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Study Evaluating Neratinib In Combination With Temsirolimus In Subjects With Solid Tumors

Sponsor
Puma Biotechnology, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT00838539
Collaborator
(none)
63
Enrollment
5
Locations
12
Arms
56
Actual Duration (Months)
12.6
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary purpose of this study is to identify the maximum tolerated dose(s) (MTD) of neratinib in combination with temsirolimus in subjects with solid tumors. This study will also include a preliminary evaluation of efficacy, and assessment of pharmacokinetic (PK) parameters of the combination.

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
63 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1 Study Of Neratinib In Combination With Temsirolimus In Subjects With Solid Tumors
Actual Study Start Date :
Apr 1, 2009
Actual Primary Completion Date :
Jun 1, 2011
Actual Study Completion Date :
Dec 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Experimental: Neratinib and Temsirolimus (Dose level 1)

Neratinib 120 mg and Temsirolimus 15 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen

Drug: Neratinib
Other Names:
  • HKI-272

    • Drug: Temsirolimus
    Other Names:
  • Torisel, CCI-779

    		•
    Experimental: Neratinib and Temsirolimus (Dose level 2)

    Neratinib 120 mg and Temsirolimus 25 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen

    Drug: Neratinib
    Other Names:
  • HKI-272

    • Drug: Temsirolimus
    Other Names:
  • Torisel, CCI-779

    		•
    Experimental: Neratinib and Temsirolimus (Dose level 3)

    Neratinib 120 mg and Temsirolimus 50 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen

    Drug: Neratinib
    Other Names:
  • HKI-272

    • Drug: Temsirolimus
    Other Names:
  • Torisel, CCI-779

    		•
    Experimental: Neratinib and Temsirolimus (Dose level 4)

    Neratinib 120 mg and Temsirolimus 75 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen

    Drug: Neratinib
    Other Names:
  • HKI-272

    • Drug: Temsirolimus
    Other Names:
  • Torisel, CCI-779

    		•
    Experimental: Neratinib and Temsirolimus (Dose level 5)

    Neratinib 160 mg and Temsirolimus 15 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen

    Drug: Neratinib
    Other Names:
  • HKI-272

    • Drug: Temsirolimus
    Other Names:
  • Torisel, CCI-779

    		•
    Experimental: Neratinib and Temsirolimus (Dose level 6)

    Neratinib 160 mg and Temsirolimus 25 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen

    Drug: Neratinib
    Other Names:
  • HKI-272

    • Drug: Temsirolimus
    Other Names:
  • Torisel, CCI-779

    		•
    Experimental: Neratinib and Temsirolimus (Dose level 7)

    Neratinib 160 mg and Temsirolimus 50 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen

    Drug: Neratinib
    Other Names:
  • HKI-272

    • Drug: Temsirolimus
    Other Names:
  • Torisel, CCI-779

    		•
    Experimental: Neratinib and Temsirolimus (Dose level 8)

    Neratinib 160 mg and Temsirolimus 75 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen

    Drug: Neratinib
    Other Names:
  • HKI-272

    • Drug: Temsirolimus
    Other Names:
  • Torisel, CCI-779

    		•
    Experimental: Neratinib and Temsirolimus (Dose level 9)

    Neratinib 200 mg and Temsirolimus 15 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen

    Drug: Neratinib
    Other Names:
  • HKI-272

    • Drug: Temsirolimus
    Other Names:
  • Torisel, CCI-779

    		•
    Experimental: Neratinib and Temsirolimus (Dose level 10)

    Neratinib 200 mg and Temsirolimus 25 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen

    Drug: Neratinib
    Other Names:
  • HKI-272

    • Drug: Temsirolimus
    Other Names:
  • Torisel, CCI-779

    		•
    Experimental: Neratinib and Temsirolimus (Dose level 11)

    Neratinib 200 mg and Temsirolimus 50 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen

    Drug: Neratinib
    Other Names:
  • HKI-272

    • Drug: Temsirolimus
    Other Names:
  • Torisel, CCI-779

    		•
    Experimental: Neratinib and Temsirolimus (Dose level 12)

    Neratinib 240 mg and Temsirolimus 15 mg: Neratinib 40 mg tablets administered orally daily for as long as tolerated and the disease under study does not worsen. Temsirolimus administered intravenously once weekly for as long as tolerated and the disease under study does not worsen

    Drug: Neratinib
    Other Names:
  • HKI-272

    • Drug: Temsirolimus
    Other Names:
  • Torisel, CCI-779

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Probability of Dose-Limiting Toxicity (DLT) [From first dose date to day 28]

      A DLT was defined as any dose-limiting Adverse Event related to neratinib + Temsirolimus as Grade 3 or higher nonhematologic toxicity (except neutropenia) or Grade 3 or higher diarrhea lasting >2 days with optimal antidiarrheal therapy etc.

    2. Maximum Tolerated Dose (MTD) of Neratinib in Combination With Temsirolimus [From first dose date to day 28]

      Identification of the daily neratinib high-dose MTD in combination with weekly temsirolimus.

    3. Maximum Tolerated Dose (MTD) of Temsirolimus in Combination With Neratinib [From first dose date to day 28]

      Identification of the weekly temsirolimus high-dose MTD in combination with daily neratinib

    4. Adverse Events Causing Dose Limiting Toxicities [From first dose date to day 21]

      A DLT was defined as any dose-limiting adverse event (AE) related to neratinib + TEMSR as follows: [1] Grade 3 or 4 nonhematologic toxicity (Grade 3 or 4 nausea, vomiting, hyperglycemia, hypophosphatemia, hypertriglyceridemia, or hypercholesterolemia was not considered a DLT unless the subject was already receiving optimal medical therapy). [2] Grade 3 or 4 diarrhea lasting >2 days while subject was on optimal vigorous antidiarrheal therapy. [3] Grade 4 neutropenia lasting >3 days or Grade 3 or 4 neutropenia of any duration with sepsis or a fever >38.5C. [4] Platelet value less than or equal to 25,000/mm3 or bleeding requiring a platelet transfusion. [5] Delayed recovery from toxicity, which delayed rescheduled re-treatment for >3 weeks. [6] Inability to maintain the original dose during the first 28 days of treatment (at least 21 doses of neratinib and 2 doses of TEMSR at the original specified dose) due to treatment-related toxicity.

