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A Study of KW-2478 in Combination With Bortezomib in Subjects With Relapsed and/or Refractory Multiple Myeloma

Sponsor
Kyowa Hakko Kirin Pharma, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT01063907
Collaborator
Kyowa Kirin Co., Ltd. (Industry)
95
Enrollment
26
Locations
5
Arms
44.1
Duration (Months)
3.7
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the safety and benefits of the investigational study drug, KW-2478, when given with bortezomib (Velcade®), a drug approved for the treatment of Multiple Myeloma (MM).

The primary objectives:

  • To establish the safety, tolerability, and recommended Phase II dose (RP2D) of KW-2478 in combination with bortezomib (Phase I);

  • To assess the overall response rate (ORR) when subjects with advanced MM are treated (Phase II).

The secondary objectives:

  • To characterize the Pharmacokinetic (PK) and Pharmacodynamic (PD) of KW-2478 with bortezomib (Phase I only);

  • To evaluate for preliminary evidence of efficacy (Phase I);

  • To determine progression free survival (PFS) and duration of response of KW-2478 with bortezomib (Phase II).

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

This is a multicenter, open label, dose escalation, Phase I / II study in subjects with relapsed and/or refractory MM. Up to 24 subjects to be enrolled in the Phase I to determine the RP2D. Up to 77 additional evaluable subjects to be enrolled in Phase II for a maximum up to 101 subjects treated in the study. Study centers in the USA and the UK will participate in Phase I and II. Centers in the Philippines will be participating in Phase II only. The planned enrollment period is 22 months and the planned study duration is 28 months.

Study Design

Study Type:
Interventional
Actual Enrollment :
95 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open Label, Dose Escalation, Multicenter Phase 1/2 Study of KW-2478 in Combination With Bortezomib in Subjects With Relapsed and/or Refractory Multiple Myeloma
Study Start Date :
Mar 1, 2010
Actual Primary Completion Date :
Nov 1, 2013
Actual Study Completion Date :
Nov 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Experimental: Phase 1: Cohort 1

Cohort 1: KW 2478 130 mg/m^2 and Bortezomib 1.0 mg/m^2

Drug: KW-2478
Administered Days 1, 4, 8 and 11 of a 21 day cycle
Other Names:
  • HSP90 Inhibitor

    • Drug: Bortezomib
    Administered on Days 1, 4, 8 and 11 of a 21 day cycle
    Other Names:
  • Velcade

    		•
    Experimental: Phase 1: Cohort 2

    Cohort 2: KW 2478 130 mg/m^2 and Bortezomib 1.3 mg/m^2

    Drug: KW-2478
    Administered Days 1, 4, 8 and 11 of a 21 day cycle
    Other Names:
  • HSP90 Inhibitor

    • Drug: Bortezomib
    Administered on Days 1, 4, 8 and 11 of a 21 day cycle
    Other Names:
  • Velcade

    		•
    Experimental: Phase 1: Cohort 3

    Cohort 3: KW 2478 175 mg/m^2 and Bortezomib 1.0 mg/m^2

    Drug: KW-2478
    Administered Days 1, 4, 8 and 11 of a 21 day cycle
    Other Names:
  • HSP90 Inhibitor

    • Drug: Bortezomib
    Administered on Days 1, 4, 8 and 11 of a 21 day cycle
    Other Names:
  • Velcade

    		•
    Experimental: Phase 1: Cohort 4

    Cohort 4: KW 2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2

    Drug: KW-2478
    Administered Days 1, 4, 8 and 11 of a 21 day cycle
    Other Names:
  • HSP90 Inhibitor

    • Drug: Bortezomib
    Administered on Days 1, 4, 8 and 11 of a 21 day cycle
    Other Names:
  • Velcade

    		•
    Experimental: Phase 2

    KW 2478 175 mg/m^2 and Bortezomib 1.0 mg/m^2

    Drug: KW-2478
    Administered Days 1, 4, 8 and 11 of a 21 day cycle
    Other Names:
  • HSP90 Inhibitor

    • Drug: Bortezomib
    Administered on Days 1, 4, 8 and 11 of a 21 day cycle
    Other Names:
  • Velcade

    		•

    Outcome Measures

    Primary Outcome Measures

    1. To Establish the Safety, Tolerability, and RP2D (Phase 1); To Assess the Overall Response Rate in Subjects With Advanced Multiple Myeloma (Phase 2). [21 day cycle, up to 52 weeks]

      The safety of KW-2478 was determined by reported TEAEs, observed DLTs, changes in PEs, vital sign measurements, ECGs, and laboratory analyses. The ORR, was defined as the best response over a specified number of cycles (calculated and summarized). Disease control rate (DCR) was defined as the best response over a specified number of cycles (calculated and summarized). Progression-free survival was defined as the time from the first day of treatment until the date of disease progression or death is first reported (calculated and summarized).

