
    MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
    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 Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
    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 Affected / at Risk (%) # Events
    Total 4/6 (66.7%) 1/4 (25%) 6/7 (85.7%) 2/7 (28.6%) 6/9 (66.7%) 0/3 (0%) 2/3 (66.7%) 3/6 (50%) 5/17 (29.4%)
    Blood and lymphatic system disorders
    Anaemia 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 2/9 (22.2%) 2 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Cardiac disorders
    Atrial flutter 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Eye disorders
    Detachment of retinal pigment epithelium 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 1/6 (16.7%) 1 0/4 (0%) 0 2/7 (28.6%) 2 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Constipation 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Diarrhoea 1/6 (16.7%) 2 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Dysphagia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Gastrointestinal haemorrhage 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 2 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Haemorrhoids 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Intestinal obstruction 1/6 (16.7%) 1 0/4 (0%) 0 2/7 (28.6%) 3 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Obstruction gastric 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Rectal haemorrhage 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Small intestinal obstruction 0/6 (0%) 0 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Stomatitis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Vomiting 2/6 (33.3%) 2 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    General disorders
    Fatigue 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Pyrexia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Infections and infestations
    Clostridium difficile colitis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Hepatitis C 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Lower respiratory tract infection 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Meningitis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Pneumonia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Pyelonephritis 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Injury, poisoning and procedural complications
    Post procedural fistula 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Renal haematoma 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Investigations
    Lipase increased 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Nervous system disorders
    Complex partial seizures 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Renal and urinary disorders
    Hydronephrosis 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Renal failure acute 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Urinary retention 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Pneumonitis 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Rash 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Vascular disorders
    Haemorrhage 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Superior vena cava syndrome 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Vena cava thrombosis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Other (Not Including Serious) Adverse Events
    MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
    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 Affected / at Risk (%) # Events
    Total 6/6 (100%) 4/4 (100%) 7/7 (100%) 7/7 (100%) 9/9 (100%) 3/3 (100%) 2/3 (66.7%) 6/6 (100%) 17/17 (100%)
    Blood and lymphatic system disorders
    Anaemia 0/6 (0%) 0 0/4 (0%) 0 2/7 (28.6%) 2 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Leukopenia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 3 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Lymphopenia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/17 (11.8%) 7
    Neutropenia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 2/7 (28.6%) 3 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/17 (11.8%) 2
    Thrombocytopenia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Cardiac disorders
    Arrhythmia supraventricular 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 2 0/17 (0%) 0
    Atrioventricular block first degree 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Bradycardia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/17 (11.8%) 2
    Left ventricular dysfunction 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Palpitations 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Tachycardia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 2 0/17 (0%) 0
    Ear and labyrinth disorders
    Auricular swelling 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Tinnitus 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Eye disorders
    Amblyopia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Blepharitis 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Cataract 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Cataract subcapsular 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Conjunctival haemorrhage 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Conjunctivitis 0/6 (0%) 0 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Detachment of macular retinal pigment epithelium 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Dry eye 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 2
    Eye pain 0/6 (0%) 0 1/4 (25%) 1 0/7 (0%) 0 1/7 (14.3%) 1 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Eye pruritus 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Eye swelling 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Eyelid oedema 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Lacrimation increased 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/17 (17.6%) 3