    Secondary Outcome Measures

    1. Best Overall Response [From first dose date to progression/death or last tumor assessment, up to 30 months]

      The best overall response was described using the data as reported by study center investigators per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

    2. Clinical Benefit Rate [From first dose date to progression/death or last tumor assessment, up to 30 months]

      Percentage of subjects with a complete response, partial response, or stable disease >= 24 weeks, as determined by investigator assessment per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

    3. Objective Response Rate [From first dose date to progression/death or last tumor assessment, up to 30 months]

      Percentage of subjects with a complete response (CR) or partial response (PR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

    4. Area Under the Curve Tau [Week 4]

      Area Under the Curve tau of neratinib concentrations, collected at 2, 4, 8, and 24 hours post-neratinib administration, at the week 4 dose.

    Eligibility Criteria

    Criteria

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

    • Pathologic diagnosis of advanced or metastatic solid tumor.

    • Measurable disease per Response Criteria in Solid Tumors (RECIST criteria).

    • Incurable cancer, with disease progression following at least 1 conventional or standard therapy for locally advanced or metastatic disease.

    • Negative pregnancy test for women of child bearing potential.

    Exclusion Criteria:

    • Chronic treatment with corticosteroids.

    • Primary central nervous system (CNS) tumors and active metastases.

    • Presence of clinically significant or uncontrolled cardiac disease.

    • Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom.

    • Symptomatic or prior history of non-infectious interstitial pneumonitis.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Massachusetts General Hospital Boston Massachusetts United States 02114
    2 Beth Israel Deaconess Medical Center Boston Massachusetts United States 02115
    3 Beth Israel Deaconess Medical Center Boston Massachusetts United States 02215
    4 Dana Farber Cancer Institute Boston Massachusetts United States 02215
    5 Institut Gustave Roussy Villejuif France 94805

    Sponsors and Collaborators

    • Puma Biotechnology, Inc.

    Investigators

    • Study Director: Puma, Biotechnology

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Puma Biotechnology, Inc.
    ClinicalTrials.gov Identifier:
    NCT00838539
    Other Study ID Numbers:
    • 3144A1-2205 / B1891016
    First Posted:
    Feb 6, 2009
    Last Update Posted:
    Sep 18, 2018
    Last Verified:
    Aug 1, 2018
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Puma Biotechnology, Inc.
    Neratinib
    solid tumors
    phase 1
    dose finding study
    HKI-272
    Nerlynx
    Temsirolimus
    PB-272
    Additional relevant MeSH terms:
    Sirolimus

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title N120 + T15 N120 + T25 N120 + T50 N120 + T75 N160 + T15 N160 + T25 N160 + T50 N160 + T75 N200 + T15 N200 + T25 N200 + T50 N240 + T15
    Arm/Group Description Neratinib 120 mg + Temsirolimus 15 mg Neratinib 120 mg + Temsirolimus 25 mg Neratinib 120 mg + Temsirolimus 50 mg Neratinib 120 mg + Temsirolimus 75 mg Neratinib 160 mg + Temsirolimus 15 mg Neratinib 160 mg + Temsirolimus 25 mg Neratinib 160 mg + Temsirolimus 50 mg Neratinib 160 mg + Temsirolimus 75 mg Neratinib 200 mg + Temsirolimus 15 mg Neratinib 200 mg + Temsirolimus 25 mg Neratinib 200 mg + Temsirolimus 50 mg Neratinib 240 mg + Temsirolimus 15 mg
    Period Title: Overall Study
    STARTED 3 6 5 4 6 4 7 6 5 8 5 4
    Received Treatment 3 5 5 4 4 4 7 6 5 8 5 4
    COMPLETED 0 0 0 0 0 0 2 0 0 0 0 0
    NOT COMPLETED 3 6 5 4 6 4 5 6 5 8 5 4

    Baseline Characteristics

    Arm/Group Title N120 + T15 N120 + T25 N120 + T50 N120 + T75 N160 + T15 N160 + T25 N160 + T50 N160 + T75 N200 + T15 N200 + T25 N200 + T50 N240 + T15 Total
    Arm/Group Description Neratinib 120 mg qd + Temsirolimus 15 mg, IV, weekly Neratinib 120 mg qd + Temsirolimus 25 mg, IV, weekly Neratinib 120 mg qd + Temsirolimus 50 mg, IV, weekly Neratinib 120 mg qd + Temsirolimus 75mg, IV, weekly Neratinib 160 mg qd + Temsirolimus 15 mg, IV, weekly Neratinib 160 mg qd + Temsirolimus 25 mg, IV, weekly Neratinib 160 mg qd + Temsirolimus 50 mg, IV, weekly Neratinib 160 mg qd + Temsirolimus 75 mg, IV, weekly Neratinib 200 mg qd + Temsirolimus 15 mg, IV, weekly Neratinib 200 mg qd + Temsirolimus 25 mg, IV, weekly Neratinib 200 mg qd + Temsirolimus 50 mg, IV, weekly Neratinib 240 mg qd + Temsirolimus 15 mg, IV, weekly Total of all reporting groups
    Overall Participants 3 5 5 4 4 4 7 6 5 8 5 4 60
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    2
    66.7%
    4
    80%
    4
    80%
    4
    100%
    4
    100%
    4
    100%
    6
    85.7%
    5
    83.3%
    3
    60%
    7
    87.5%
    5
    100%
    4
    100%
    52
    86.7%
    >=65 years
    1
    33.3%
    1
    20%
    1
    20%
    0
    0%
    0
    0%
    0
    0%
    1
    14.3%
    1
    16.7%
    2
    40%
    1
    12.5%
    0
    0%
    0
    0%
    8
    13.3%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    50.00
    (26.15)
    58.60
    (10.26)
    43.00
    (16.40)
    49.50
    (7.94)
    49.75
    (4.79)
    49.75
    (5.68)
    49.29
    (12.20)
    53.17
    (11.62)
    59.60
    (10.62)
    44.50
    (18.72)
    50.00
    (7.00)
    56.75
    (5.74)
    50.82
    (12.70)
    Sex: Female, Male (Count of Participants)
    Female
    1
    33.3%
    3
    60%
    1
    20%
    4
    100%
    3
    75%
    4
    100%
    4
    57.1%
    5
    83.3%
    4
    80%
    3
    37.5%
    4
    80%
    4
    100%
    40
    66.7%
    Male
    2
    66.7%
    2
    40%
    4
    80%
    0
    0%
    1
    25%
    0
    0%
    3
    42.9%
    1
    16.7%
    1
    20%
    5
    62.5%
    1
    20%
    0
    0%
    20
    33.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    20%
    1
    25%
    2
    3.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    0
    0%
    1
    1.7%
    White
    1
    33.3%
    3
    60%
    2
    40%
    1
    25%
    1
    25%
    3
    75%
    4
    57.1%
    3
    50%
    2
    40%
    2
    25%
    3
    60%
    1
    25%
    26
    43.3%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    2
    66.7%
    2
    40%
    3
    60%
    3
    75%
    3
    75%
    1
    25%
    3
    42.9%
    3
    50%
    3
    60%
    5
    62.5%
    1
    20%
    2
    50%
    31
    51.7%