    Secondary Outcome Measures

    1. Phase 1: PK Absorption Tmax hr Day 11 [PK collected Day 11 of 21-day cycle]

      Descriptive summary statistics (number, arithmetic mean, standard deviation [SDev], coefficient of variation [CV%]) for concentration and PK data for KW-2478 and Bortezomib in Phase 1 were presented by cohort, dose level and day.

    2. Phase 1: PK Exposure Cmax ng/mL Day 11 [PK collected Day 11 of 21-day cycle]

      Descriptive summary statistics (number, arithmetic mean, standard deviation [SDev], coefficient of variation [CV%]) for concentration and PK data for KW-2478 and Bortezomib in Phase 1 were presented by cohort, dose level and day.

    3. Phase 1: PK Exposure AUC0-t hr*ng/mL Day 11 [PK collected Day 11 of 21-day cycle]

      Descriptive summary statistics (number, arithmetic mean, standard deviation [SDev], coefficient of variation [CV%]) for concentration and PK data for KW-2478 and Bortezomib in Phase 1 were presented by cohort, dose level and day.

    4. Phase 1: PK Elimination t½ hr Day 11 [PK collected Day 11 of 21-day cycle]

      Descriptive summary statistics (number, arithmetic mean, standard deviation [SDev], coefficient of variation [CV%]) for concentration and PK data for KW-2478 and Bortezomib in Phase 1 were presented by cohort, dose level and day.

    Eligibility Criteria

    Criteria

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

    Accepts Healthy Volunteers: No

    Inclusion Criteria:

    1. Subjects with a confirmed diagnosis of Multiple Myeloma who have had one and no more than three prior regimens for MM to which they did not respond (failed) or from which they have relapsed.

    2. Signed either an IRB or IEC approved informed consent

    3. ECOG performance status of ≤ 2

    4. Life expectancy of at least 3 months

    5. M protein in either serum or urine, or free light chains if not measurable M protein in serum or urine, and clonal bone marrow plasma cells > 10%, and evidence of end organ damage

    6. Adequate hematologic status, liver and renal function

    7. Subjects of reproductive potential must agree to follow accepted pregnancy prevention methods during the study.

    Exclusion Criteria:

    1. No anti-cancer treatment for ≥ 4 weeks and no bortezomib treatment ≥ 60 days prior to receiving study drug

    2. Any other severe, acute or chronic illness

    3. No other prior or concurrent malignancy

    4. No immunosuppressant therapy

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Arizona Clinical Research Center, Inc. / Arizona Oncology Associates, 1825 N Kolb, Tucson Arizona United States 85715
    2 Pacific Shores Medical Group 1043 Elm Ave, Suite 104 Long Beach California United States 90813
    3 UCLA Medical Center Hematology / Oncology Division, 10945 Le Conte Ave #2333, Los Angeles California United States 90095-7059
    4 Collaborative Research Group 2320 S Seacrest Blvd, Suite 202 Boynton Beach Florida United States 33435
    5 Rush University Medical Center / Division of Hematology/Oncology Research 1725 W Harrison Street, Suite 834 Chicago Illinois United States 60612
    6 Cancer Institute of New Jersey 195 Little Albany Street New Brunswick New Jersey United States 08903-2681
    7 The Jones Clinic 7710 Wolf River Circle Germantown Tennessee United States 38138
    8 UT MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston Texas United States 77030
    9 Gundersen Clinic Center for Cancer and Blood Disorders, 1900 South Ave, EB2-001, La Crosse Wisconsin United States 54601
    10 National Kidney and Transplant Institute, Rm 3215 Doctors Clinic, East Avenue Diliman Quezon City Philippines
    11 Makati Medical Center, New Wing Hall C372, #2 Amorsolo Street, Legaspi Village, Makati City Philippines
    12 The Medical City, 1609 MATI Building, The Medical City, Ortigas Avenue, Pasig City, Metro Manila Philippines
    13 Saint Lukes Medical Center, Rm 222 MAB Saint Lukes Medical Center, E. Rodriguez Quezon City Philippines
    14 Darent Valley Hospital Dept of Haematology, Acorn House, Darenth Wood Road Dartford Kent United Kingdom DA2 8DA
    15 St Bartholomew's Hospital Haematology Department, 1st Floor, Pathology Dominion House, 59 Bartholomew Close London United Kingdom EC1 7ED
    16 Christie Hospital - Department Haematology, 550 Wilmslow Road Withington Manchester, Greater Manchester United Kingdom M20 4BX
    17 Hillingdon Hospital Dept of Haematology, Pield Health Road Uxbridge Middlesex United Kingdom UB8 3NN
    18 Nottingham University Hospitals NHS Trust, Centre for Clinical Haemotology Hucknall Road Nottingham United Kingdom NG5 1PB
    19 Royal Marsden Hospital, Orchard House Downs Road Sutton, Surrey United Kingdom SM2 5PT
    20 Royal Bournemouth Hospital, Dept. of Haematolgy, Castle Lane East, Bournemouth United Kingdom BH7 7DW
    21 Royal Devon & Exeter Hospital Haematology Centre, Barrack Road Exeter United Kingdom EX2 5DW
    22 Northwick Park Hospital Dept of Haematology, Watford Road Harrow United Kingdom HA1 3UJ
    23 St James Hospital, St James' Institute of Oncology, Department of Haematology, Level 03, Bexley Wing, Leeds United Kingdom LS9 7TF
    24 UCL Cancer Institute, Paul O'Gorman Building, University College London,72 Huntley Street London United Kingdom WC1E 6DD
    25 Manchester Royal Infirmary Dept of Haematology, Oxford Road Manchester United Kingdom M13 9WL
    26 Royal Cornwall Hospital Haematology Clinic Truro United Kingdom TR1 3LS

    Sponsors and Collaborators

    • Kyowa Hakko Kirin Pharma, Inc.
    • Kyowa Kirin Co., Ltd.

    Investigators

    • Study Director: Michael Kurman, MD, Kyowa Hakko Kirin Pharma, Inc.
    • Study Chair: Loan Hoang-Sayag, MD, Quintiles, Inc.
    • Study Chair: Noel Pingoy, MD, Gleneagles CRC

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Kyowa Hakko Kirin Pharma, Inc.
    ClinicalTrials.gov Identifier:
    NCT01063907
    Other Study ID Numbers:
    • 2478-INT-001
    • 2009-016223-56
    First Posted:
    Feb 5, 2010
    Last Update Posted:
    Dec 16, 2014
    Last Verified:
    Dec 1, 2014
    Keywords provided by Kyowa Hakko Kirin Pharma, Inc.
    Leukemia
    Immunoproliferative Disorder
    Neoplasma by Histologic Type
    Immune System Diseases
    Hematologic Diseases
    Blood Protein Disorders
    Paraproteinemias
    Multiple Myeloma
    Hematologic Disorders
    Leukemia, Chronic, B-cell
    Leukemia, B-cell
    Leukemia, Chronic
    Neoplasms, Plasma Cell
    Monoclonal Gammopathy of unknown significance (MGUS)
    Additional relevant MeSH terms:
    Multiple Myeloma
    Neoplasms, Plasma Cell
    Bortezomib