    Macular fibrosis 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Macular pigmentation 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Maculopathy 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Ocular hypertension 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Periorbital oedema 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/17 (11.8%) 2
    Photophobia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Retinal detachment 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Retinal pigment epitheliopathy 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Scleral hyperaemia 0/6 (0%) 0 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Vision blurred 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 2 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Visual impairment 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Gastrointestinal disorders
    Abdominal discomfort 0/6 (0%) 0 0/4 (0%) 0 2/7 (28.6%) 3 0/7 (0%) 0 1/9 (11.1%) 1 1/3 (33.3%) 1 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Abdominal distension 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 2/9 (22.2%) 2 2/3 (66.7%) 2 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Abdominal pain 2/6 (33.3%) 2 0/4 (0%) 0 2/7 (28.6%) 3 1/7 (14.3%) 1 3/9 (33.3%) 3 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 2
    Abdominal pain lower 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Abdominal pain upper 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Ascites 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Constipation 1/6 (16.7%) 1 0/4 (0%) 0 1/7 (14.3%) 1 2/7 (28.6%) 2 2/9 (22.2%) 2 2/3 (66.7%) 2 1/3 (33.3%) 1 1/6 (16.7%) 1 2/17 (11.8%) 2
    Diarrhoea 3/6 (50%) 8 3/4 (75%) 3 3/7 (42.9%) 7 3/7 (42.9%) 6 5/9 (55.6%) 6 3/3 (100%) 5 0/3 (0%) 0 2/6 (33.3%) 4 14/17 (82.4%) 20
    Dry mouth 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 4/17 (23.5%) 6
    Dyspepsia 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 3/9 (33.3%) 3 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 1/17 (5.9%) 1
    Eructation 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Faecal incontinence 1/6 (16.7%) 2 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Flatulence 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Gastrointestinal haemorrhage 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Haemorrhoids 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Lip ulceration 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Mouth ulceration 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Nausea 2/6 (33.3%) 2 1/4 (25%) 1 5/7 (71.4%) 6 4/7 (57.1%) 5 1/9 (11.1%) 1 1/3 (33.3%) 1 2/3 (66.7%) 3 3/6 (50%) 3 8/17 (47.1%) 13
    Odynophagia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Oesophageal pain 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 2 0/17 (0%) 0
    Oral pain 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Proctalgia 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Rectal haemorrhage 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 1/17 (5.9%) 1
    Stomatitis 2/6 (33.3%) 2 1/4 (25%) 2 1/7 (14.3%) 1 0/7 (0%) 0 5/9 (55.6%) 7 1/3 (33.3%) 1 0/3 (0%) 0 1/6 (16.7%) 2 3/17 (17.6%) 4
    Varices oesophageal 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Vomiting 2/6 (33.3%) 2 1/4 (25%) 1 7/7 (100%) 10 4/7 (57.1%) 4 0/9 (0%) 0 0/3 (0%) 0 2/3 (66.7%) 4 3/6 (50%) 3 4/17 (23.5%) 4
    General disorders
    Asthenia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Axillary pain 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Chest discomfort 1/6 (16.7%) 2 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Chest pain 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Chills 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Face oedema 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 2 0/17 (0%) 0
    Fatigue 3/6 (50%) 6 1/4 (25%) 1 4/7 (57.1%) 11 3/7 (42.9%) 4 3/9 (33.3%) 6 2/3 (66.7%) 4 1/3 (33.3%) 1 3/6 (50%) 4 11/17 (64.7%) 15
    Influenza like illness 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Localised oedema 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Malaise 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Mucosal inflammation 0/6 (0%) 0 0/4 (0%) 0 3/7 (42.9%) 7 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 7/17 (41.2%) 10
    Oedema 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Oedema peripheral 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 1/7 (14.3%) 1 1/9 (11.1%) 1 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Pain 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Pyrexia 0/6 (0%) 0 1/4 (25%) 1 1/7 (14.3%) 1 1/7 (14.3%) 1 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 2
    Infections and infestations
    Cystitis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Ear infection 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Eyelid infection 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Infection 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Lower respiratory tract infection 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 2 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/6 (16.7%) 2 0/17 (0%) 0
    Nasopharyngitis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Oral candidiasis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Oral herpes 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Paronychia 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 2 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 2/17 (11.8%) 3
    Pharyngitis 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Rhinitis 1/6 (16.7%) 1 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Sinusitis 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Upper respiratory tract infection 0/6 (0%) 0 1/4 (25%) 1 1/7 (14.3%) 1 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Urinary tract infection 0/6 (0%) 0 0/4 (0%) 0 2/7 (28.6%) 2 0/7 (0%) 0 1/9 (11.1%) 1 1/3 (33.3%) 1 1/3 (33.3%) 1 0/6 (0%) 0 4/17 (23.5%) 5