    Outcome Measures

    1. Primary Outcome
    Title Probability of Dose-Limiting Toxicity (DLT)
    Description A DLT was defined as any dose-limiting Adverse Event related to neratinib + Temsirolimus as Grade 3 or higher nonhematologic toxicity (except neutropenia) or Grade 3 or higher diarrhea lasting >2 days with optimal antidiarrheal therapy etc.
    Time Frame From first dose date to day 28

    Outcome Measure Data

    Analysis Population Description
    Evaluable subjects for the Maximum Tolerated Dose (MTD) contour estimation were those who either experienced a DLT within the first 28 days, regardless of the number of doses of treatment received, or received at least 21 doses of neratinib and at least 2 doses of Temsirolimus in the first 28 days of treatment.
    Arm/Group Title Neratinib 120 mg Neratinib 160 mg Neratinib 200 mg Neratinib 240 mg
    Arm/Group Description Neratinib 120 mg/day with indicated level of Temsirolimus, weekly, IV. Neratinib 160 mg/day with indicated level of Temsirolimus, weekly, IV. Neratinib 200 mg/day with indicated level of Temsirolimus, weekly, IV. Neratinib 240 mg/day with indicated level of Temsirolimus, weekly, IV.
    Measure Participants 14 20 13 4
    Temsirolimus 15 mg
    0
    12.5
    12.5
    50
    Temsirolimus 25 mg
    13.63
    13.64
    12.5
    Temsirolimus 50 mg
    13.63
    13.64
    100
    Temsirolimus 75 mg
    13.63
    50
    2. Primary Outcome
    Title Maximum Tolerated Dose (MTD) of Neratinib in Combination With Temsirolimus
    Description Identification of the daily neratinib high-dose MTD in combination with weekly temsirolimus.
    Time Frame From first dose date to day 28

    Outcome Measure Data

    Analysis Population Description
    Evaluable subjects were those that either experienced a dose limiting toxicity within the first 28 days, regardless of the number of doses of treatment received, or those that received at least 21 doses of neratinib and at least 2 doses of Temsirolimus in the first 28 days of treatment at the original dose level prescribed.
    Arm/Group Title MTD Ner With TEMS
    Arm/Group Description Neratinib MTD in combination with Temsirolimus
    Measure Participants 51
    Number [mg]
    200
    3. Primary Outcome
    Title Maximum Tolerated Dose (MTD) of Temsirolimus in Combination With Neratinib
    Description Identification of the weekly temsirolimus high-dose MTD in combination with daily neratinib
    Time Frame From first dose date to day 28

    Outcome Measure Data

    Analysis Population Description
    Evaluable subjects include those that either experienced a dose limiting toxicity within the first 28 days, regardless of the number of doses of treatment received, or those that received at least 21 doses of neratinib and at least 2 doses of Temsirolimus in the first 28 days of treatment at the original dose level prescribed.
    Arm/Group Title MTD TEMS With Ner
    Arm/Group Description Temsirolimus MTD in combination with Neratinib
    Measure Participants 51
    Number [mg]
    50
    4. Primary Outcome
    Title Adverse Events Causing Dose Limiting Toxicities
    Description A DLT was defined as any dose-limiting adverse event (AE) related to neratinib + TEMSR as follows: [1] Grade 3 or 4 nonhematologic toxicity (Grade 3 or 4 nausea, vomiting, hyperglycemia, hypophosphatemia, hypertriglyceridemia, or hypercholesterolemia was not considered a DLT unless the subject was already receiving optimal medical therapy). [2] Grade 3 or 4 diarrhea lasting >2 days while subject was on optimal vigorous antidiarrheal therapy. [3] Grade 4 neutropenia lasting >3 days or Grade 3 or 4 neutropenia of any duration with sepsis or a fever >38.5C. [4] Platelet value less than or equal to 25,000/mm3 or bleeding requiring a platelet transfusion. [5] Delayed recovery from toxicity, which delayed rescheduled re-treatment for >3 weeks. [6] Inability to maintain the original dose during the first 28 days of treatment (at least 21 doses of neratinib and 2 doses of TEMSR at the original specified dose) due to treatment-related toxicity.
    Time Frame From first dose date to day 21

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title N120 + T15 N120 + T25 N120 + T50 N120 + T75 N160 + T15 N160 + T25 N160 + T50 N160 + T75 N200 + T15 N200 + T25 N200 + T50 N240 + T15
    Arm/Group Description Neratinib 120 mg qd + Temsirolimus 15 mg, IV, weekly Neratinib 120 mg qd + Temsirolimus 25 mg, IV, weekly Neratinib 120 mg qd + Temsirolimus 50 mg, IV, weekly Neratinib 120 mg qd + Temsirolimus 75mg, IV, weekly Neratinib 160 mg qd + Temsirolimus 15 mg, IV, weekly Neratinib 160 mg qd + Temsirolimus 25 mg, IV, weekly Neratinib 160 mg qd + Temsirolimus 50 mg, IV, weekly Neratinib 160 mg qd + Temsirolimus 75 mg, IV, weekly Neratinib 200 mg qd + Temsirolimus 15 mg, IV, weekly Neratinib 200 mg qd + Temsirolimus 25 mg, IV, weekly Neratinib 200 mg qd + Temsirolimus 50 mg, IV, weekly Neratinib 240 mg qd + Temsirolimus 15 mg, IV, weekly
    Measure Participants 3 5 5 4 4 4 7 6 5 8 5 4
    Count of Participants [Participants]
    0
    0%
    1
    20%
    1
    20%
    0
    0%
    1
    25%
    1
    25%
    0
    0%
    3
    50%
    0
    0%
    1
    12.5%
    1
    20%
    2
    50%
    5. Secondary Outcome
    Title Best Overall Response
    Description The best overall response was described using the data as reported by study center investigators per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
    Time Frame From first dose date to progression/death or last tumor assessment, up to 30 months