    Study Results

    Participant Flow

    Recruitment Details Study centers in the USA and the UK participated in the Phase 1 portion, and study centers in the USA, UK, and Philippines participated in the Phase 2 portion.
    Pre-assignment Detail
    Arm/Group Title Phase 1: KW-2478 and Bortezomib Phase II: KW-2478 130mg/m^2 and Bortezomib 1.3mg/m^2
    Arm/Group Description The target population in Phase 1 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1-3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine. For Phase 1, the design was a standard 3+3 study of KW-2478 (130 or 175 mg/m^2) and bortezomib(1.0 or 1.3 mg/m^2) on Days 1, 4, 8, and 11 of a 21-day cycle utilizing four dose-escalation cohorts. The target population in Phase 2 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1-3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine. For the Phase 2 portion of the study was designed to determine the preliminary efficacy of KW 2478 and bortezomib at the RP2D (KW-2478 175 mg/m^2/bortezomib1.3 mg/m^2).
    Period Title: Overall Study
    STARTED 15 80
    COMPLETED 15 80
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title KW-2478 and Bortezomib
    Arm/Group Description The target population in both Phase 1 and 2 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1-3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine. For Phase 1, the design was a standard 3+3 study of KW-2478 (130 or 175 mg/m^2) and Bortezomib(1.0 or 1.3 mg/m^2) on Days 1, 4, 8, and 11 of a 21-day cycle utilizing four dose-escalation cohorts (overall N=15). The Phase 2 portion of the study enrolled 80 subjects to determine the preliminary efficacy of KW 2478 and Bortezomib at the RP2D (KW-2478 175 mg/m^2 / Bortezomib 1.3 mg/m^2).
    Overall Participants 95
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    64.3
    (9.3)
    Sex: Female, Male (Count of Participants)
    Female
    41
    43.2%
    Male
    54
    56.8%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    22
    23.2%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    8
    8.4%
    White
    61
    64.2%
    More than one race
    0
    0%
    Unknown or Not Reported
    4
    4.2%
    Region of Enrollment (participants) [Number]
    United States
    18
    18.9%
    Philippines
    20
    21.1%
    United Kingdom
    57
    60%
    Body Surface Area (BSA) (m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [m^2]
    1.87
    (0.27)

    Outcome Measures

    1. Primary Outcome
    Title To Establish the Safety, Tolerability, and RP2D (Phase 1); To Assess the Overall Response Rate in Subjects With Advanced Multiple Myeloma (Phase 2).
    Description The safety of KW-2478 was determined by reported TEAEs, observed DLTs, changes in PEs, vital sign measurements, ECGs, and laboratory analyses. The ORR, was defined as the best response over a specified number of cycles (calculated and summarized). Disease control rate (DCR) was defined as the best response over a specified number of cycles (calculated and summarized). Progression-free survival was defined as the time from the first day of treatment until the date of disease progression or death is first reported (calculated and summarized).
    Time Frame 21 day cycle, up to 52 weeks

    Outcome Measure Data

    Analysis Population Description
    All subjects who received at least 1 dose, including a partial dose, of KW-2478 were evaluated for safety.
    Arm/Group Title Phase 1 & 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2 Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2 Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2 Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2 Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2 Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2
    Arm/Group Description The target population in both Phase 1 and 2 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1-3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine. The Phase 1 portion of the study was a standard 3+3 study design of KW-2478 (130 or 175 mg/m^2) and Bortezomib (1.0 or 1.3 mg/m^2) on Days 1, 4, 8, and 11 of a 21-day cycle utilizing four dose-escalation cohorts. The Phase 2 portion of the study was designed to determine the preliminary efficacy of KW 2478 and Bortezomib at the RP2D (KW-2478 175 mg/m^2/Bortezomib 1.3 mg/m^2). Cohort 1: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design. Cohort 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design. Cohort 3: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design. Cohort 4: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design. Phase 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle designed to determine the preliminary efficacy of KW 2478 and Bortezomib at the RP2D (KW-2478 175 mg/m^2/Bortezomib 1.3 mg/m^2).
    Measure Participants 95 3 3 3 6 80
    Subjects with Any TEAE
    95
    100%
    3
    NaN
    3
    NaN
    3
    NaN
    6
    NaN
    80
    NaN
    Related TEAE
    88
    92.6%
    3
    NaN
    3
    NaN
    2
    NaN
    6
    NaN
    74
    NaN
    Moderate (CTCAE 2) TEAE
    22
    23.2%
    0
    NaN
    0
    NaN
    0
    NaN
    0
    NaN
    22
    NaN
    Severe (CTCAE 3) TEAE
    54
    56.8%
    3
    NaN
    2
    NaN
    2
    NaN
    5
    NaN
    42
    NaN
    Life Threatening TEAE
    13
    13.7%
    0
    NaN
    1
    NaN
    0
    NaN
    0
    NaN
    12
    NaN
    Serious Treatment-Emergent AE
    48
    50.5%
    2
    NaN
    3
    NaN
    3
    NaN
    4
    NaN
    36
    NaN
    Subjects with Any DLT
    1
    1.1%
    0
    NaN
    0
    NaN
    1
    NaN
    0
    NaN
    0
    NaN
    2. Secondary Outcome
    Title Phase 1: PK Absorption Tmax hr Day 11
    Description Descriptive summary statistics (number, arithmetic mean, standard deviation [SDev], coefficient of variation [CV%]) for concentration and PK data for KW-2478 and Bortezomib in Phase 1 were presented by cohort, dose level and day.
    Time Frame PK collected Day 11 of 21-day cycle