    Injury, poisoning and procedural complications
    Accidental overdose 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Contusion 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Fall 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 2
    Laceration 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Nail injury 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Post-traumatic neck syndrome 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Tooth fracture 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Investigations
    Activated partial thromboplastin time prolonged 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Alanine aminotransferase increased 1/6 (16.7%) 2 1/4 (25%) 7 1/7 (14.3%) 1 1/7 (14.3%) 2 2/9 (22.2%) 2 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/17 (17.6%) 7
    Aspartate aminotransferase increased 1/6 (16.7%) 2 1/4 (25%) 3 0/7 (0%) 0 1/7 (14.3%) 3 2/9 (22.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 4/17 (23.5%) 6
    Blood albumin decreased 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Blood alkaline phosphatase increased 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 3/7 (42.9%) 3 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Blood bilirubin increased 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 2
    Blood creatine phosphokinase increased 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 10 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 3/17 (17.6%) 3
    Blood creatinine increased 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 1/17 (5.9%) 1
    Blood glucose increased 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Blood potassium decreased 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Blood urea increased 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Culture urine positive 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Electrocardiogram QT prolonged 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Electrocardiogram T wave amplitude decreased 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Haemoglobin 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 2
    Lymphocyte count decreased 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 3
    Neutrophil count decreased 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Weight decreased 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    White blood cell count decreased 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Metabolism and nutrition disorders
    Decreased appetite 1/6 (16.7%) 1 1/4 (25%) 1 3/7 (42.9%) 3 1/7 (14.3%) 1 1/9 (11.1%) 1 0/3 (0%) 0 2/3 (66.7%) 2 1/6 (16.7%) 1 4/17 (23.5%) 8
    Dehydration 1/6 (16.7%) 1 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Hyperglycaemia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 2/7 (28.6%) 5 1/9 (11.1%) 3 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 2/17 (11.8%) 2
    Hyperphosphataemia 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Hypoalbuminaemia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 2 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Hypocalcaemia 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 2 1/7 (14.3%) 1 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Hypokalaemia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/17 (17.6%) 3
    Hypomagnesaemia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Hyponatraemia 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 2
    Hypophosphataemia 0/6 (0%) 0 1/4 (25%) 1 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 4
    Musculoskeletal and connective tissue disorders
    Back pain 0/6 (0%) 0 0/4 (0%) 0 2/7 (28.6%) 2 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/17 (17.6%) 3
    Bone pain 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Flank pain 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 3 0/17 (0%) 0
    Joint swelling 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Muscle spasms 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 2 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Muscle twitching 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Musculoskeletal discomfort 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 2/9 (22.2%) 5 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Musculoskeletal pain 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 3 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Myalgia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Neck pain 0/6 (0%) 0 0/4 (0%) 0 2/7 (28.6%) 4 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 1/17 (5.9%) 1
    Pain in extremity 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Nervous system disorders
    Brachial plexopathy 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Cognitive disorder 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Convulsion 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Dizziness 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 5 1/17 (5.9%) 1
    Dysgeusia 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 2/9 (22.2%) 2 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 2/17 (11.8%) 3
    Headache 0/6 (0%) 0 1/4 (25%) 1 1/7 (14.3%) 2 2/7 (28.6%) 3 0/9 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 1/6 (16.7%) 1 5/17 (29.4%) 6
    Hypoaesthesia 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Lethargy 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 1/17 (5.9%) 1
    Migraine 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Paraesthesia 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Sciatica 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Somnolence 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Psychiatric disorders
    Affective disorder 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Depression 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/17 (17.6%) 3
    Renal and urinary disorders