    Outcome Measure Data

    Analysis Population Description
    Subjects who completed at least 1 tumor assessment post-baseline after starting treatment and received sufficient drug (>= 21 doses of neratinib and >= 2 doses of temsirolimus in the first 28 days unless the subject discontinued treatment early for documented progression or symptomatic deterioration after taking at least 1 dose of test article[s])
    Arm/Group Title Neratinib 120 mg + Temsirolimus Neratinib 160 mg + Temsirolimus Neratinib 200 mg + Temsirolimus Neratinib 240 mg + Temsirolimus
    Arm/Group Description Neratinib 120 mg, qd, with various dose levels of temsirolimus, IV, once weekly. Neratinib 160 mg, qd, with various dose levels of temsirolimus, IV, once weekly. Neratinib 200 mg, qd, with various dose levels of temsirolimus, IV, once weekly. Neratinib 240 mg, qd, with various dose levels of temsirolimus, IV, once weekly.
    Measure Participants 13 18 10 4
    Complete Response
    1
    33.3%
    0
    0%
    1
    20%
    0
    0%
    Partial Response
    1
    33.3%
    3
    60%
    1
    20%
    1
    25%
    Stable Disease
    8
    266.7%
    11
    220%
    6
    120%
    1
    25%
    Progressive Disease
    3
    100%
    3
    60%
    2
    40%
    1
    25%
    Unknown
    0
    0%
    1
    20%
    0
    0%
    1
    25%
    6. Secondary Outcome
    Title Clinical Benefit Rate
    Description Percentage of subjects with a complete response, partial response, or stable disease >= 24 weeks, as determined by investigator assessment per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
    Time Frame From first dose date to progression/death or last tumor assessment, up to 30 months

    Outcome Measure Data

    Analysis Population Description
    Subjects who completed at least 1 tumor assessment post-baseline after starting treatment and received sufficient drug (>= 21 doses of neratinib and >= 2 doses of temsirolimus in the first 28 days unless the subject discontinued treatment early for documented progression or symptomatic deterioration after taking at least 1 dose of test article[s]).
    Arm/Group Title Neratinib 120 mg + Temsirolimus Neratinib 160 mg + Temsirolimus Neratinib 200 mg + Temsirolimus Neratinib 240 mg + Temsirolimus
    Arm/Group Description Neratinib 120 mg, qd, with various dose levels of temsirolimus, IV, once weekly. Neratinib 160 mg, qd, with various dose levels of temsirolimus, IV, once weekly. Neratinib 200 mg, qd, with various dose levels of temsirolimus, IV, once weekly. Neratinib 240 mg, qd, with various dose levels of temsirolimus, IV, once weekly.
    Measure Participants 13 18 10 4
    Number (95% Confidence Interval) [percentage of participants]
    38.5
    1283.3%
    27.8
    556%
    20.0
    400%
    25.0
    625%
    7. Secondary Outcome
    Title Objective Response Rate
    Description Percentage of subjects with a complete response (CR) or partial response (PR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
    Time Frame From first dose date to progression/death or last tumor assessment, up to 30 months

    Outcome Measure Data

    Analysis Population Description
    Subjects who completed at least 1 tumor assessment post-baseline after starting treatment and received sufficient drug (>= 21 doses of neratinib and >= 2 doses of Temsirolimus in the first 28 days unless the subject discontinued treatment early for documented progression or symptomatic deterioration after taking at least 1 dose of test article[s])
    Arm/Group Title Neratinib 120 mg + Temsirolimus Neratinib 160 mg + Temsirolimus Neratinib 200 mg + Temsirolimus Neratinib 240 mg + Temsirolimus
    Arm/Group Description Neratinib 120 mg, qd, with various dose levels of temsirolimus, IV, once weekly. Neratinib 160 mg, qd, with various dose levels of temsirolimus, IV, once weekly. Neratinib 200 mg, qd, with various dose levels of temsirolimus, IV, once weekly. Neratinib 240 mg, qd, with various dose levels of temsirolimus, IV, once weekly.
    Measure Participants 13 18 10 4
    Number (95% Confidence Interval) [percentage of participants]
    15.4
    513.3%
    16.7
    334%
    20.0
    400%
    25.0
    625%
    8. Secondary Outcome
    Title Area Under the Curve Tau
    Description Area Under the Curve tau of neratinib concentrations, collected at 2, 4, 8, and 24 hours post-neratinib administration, at the week 4 dose.
    Time Frame Week 4

    Outcome Measure Data

    Analysis Population Description
    Subjects who had pharmacokinetic concentrations available at the dose combination, at day 22.
    Arm/Group Title Temsirolimus 15 mg Temsirolimus 25 mg Temsirolimus 50 mg Temsirolums 75 mg
    Arm/Group Description Neratinib at indicated dose levels with Temsirolimus 15 mg, IV, once weekly Neratinib at indicated dose levels with Temsirolimus 15 mg, IV, once weekly Neratinib at indicated dose levels with Temsirolimus 50 mg, IV, once weekly Neratinib at indicated dose levels with Temsirolimus 75 mg, IV, once weekly
    Measure Participants 11 15 11 9
    Neratinib 120 mg
    390.65
    621.20
    408.98
    477.37
    Neratinib 160 mg
    1146.53
    775.89
    640.36
    753.47
    Neratinib 200 mg
    1396.48
    357.30
    963.19
    NA
    Neratinib 240 mg
    1402.37
    NA
    NA
    NA