    Outcome Measure Data

    Analysis Population Description
    The PK of KW-2478 was characterized after single administrations through @25 hours post start of infusion dose on Day 1 and through @7 hours post start of infusion dose on Day 11in Phase 1 only.
    Arm/Group Title Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2 Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2 Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2 Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2
    Arm/Group Description Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle
    Measure Participants 3 3 3 6
    Mean (Standard Deviation) [hr]
    1.03
    (0.0441)
    1.03
    (0.0481)
    1.11
    (0.129)
    1.07
    (0.0638)
    3. Secondary Outcome
    Title Phase 1: PK Exposure Cmax ng/mL Day 11
    Description Descriptive summary statistics (number, arithmetic mean, standard deviation [SDev], coefficient of variation [CV%]) for concentration and PK data for KW-2478 and Bortezomib in Phase 1 were presented by cohort, dose level and day.
    Time Frame PK collected Day 11 of 21-day cycle

    Outcome Measure Data

    Analysis Population Description
    The PK of KW-2478 was characterized after single administrations through @25 hours post start of infusion dose on Day 1 and through @7 hours post start of infusion dose on Day 11 in Phase 1 only.
    Arm/Group Title Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2 Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2 Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2 Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2
    Arm/Group Description Cohort 1: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design. Cohort 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design. Cohort 3: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design. Cohort 4: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.
    Measure Participants 3 3 3 6
    Mean (Standard Deviation) [ng/mL]
    7910
    (5360)
    41000
    (64100)
    5990
    (2720)
    5280
    (2290)
    4. Secondary Outcome
    Title Phase 1: PK Exposure AUC0-t hr*ng/mL Day 11
    Description Descriptive summary statistics (number, arithmetic mean, standard deviation [SDev], coefficient of variation [CV%]) for concentration and PK data for KW-2478 and Bortezomib in Phase 1 were presented by cohort, dose level and day.
    Time Frame PK collected Day 11 of 21-day cycle

    Outcome Measure Data

    Analysis Population Description
    The PK of KW-2478 was characterized after single administrations through @25 hours post start of infusion dose on Day 1 and through @7 hours post start of infusion dose on Day 11 in Phase 1 only.
    Arm/Group Title Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2 Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2 Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2 Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2
    Arm/Group Description Cohort 1: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design. Cohort 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design. Cohort 3: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design. Cohort 4: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.
    Measure Participants 3 3 3 6
    Mean (Standard Deviation) [hr*ng/mL]
    7940
    (2580)
    26200
    (36700)
    7190
    (2150)
    6040
    (2280)
    5. Secondary Outcome
    Title Phase 1: PK Elimination t½ hr Day 11
    Description Descriptive summary statistics (number, arithmetic mean, standard deviation [SDev], coefficient of variation [CV%]) for concentration and PK data for KW-2478 and Bortezomib in Phase 1 were presented by cohort, dose level and day.
    Time Frame PK collected Day 11 of 21-day cycle

    Outcome Measure Data

    Analysis Population Description
    The PK of KW-2478 was characterized after single administrations through @25 hours post start of infusion dose on Day 1 and through @7 hours post start of infusion dose on Day 11in Phase 1 only.
    Arm/Group Title Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2 Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2 Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2 Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2
    Arm/Group Description Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle
    Measure Participants 3 3 3 6
    Mean (Standard Deviation) [hr]
    1.88
    (0.076)
    2.02
    (0)
    1.84
    (0.206)
    1.77
    (0.262)