    Bladder spasm 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Dysuria 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 3 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Haematuria 1/6 (16.7%) 1 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Hydronephrosis 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 2 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Micturition urgency 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 1/7 (14.3%) 1 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Pollakiuria 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Proteinuria 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Urinary hesitation 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Urinary incontinence 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Urinary retention 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Urinary tract pain 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Reproductive system and breast disorders
    Vaginal haemorrhage 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Vulvovaginal discomfort 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Vulvovaginal dryness 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Vulvovaginal pain 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Allergic cough 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Cough 1/6 (16.7%) 1 0/4 (0%) 0 1/7 (14.3%) 1 1/7 (14.3%) 1 3/9 (33.3%) 3 1/3 (33.3%) 2 2/3 (66.7%) 2 2/6 (33.3%) 4 3/17 (17.6%) 3
    Dry throat 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Dysphonia 0/6 (0%) 0 2/4 (50%) 2 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/17 (11.8%) 2
    Dyspnoea 1/6 (16.7%) 2 0/4 (0%) 0 2/7 (28.6%) 3 0/7 (0%) 0 1/9 (11.1%) 2 0/3 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 2 4/17 (23.5%) 5
    Dyspnoea exertional 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Epistaxis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 1/6 (16.7%) 1 0/17 (0%) 0
    Haemoptysis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 3 0/17 (0%) 0
    Nasal congestion 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Nasal dryness 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Nasal inflammation 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Oropharyngeal pain 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 2/7 (28.6%) 2 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/17 (11.8%) 2
    Paranasal sinus hypersecretion 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Pleural effusion 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 2 0/17 (0%) 0
    Pleuritic pain 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Pneumonitis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 2
    Productive cough 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Rhinitis allergic 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Rhinorrhoea 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 1/17 (5.9%) 1
    Skin and subcutaneous tissue disorders
    Acne 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 2
    Alopecia 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Dermatitis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Dermatitis acneiform 1/6 (16.7%) 1 2/4 (50%) 2 5/7 (71.4%) 10 4/7 (57.1%) 6 3/9 (33.3%) 5 1/3 (33.3%) 1 1/3 (33.3%) 1 2/6 (33.3%) 2 6/17 (35.3%) 10
    Dry skin 3/6 (50%) 3 1/4 (25%) 1 2/7 (28.6%) 3 2/7 (28.6%) 2 1/9 (11.1%) 1 2/3 (66.7%) 2 1/3 (33.3%) 1 0/6 (0%) 0 6/17 (35.3%) 8
    Erythema 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Erythema annulare 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Exfoliative rash 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/17 (11.8%) 5
    Madarosis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Nail disorder 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Onychomadesis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Pain of skin 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Pigmentation disorder 0/6 (0%) 0 0/4 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Pruritus 2/6 (33.3%) 4 1/4 (25%) 1 2/7 (28.6%) 2 1/7 (14.3%) 2 2/9 (22.2%) 2 2/3 (66.7%) 2 1/3 (33.3%) 1 0/6 (0%) 0 7/17 (41.2%) 9
    Psoriasis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Rash 6/6 (100%) 9 3/4 (75%) 8 3/7 (42.9%) 5 1/7 (14.3%) 1 5/9 (55.6%) 9 3/3 (100%) 7 1/3 (33.3%) 1 4/6 (66.7%) 13 9/17 (52.9%) 20
    Rash generalised 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 2 0/17 (0%) 0
    Rash macular 1/6 (16.7%) 1 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/9 (11.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/17 (17.6%) 7
    Rash maculo-papular 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 0/6 (0%) 0 3/17 (17.6%) 7
    Rash papular 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/17 (11.8%) 2
    Scab 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/17 (0%) 0
    Skin erosion 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Skin fissures 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/17 (11.8%) 2
    Swelling face 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Urticaria 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/17 (0%) 0
    Vascular disorders
    Deep vein thrombosis 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/17 (0%) 0
    Flushing 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Hot flush 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/17 (5.9%) 1
    Hypertension 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 3/17 (17.6%) 3
    Hypotension 0/6 (0%) 0 0/4 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/9 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 2 1/17 (5.9%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission.

    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:
    NCT01021748
    Other Study ID Numbers:
    • 2206-010
    • 2009_698
    First Posted:
    Nov 30, 2009
    Last Update Posted:
    Aug 7, 2018
    Last Verified:
    Nov 1, 2017