    Adverse Events

    Time Frame From first dose through 28 days after last dose, up to 30 months.
    Adverse Event Reporting Description
    Arm/Group Title N120 + T15 N120 + T25 N120 + T50 N120 + T75 N160 + T15 N160 + T25 N160 + T50 N160 + T75 N200 + T15 N200 + T25 N200 + T50 N240 + T15
    Arm/Group Description Neratinib 120 mg qd + Temsirolimus 15 mg, IV, weekly Neratinib 120 mg qd + Temsirolimus 25 mg, IV, weekly Neratinib 120 mg qd + Temsirolimus 50 mg, IV, weekly Neratinib 120 mg qd + Temsirolimus 75 mg, IV, weekly Neratinib 160 mg qd + Temsirolimus 15 mg, IV, weekly Neratinib 160 mg qd + Temsirolimus 25 mg, IV, weekly Neratinib 160 mg qd + Temsirolimus 50 mg, IV, weekly Neratinib 160 mg qd + Temsirolimus 75 mg, IV, weekly Neratinib 200 mg qd + Temsirolimus 15 mg, IV, weekly Neratinib 200 mg qd + Temsirolimus 25 mg, IV, weekly Neratinib 200 mg qd + Temsirolimus 50 mg, IV, weekly Neratinib 240 mg qd + Temsirolimus 15 mg, IV, weekly
    All Cause Mortality
    N120 + T15 N120 + T25 N120 + T50 N120 + T75 N160 + T15 N160 + T25 N160 + T50 N160 + T75 N200 + T15 N200 + T25 N200 + T50 N240 + T15
    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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    N120 + T15 N120 + T25 N120 + T50 N120 + T75 N160 + T15 N160 + T25 N160 + T50 N160 + T75 N200 + T15 N200 + T25 N200 + T50 N240 + T15
    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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/3 (33.3%) 2/6 (33.3%) 1/5 (20%) 1/4 (25%) 3/6 (50%) 2/4 (50%) 5/7 (71.4%) 3/6 (50%) 4/5 (80%) 5/8 (62.5%) 3/5 (60%) 3/4 (75%)
    Blood and lymphatic system disorders
    Anaemia 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Thrombocytopenia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Cardiac disorders
    Supraventricular tachycardia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Congenital, familial and genetic disorders
    Aplasia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Gastrointestinal disorders
    Abdominal pain 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 2/5 (40%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Colitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Diarrhoea 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 2/6 (33.3%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 1/4 (25%)
    Gastritis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Ileus 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Nausea 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Proctalgia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Proctitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Stomatitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Subileus 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Vomiting 1/3 (33.3%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    General disorders
    Mucosal inflammation 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Pyrexia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Hepatobiliary disorders
    Hepatocellular injury 1/3 (33.3%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Infections and infestations
    Device related infection 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Infection 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Lobar pneumonia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Lung abscess 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Lymphangitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Meningitis bacterial 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Oral herpes 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Pneumonia 0/3 (0%) 1/6 (16.7%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Pyelonephritis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Pyelonephritis acute 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Urinary tract infection 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Injury, poisoning and procedural complications
    Overdose 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Investigations
    International normalised ratio increased 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Metabolism and nutrition disorders
    Dehydration 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Hypertriglyceridaemia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Hypokalaemia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 2/4 (50%)
    Hypophosphataemia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Musculoskeletal and connective tissue disorders
    Back pain 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Hypercreatinaemia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Rhabdomyolysis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer metastatic 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Nervous system disorders
    Cerebral ischaemia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Convulsion 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Hemianopia homonymous 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Hypoaesthesia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Radiculopathy 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Renal and urinary disorders
    Renal tubular necrosis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Urinary retention 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 2/6 (33.3%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Epistaxis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Hypoxia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Pneumonitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Pulmonary embolism 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Pulmonary hypertension 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Vascular disorders
    Deep vein thrombosis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Venous thrombosis limb 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Other (Not Including Serious) Adverse Events
    N120 + T15 N120 + T25 N120 + T50 N120 + T75 N160 + T15 N160 + T25 N160 + T50 N160 + T75 N200 + T15 N200 + T25 N200 + T50 N240 + T15
    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 Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/3 (100%) 5/6 (83.3%) 5/5 (100%) 4/4 (100%) 4/6 (66.7%) 4/4 (100%) 7/7 (100%) 6/6 (100%) 5/5 (100%) 8/8 (100%) 5/5 (100%) 4/4 (100%)
    Blood and lymphatic system disorders
    Anaemia 0/3 (0%) 3/6 (50%) 3/5 (60%) 2/4 (50%) 3/6 (50%) 3/4 (75%) 4/7 (57.1%) 4/6 (66.7%) 2/5 (40%) 2/8 (25%) 2/5 (40%) 3/4 (75%)
    Hypoprothrombinaemia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Leukocytosis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Leukopenia 0/3 (0%) 3/6 (50%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 2/7 (28.6%) 1/6 (16.7%) 2/5 (40%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%)
    Lymphopenia 1/3 (33.3%) 1/6 (16.7%) 0/5 (0%) 2/4 (50%) 1/6 (16.7%) 0/4 (0%) 2/7 (28.6%) 0/6 (0%) 2/5 (40%) 2/8 (25%) 0/5 (0%) 1/4 (25%)
    Neutropenia 0/3 (0%) 3/6 (50%) 2/5 (40%) 1/4 (25%) 2/6 (33.3%) 1/4 (25%) 3/7 (42.9%) 1/6 (16.7%) 2/5 (40%) 1/8 (12.5%) 3/5 (60%) 0/4 (0%)
    Thrombocytopenia 0/3 (0%) 2/6 (33.3%) 2/5 (40%) 2/4 (50%) 0/6 (0%) 1/4 (25%) 3/7 (42.9%) 3/6 (50%) 3/5 (60%) 4/8 (50%) 4/5 (80%) 2/4 (50%)
    Cardiac disorders
    Mitral valve incompetence 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Tachycardia 0/3 (0%) 0/6 (0%) 1/5 (20%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Ventricular hypokinesia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Ear and labyrinth disorders
    Ear pain 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Ear pruritus 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Tinnitus 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 2/7 (28.6%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Vertigo 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 2/4 (50%)
    Eye disorders
    Cataract 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Diplopia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Dry eye 0/3 (0%) 1/6 (16.7%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Eye irritation 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Eyelid function disorder 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Eyelid oedema 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Keratitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Ocular hyperaemia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Visual impairment 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Vitreous floaters 1/3 (33.3%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Gastrointestinal disorders