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Phase 1 and 2: KW-2478 and Bortezomib Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0 mg/m^2 Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3 mg/m^2 Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0 mg/m^2 Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2 Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2
    Arm/Group Description KW-2478 and bortezomib: KW 2478 and bortezomib given on Days 1, 4, 8 and 11 of a 21 day cycle Cohort 1: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design. Cohort 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design. Cohort 3: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design. Cohort 4: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design. Phase 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle designed to determine the preliminary efficacy of KW 2478 + BTZ at the RP2D (KW-2478 175 mg/m^2/BTZ 1.3 mg/m^2).
    All Cause Mortality
    Phase 1 and 2: KW-2478 and Bortezomib Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0 mg/m^2 Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3 mg/m^2 Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0 mg/m^2 Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2 Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2
    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)
    Serious Adverse Events
    Phase 1 and 2: KW-2478 and Bortezomib Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0 mg/m^2 Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3 mg/m^2 Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0 mg/m^2 Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2 Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2
    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 48/95 (50.5%) 2/3 (66.7%) 3/3 (100%) 3/3 (100%) 4/6 (66.7%) 36/80 (45%)
    Blood and lymphatic system disorders
    Anaemia 4/95 (4.2%) 4 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 4/80 (5%) 4
    Febrile neutropenia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Thrombocytopenia 2/95 (2.1%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 3
    Cardiac disorders
    Angina pectoris 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/80 (0%) 0
    Angina unstable 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Myocardial ischaemia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Right ventricular failure 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Eye disorders
    Vision blurred 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/80 (0%) 0
    Gastrointestinal disorders
    Abdominal hernia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Abdominal pain 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Constipation 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Diarrhoea 4/95 (4.2%) 4 1/3 (33.3%) 1 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Nausea 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Pancreatitis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/80 (0%) 0
    Small intestinal obstruction 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Vomiting 3/95 (3.2%) 3 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 1/80 (1.3%) 1
    General disorders
    Chest pain 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/80 (0%) 0
    Oedema peripheral 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/80 (0%) 0
    Pain 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Pyrexia 3/95 (3.2%) 4 0/3 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Infections and infestations
    Appendicitis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Bacteraemia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Catheter sepsis 1/95 (1.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 2
    Gastroenteritis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Influenza 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Listeriosis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Lower respiratory tract infection 4/95 (4.2%) 4 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 2/80 (2.5%) 2
    Lung infection 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Lung infection pseudomonal 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Pneumonia 7/95 (7.4%) 7 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 6/80 (7.5%) 6
    Pneumonia respiratory syncytial viral 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Respiratory tract infection 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Sepsis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Upper respiratory tract infection 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/80 (0%) 0
    Urinary tract infection 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Injury, poisoning and procedural complications
    Accidental overdose 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Clavicle fracture 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/80 (0%) 0
    Fall 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Femur fracture 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Hip fracture 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/80 (0%) 0
    Investigations
    Blood creatinine increased 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Troponin T increased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/80 (0%) 0
    Viral test positive 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Weight decreased 1/95 (1.1%) 1 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Metabolism and nutrition disorders
    Dehydration 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Hypercalcaemia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Hyponatraemia 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Musculoskeletal and connective tissue disorders
    Arthralgia 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 1/80 (1.3%) 1
    Back pain 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Bone pain 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Musculoskeletal chest pain 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Musculoskeletal pain 2/95 (2.1%) 2 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Multiple myeloma 2/95 (2.1%) 2 0/3 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 0/6 (0%) 0 0/80 (0%) 0
    Nervous system disorders
    Loss of consciousness 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Neuropathy peripheral 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Presyncope 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/80 (0%) 0
    Transient ischaemic attack 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Psychiatric disorders
    Confusional state 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 2/80 (2.5%) 2
    Renal and urinary disorders
    Haematuria 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Neurogenic bladder 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 4/95 (4.2%) 5 0/3 (0%) 0 1/3 (33.3%) 2 1/3 (33.3%) 1 0/6 (0%) 0 2/80 (2.5%) 2