    Abdominal distension 0/3 (0%) 2/6 (33.3%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Abdominal pain 2/3 (66.7%) 2/6 (33.3%) 2/5 (40%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 2/7 (28.6%) 0/6 (0%) 1/5 (20%) 2/8 (25%) 0/5 (0%) 0/4 (0%)
    Abdominal pain lower 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Abdominal pain upper 0/3 (0%) 2/6 (33.3%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 1/4 (25%) 2/7 (28.6%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Aerophagia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Anorectal discomfort 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Aphthous stomatitis 0/3 (0%) 1/6 (16.7%) 2/5 (40%) 2/4 (50%) 3/6 (50%) 1/4 (25%) 1/7 (14.3%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Chapped lips 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Cheilitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Colitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Constipation 0/3 (0%) 3/6 (50%) 1/5 (20%) 1/4 (25%) 2/6 (33.3%) 1/4 (25%) 1/7 (14.3%) 2/6 (33.3%) 2/5 (40%) 5/8 (62.5%) 0/5 (0%) 1/4 (25%)
    Diarrhoea 3/3 (100%) 5/6 (83.3%) 5/5 (100%) 4/4 (100%) 3/6 (50%) 4/4 (100%) 7/7 (100%) 5/6 (83.3%) 5/5 (100%) 6/8 (75%) 4/5 (80%) 4/4 (100%)
    Distal ileal obstruction syndrome 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Dry mouth 0/3 (0%) 1/6 (16.7%) 1/5 (20%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 2/8 (25%) 0/5 (0%) 0/4 (0%)
    Dyspepsia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Dysphagia 1/3 (33.3%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Epigastric discomfort 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Gastrooesophageal reflux disease 0/3 (0%) 2/6 (33.3%) 0/5 (0%) 1/4 (25%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Gingival bleeding 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Glossodynia 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Haematochezia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Haemorrhoids 0/3 (0%) 2/6 (33.3%) 2/5 (40%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 1/7 (14.3%) 1/6 (16.7%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Lip dry 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Lip pain 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Mouth ulceration 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Nausea 2/3 (66.7%) 3/6 (50%) 2/5 (40%) 3/4 (75%) 2/6 (33.3%) 3/4 (75%) 5/7 (71.4%) 2/6 (33.3%) 5/5 (100%) 4/8 (50%) 2/5 (40%) 3/4 (75%)
    Odynophagia 0/3 (0%) 0/6 (0%) 1/5 (20%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Oesophageal pain 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Oral mucosal erythema 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Oral pain 0/3 (0%) 1/6 (16.7%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Proctalgia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Rectal haemorrhage 1/3 (33.3%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Salivary hypersecretion 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Stomatitis 2/3 (66.7%) 2/6 (33.3%) 3/5 (60%) 3/4 (75%) 2/6 (33.3%) 2/4 (50%) 3/7 (42.9%) 3/6 (50%) 2/5 (40%) 5/8 (62.5%) 3/5 (60%) 2/4 (50%)
    Subileus 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Toothache 0/3 (0%) 0/6 (0%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Vomiting 0/3 (0%) 3/6 (50%) 1/5 (20%) 3/4 (75%) 2/6 (33.3%) 2/4 (50%) 5/7 (71.4%) 2/6 (33.3%) 4/5 (80%) 4/8 (50%) 1/5 (20%) 4/4 (100%)
    General disorders
    Asthenia 2/3 (66.7%) 2/6 (33.3%) 2/5 (40%) 2/4 (50%) 3/6 (50%) 1/4 (25%) 3/7 (42.9%) 3/6 (50%) 3/5 (60%) 5/8 (62.5%) 1/5 (20%) 2/4 (50%)
    Catheter site haemorrhage 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Catheter site pain 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Chest discomfort 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Chest pain 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Chills 0/3 (0%) 0/6 (0%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Fatigue 1/3 (33.3%) 3/6 (50%) 2/5 (40%) 0/4 (0%) 2/6 (33.3%) 2/4 (50%) 4/7 (57.1%) 0/6 (0%) 1/5 (20%) 2/8 (25%) 1/5 (20%) 1/4 (25%)
    Granuloma 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Inflammation 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Influenza like illness 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Local swelling 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Malaise 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Mucosal inflammation 0/3 (0%) 2/6 (33.3%) 3/5 (60%) 0/4 (0%) 3/6 (50%) 2/4 (50%) 4/7 (57.1%) 3/6 (50%) 2/5 (40%) 1/8 (12.5%) 1/5 (20%) 3/4 (75%)
    Non-cardiac chest pain 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Oedema 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Oedema peripheral 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 1/4 (25%) 2/7 (28.6%) 1/6 (16.7%) 1/5 (20%) 1/8 (12.5%) 0/5 (0%) 1/4 (25%)
    Pyrexia 0/3 (0%) 3/6 (50%) 3/5 (60%) 2/4 (50%) 3/6 (50%) 1/4 (25%) 4/7 (57.1%) 0/6 (0%) 2/5 (40%) 5/8 (62.5%) 1/5 (20%) 1/4 (25%)
    Thrombosis in device 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Xerosis 0/3 (0%) 0/6 (0%) 1/5 (20%) 0/4 (0%) 2/6 (33.3%) 1/4 (25%) 2/7 (28.6%) 1/6 (16.7%) 0/5 (0%) 2/8 (25%) 0/5 (0%) 1/4 (25%)
    Hepatobiliary disorders
    Hepatocellular injury 1/3 (33.3%) 1/6 (16.7%) 1/5 (20%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 2/7 (28.6%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Hepatotoxicity 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 1/5 (20%) 1/4 (25%)
    Hyperbilirubinaemia 1/3 (33.3%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Immune system disorders
    Hypogammaglobulinaemia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Infections and infestations
    Botryomycosis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Bronchitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 1/4 (25%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Candida infection 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Clostridium difficile colitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Conjunctivitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Cystitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Ear infection 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 2/8 (25%) 0/5 (0%) 0/4 (0%)
    Ecthyma 0/3 (0%) 0/6 (0%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Erysipeloid 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Folliculitis 0/3 (0%) 1/6 (16.7%) 2/5 (40%) 1/4 (25%) 3/6 (50%) 1/4 (25%) 2/7 (28.6%) 3/6 (50%) 0/5 (0%) 5/8 (62.5%) 1/5 (20%) 0/4 (0%)
    Gastroenteritis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Genital herpes 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Gingivitis 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Herpes pharyngitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Herpes virus infection 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Hordeolum 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Infection 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Laryngitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Localised infection 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Lung infection 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Lymphangitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Nasopharyngitis 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 1/4 (25%) 1/6 (16.7%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Oral candidiasis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Oral herpes 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 1/6 (16.7%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Paronychia 1/3 (33.3%) 3/6 (50%) 1/5 (20%) 1/4 (25%) 2/6 (33.3%) 1/4 (25%) 1/7 (14.3%) 2/6 (33.3%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 1/4 (25%)
    Pharyngitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Pneumonia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Pyelonephritis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Rash pustular 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Rhinitis 0/3 (0%) 1/6 (16.7%) 2/5 (40%) 1/4 (25%) 1/6 (16.7%) 1/4 (25%) 2/7 (28.6%) 1/6 (16.7%) 0/5 (0%) 3/8 (37.5%) 0/5 (0%) 0/4 (0%)
    Sinusitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 2/7 (28.6%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Tonsillitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 2/8 (25%) 0/5 (0%) 0/4 (0%)
    Tooth abscess 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Tooth infection 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Urinary tract infection 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 1/4 (25%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 2/8 (25%) 0/5 (0%) 0/4 (0%)
    Vaginal infection 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Vulvovaginal mycotic infection 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Injury, poisoning and procedural complications
    Contusion 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Cystitis radiation 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Eye injury 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Infusion related reaction 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Rib fracture 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Investigations
    Activated partial thromboplastin time prolonged 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Alanine aminotransferase increased 0/3 (0%) 0/6 (0%) 3/5 (60%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 2/7 (28.6%) 3/6 (50%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Amylase increased 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Aspartate aminotransferase increased 0/3 (0%) 0/6 (0%) 2/5 (40%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 2/7 (28.6%) 3/6 (50%) 2/5 (40%) 1/8 (12.5%) 2/5 (40%) 1/4 (25%)
    Blood alkaline phosphatase increased 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 1/6 (16.7%) 2/5 (40%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Blood bicarbonate decreased 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Blood cholesterol increased 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Blood creatine phosphokinase 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Blood creatine phosphokinase increased 1/3 (33.3%) 1/6 (16.7%) 0/5 (0%) 1/4 (25%) 1/6 (16.7%) 1/4 (25%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 2/8 (25%) 0/5 (0%) 0/4 (0%)
    Blood creatinine increased 0/3 (0%) 0/6 (0%) 2/5 (40%) 0/4 (0%) 1/6 (16.7%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Blood magnesium decreased 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Blood triglycerides increased 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 2/5 (40%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Cardiac murmur 1/3 (33.3%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Chest X-ray abnormal 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Gamma-glutamyltransferase increased 0/3 (0%) 0/6 (0%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Haemoglobin decreased 0/3 (0%) 1/6 (16.7%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 2/7 (28.6%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    International normalised ratio increased 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Lipase increased 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Platelet count decreased 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 2/7 (28.6%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Troponin increased 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Weight decreased 1/3 (33.3%) 0/6 (0%) 2/5 (40%) 0/4 (0%) 2/6 (33.3%) 0/4 (0%) 2/7 (28.6%) 0/6 (0%) 0/5 (0%) 2/8 (25%) 0/5 (0%) 1/4 (25%)
    White blood cell count decreased 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 1/7 (14.3%) 1/6 (16.7%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 2/3 (66.7%) 3/6 (50%) 0/5 (0%) 3/4 (75%) 1/6 (16.7%) 2/4 (50%) 5/7 (71.4%) 2/6 (33.3%) 3/5 (60%) 3/8 (37.5%) 0/5 (0%) 2/4 (50%)
    Dehydration 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 1/5 (20%) 1/4 (25%)
    Hyperamylasaemia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Hypercalcaemia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Hypercholesterolaemia 0/3 (0%) 2/6 (33.3%) 2/5 (40%) 0/4 (0%) 2/6 (33.3%) 2/4 (50%) 2/7 (28.6%) 2/6 (33.3%) 1/5 (20%) 1/8 (12.5%) 2/5 (40%) 1/4 (25%)
    Hyperglycaemia 0/3 (0%) 2/6 (33.3%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 3/4 (75%) 2/7 (28.6%) 1/6 (16.7%) 1/5 (20%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%)
    Hyperkalaemia 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Hypermagnesaemia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Hypernatraemia 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Hypertriglyceridaemia 0/3 (0%) 2/6 (33.3%) 1/5 (20%) 0/4 (0%) 1/6 (16.7%) 1/4 (25%) 4/7 (57.1%) 2/6 (33.3%) 2/5 (40%) 1/8 (12.5%) 0/5 (0%) 1/4 (25%)
    Hypoalbuminaemia 0/3 (0%) 2/6 (33.3%) 1/5 (20%) 1/4 (25%) 1/6 (16.7%) 2/4 (50%) 4/7 (57.1%) 1/6 (16.7%) 2/5 (40%) 1/8 (12.5%) 0/5 (0%) 1/4 (25%)
    Hypocalcaemia 0/3 (0%) 2/6 (33.3%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 2/4 (50%) 3/7 (42.9%) 2/6 (33.3%) 2/5 (40%) 1/8 (12.5%) 1/5 (20%) 2/4 (50%)
    Hypoglycaemia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Hypokalaemia 0/3 (0%) 2/6 (33.3%) 0/5 (0%) 2/4 (50%) 2/6 (33.3%) 2/4 (50%) 3/7 (42.9%) 1/6 (16.7%) 1/5 (20%) 3/8 (37.5%) 1/5 (20%) 3/4 (75%)
    Hypomagnesaemia 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 2/4 (50%) 0/6 (0%) 3/4 (75%) 3/7 (42.9%) 2/6 (33.3%) 2/5 (40%) 4/8 (50%) 1/5 (20%) 1/4 (25%)
    Hyponatraemia 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 1/6 (16.7%) 2/5 (40%) 2/8 (25%) 1/5 (20%) 1/4 (25%)
    Hypophosphataemia 0/3 (0%) 1/6 (16.7%) 2/5 (40%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 6/7 (85.7%) 1/6 (16.7%) 1/5 (20%) 4/8 (50%) 0/5 (0%) 4/4 (100%)
    Polydipsia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 1/6 (16.7%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 1/4 (25%)
    Back pain 2/3 (66.7%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 1/4 (25%) 2/7 (28.6%) 2/6 (33.3%) 2/5 (40%) 3/8 (37.5%) 0/5 (0%) 1/4 (25%)
    Coccydynia 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Muscle spasms 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 1/4 (25%) 2/6 (33.3%) 1/4 (25%) 3/7 (42.9%) 1/6 (16.7%) 1/5 (20%) 1/8 (12.5%) 0/5 (0%) 2/4 (50%)
    Muscular weakness 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Musculoskeletal chest pain 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 1/5 (20%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Musculoskeletal pain 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Myalgia 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 1/4 (25%) 1/7 (14.3%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Neck pain 0/3 (0%) 0/6 (0%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Osteonecrosis of jaw 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Pain in extremity 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 1/5 (20%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%)
    Pain in jaw 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Spinal pain 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Tendonitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour embolism 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Nervous system disorders
    Amnesia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Dizziness 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Dysgeusia 1/3 (33.3%) 1/6 (16.7%) 0/5 (0%) 3/4 (75%) 0/6 (0%) 2/4 (50%) 3/7 (42.9%) 2/6 (33.3%) 1/5 (20%) 1/8 (12.5%) 0/5 (0%) 1/4 (25%)
    Dystonia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Headache 0/3 (0%) 4/6 (66.7%) 2/5 (40%) 2/4 (50%) 1/6 (16.7%) 1/4 (25%) 1/7 (14.3%) 1/6 (16.7%) 3/5 (60%) 4/8 (50%) 0/5 (0%) 2/4 (50%)
    Hyperaesthesia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Hypoaesthesia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Migraine 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Myoclonus 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Neuralgia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Neuropathy peripheral 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Paraesthesia 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 1/6 (16.7%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Sciatica 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Somnolence 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Tremor 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 1/5 (20%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Vocal cord paralysis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Psychiatric disorders
    Anorgasmia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Anxiety 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 2/6 (33.3%) 0/4 (0%) 1/7 (14.3%) 1/6 (16.7%) 2/5 (40%) 2/8 (25%) 1/5 (20%) 2/4 (50%)
    Confusional state 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Depression 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 2/8 (25%) 0/5 (0%) 0/4 (0%)
    Hallucination 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Insomnia 0/3 (0%) 2/6 (33.3%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 1/5 (20%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%)
    Renal and urinary disorders
    Dysuria 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 1/4 (25%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Haematuria 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Incontinence 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Micturition urgency 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Pollakiuria 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Renal failure 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Reproductive system and breast disorders
    Erectile dysfunction 1/3 (33.3%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Genital rash 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Pelvic pain 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 1/5 (20%) 0/4 (0%)
    Penile erythema 0/3 (0%) 0/6 (0%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Scrotal oedema 1/3 (33.3%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Vaginal discharge 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Vaginal haemorrhage 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Vaginal inflammation 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Vaginal lesion 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Vulvovaginal dryness 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Vulvovaginal pruritus 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Respiratory, thoracic and mediastinal disorders
    Asthma 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Asthmatic crisis 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Cough 1/3 (33.3%) 4/6 (66.7%) 1/5 (20%) 1/4 (25%) 3/6 (50%) 1/4 (25%) 4/7 (57.1%) 2/6 (33.3%) 0/5 (0%) 4/8 (50%) 0/5 (0%) 0/4 (0%)
    Dysphonia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Dyspnoea 0/3 (0%) 3/6 (50%) 0/5 (0%) 1/4 (25%) 4/6 (66.7%) 2/4 (50%) 3/7 (42.9%) 1/6 (16.7%) 0/5 (0%) 2/8 (25%) 0/5 (0%) 1/4 (25%)
    Dyspnoea exertional 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 2/8 (25%) 0/5 (0%) 0/4 (0%)
    Epistaxis 0/3 (0%) 1/6 (16.7%) 3/5 (60%) 1/4 (25%) 2/6 (33.3%) 1/4 (25%) 3/7 (42.9%) 3/6 (50%) 0/5 (0%) 3/8 (37.5%) 0/5 (0%) 1/4 (25%)
    Hiccups 0/3 (0%) 0/6 (0%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Hypoxia 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Interstitial lung disease 0/3 (0%) 2/6 (33.3%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Oropharyngeal pain 0/3 (0%) 0/6 (0%) 1/5 (20%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Pharyngeal erythema 1/3 (33.3%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Pleural effusion 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Pneumonitis 0/3 (0%) 1/6 (16.7%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Productive cough 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 2/6 (33.3%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Pulmonary congestion 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Rhinorrhoea 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 1/4 (25%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Sputum increased 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Upper respiratory tract congestion 0/3 (0%) 0/6 (0%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Wheezing 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Skin and subcutaneous tissue disorders
    Acne 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Alopecia 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Decubitus ulcer 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Dermatitis acneiform 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 2/8 (25%) 1/5 (20%) 0/4 (0%)
    Dry skin 1/3 (33.3%) 1/6 (16.7%) 1/5 (20%) 2/4 (50%) 2/6 (33.3%) 1/4 (25%) 0/7 (0%) 1/6 (16.7%) 1/5 (20%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Ecchymosis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Eczema 1/3 (33.3%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Erythema 0/3 (0%) 1/6 (16.7%) 1/5 (20%) 1/4 (25%) 2/6 (33.3%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 2/8 (25%) 0/5 (0%) 1/4 (25%)
    Hyperhidrosis 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Hyperkeratosis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Ingrowing nail 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Melanoderma 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Nail discolouration 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Nail disorder 0/3 (0%) 2/6 (33.3%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 2/4 (50%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Nail dystrophy 0/3 (0%) 1/6 (16.7%) 1/5 (20%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Nail ridging 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 1/6 (16.7%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Nail toxicity 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Night sweats 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Onychoclasis 0/3 (0%) 0/6 (0%) 1/5 (20%) 1/4 (25%) 1/6 (16.7%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 1/8 (12.5%) 0/5 (0%) 1/4 (25%)
    Onycholysis 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Prurigo 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Pruritus 0/3 (0%) 2/6 (33.3%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 1/4 (25%) 2/7 (28.6%) 0/6 (0%) 0/5 (0%) 3/8 (37.5%) 0/5 (0%) 0/4 (0%)
    Rash 0/3 (0%) 3/6 (50%) 2/5 (40%) 1/4 (25%) 2/6 (33.3%) 2/4 (50%) 5/7 (71.4%) 1/6 (16.7%) 2/5 (40%) 3/8 (37.5%) 0/5 (0%) 2/4 (50%)
    Rash erythematous 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 1/5 (20%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Rash macular 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Rash maculo-papular 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Rash papular 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Seborrhoeic dermatitis 0/3 (0%) 0/6 (0%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Skin disorder 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 1/7 (14.3%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Skin exfoliation 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 1/4 (25%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 1/6 (16.7%) 0/5 (0%) 0/8 (0%) 1/5 (20%) 0/4 (0%)
    Skin fissures 1/3 (33.3%) 0/6 (0%) 0/5 (0%) 2/4 (50%) 1/6 (16.7%) 1/4 (25%) 0/7 (0%) 1/6 (16.7%) 1/5 (20%) 1/8 (12.5%) 0/5 (0%) 1/4 (25%)
    Skin irritation 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Skin lesion 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Swelling face 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Xeroderma 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 1/4 (25%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Vascular disorders
    Haematoma 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Haemorrhage 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Hot flush 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Orthostatic hypotension 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 1/4 (25%)
    Peripheral vascular disorder 0/3 (0%) 0/6 (0%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 1/8 (12.5%) 0/5 (0%) 0/4 (0%)
    Thrombophlebitis 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)
    Thrombosis 0/3 (0%) 1/6 (16.7%) 0/5 (0%) 0/4 (0%) 0/6 (0%) 0/4 (0%) 0/7 (0%) 0/6 (0%) 0/5 (0%) 0/8 (0%) 0/5 (0%) 0/4 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Senior Director, Clinical Operations
    Organization Puma Biotechnology, Inc.
    Phone +1 (424) 248-6500
    Email clinicaltrials@pumabiotechnology.com
    Responsible Party:
    Puma Biotechnology, Inc.
    ClinicalTrials.gov Identifier:
    NCT00838539
    Other Study ID Numbers:
    • 3144A1-2205 / B1891016
    First Posted:
    Feb 6, 2009
    Last Update Posted:
    Sep 18, 2018
    Last Verified:
    Aug 1, 2018