    Epistaxis 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Pneumonia aspiration 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Skin and subcutaneous tissue disorders
    Rash erythematous 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Vascular disorders
    Circulatory collapse 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Other (Not Including Serious) Adverse Events
    Phase 1 and 2: KW-2478 and Bortezomib Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0 mg/m^2 Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3 mg/m^2 Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0 mg/m^2 Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2 Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2
    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 95/95 (100%) 3/3 (100%) 3/3 (100%) 3/3 (100%) 6/6 (100%) 80/80 (100%)
    Blood and lymphatic system disorders
    Anaemia 17/95 (17.9%) 30 0/3 (0%) 0 0/3 (0%) 0 2/3 (66.7%) 2 1/6 (16.7%) 1 14/80 (17.5%) 27
    Febrile neutropenia 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 1/80 (1.3%) 1
    Leukocytosis 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Leukopenia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/80 (0%) 0
    Neutropenia 15/95 (15.8%) 37 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 14/80 (17.5%) 36
    Thrombocytopenia 19/95 (20%) 41 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 2 17/80 (21.3%) 39
    Cardiac disorders
    Angina pectoris 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Extrasystoles 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Palpitations 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/80 (0%) 0
    Tachycardia 2/95 (2.1%) 4 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 3 0/6 (0%) 0 1/80 (1.3%) 1
    Ventricular extrasystoles 1/95 (1.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 2
    Ear and labyrinth disorders
    Cerumen impaction 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Ear discomfort 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Ear pain 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Tinnitus 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Vertigo 1/95 (1.1%) 1 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Eye disorders
    Abnormal sensation in eye 1/95 (1.1%) 1 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Blepharitis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Conjunctival hyperaemia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Conjunctivitis 4/95 (4.2%) 4 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 4/80 (5%) 4
    Diplopia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Dry eye 4/95 (4.2%) 4 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Erythema of eyelid 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Eye discharge 3/95 (3.2%) 3 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 1/80 (1.3%) 1
    Eye irritation 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Eye pain 4/95 (4.2%) 4 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 4/80 (5%) 4
    Eye pruritus 2/95 (2.1%) 2 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Eye swelling 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/80 (0%) 0
    Eyelid disorder 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Eyelid oedema 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Eyelids pruritus 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Foreign body sensation in eyes 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 2/80 (2.5%) 2
    Lacrimation increased 12/95 (12.6%) 15 1/3 (33.3%) 1 0/3 (0%) 0 2/3 (66.7%) 3 1/6 (16.7%) 1 8/80 (10%) 10
    Macular degeneration 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Metamorphopsia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/80 (0%) 0
    Ocular hyperaemia 2/95 (2.1%) 2 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Photophobia 1/95 (1.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 2
    Retinal disorder 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Vision blurred 16/95 (16.8%) 19 1/3 (33.3%) 1 0/3 (0%) 0 1/3 (33.3%) 1 2/6 (33.3%) 2 12/80 (15%) 15
    Visual acuity reduced 4/95 (4.2%) 5 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 4
    Gastrointestinal disorders
    Abdominal discomfort 5/95 (5.3%) 5 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 5/80 (6.3%) 5
    Abdominal distension 13/95 (13.7%) 19 2/3 (66.7%) 6 0/3 (0%) 0 2/3 (66.7%) 2 0/6 (0%) 0 9/80 (11.3%) 11
    Abdominal pain 17/95 (17.9%) 31 2/3 (66.7%) 5 0/3 (0%) 0 1/3 (33.3%) 1 1/6 (16.7%) 4 13/80 (16.3%) 21
    Abdominal pain lower 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Abdominal pain upper 11/95 (11.6%) 12 3/3 (100%) 3 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 8/80 (10%) 9
    Abdominal tenderness 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/80 (0%) 0
    Anal haemorrhage 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Constipation 42/95 (44.2%) 71 3/3 (100%) 8 2/3 (66.7%) 4 2/3 (66.7%) 2 2/6 (33.3%) 3 33/80 (41.3%) 54
    Diarrhoea 70/95 (73.7%) 199 3/3 (100%) 29 2/3 (66.7%) 9 3/3 (100%) 7 4/6 (66.7%) 6 58/80 (72.5%) 148
    Dry mouth 7/95 (7.4%) 7 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 6/80 (7.5%) 6
    Dyspepsia 13/95 (13.7%) 20 2/3 (66.7%) 3 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 10/80 (12.5%) 16
    Dysphagia 1/95 (1.1%) 1 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Flatulence 3/95 (3.2%) 5 1/3 (33.3%) 3 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 1/80 (1.3%) 1
    Frequent bowel movements 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Gastritis 1/95 (1.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 2
    Gastrointestinal hypermotility 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Gastrooesophageal reflux disease 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 2/80 (2.5%) 2
    Gingival pain 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Gingivitis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Glossodynia 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Haematochezia 1/95 (1.1%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 3
    Haemorrhoids 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Irritable bowel syndrome 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Mouth ulceration 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Nausea 55/95 (57.9%) 114 3/3 (100%) 11 1/3 (33.3%) 2 1/3 (33.3%) 2 5/6 (83.3%) 6 45/80 (56.3%) 93
    Oral pain 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Pneumatosis intestinalis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Proctalgia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Rectal haemorrhage 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Tongue coated 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Toothache 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Vomiting 38/95 (40%) 72 1/3 (33.3%) 1 1/3 (33.3%) 3 1/3 (33.3%) 1 0/6 (0%) 0 35/80 (43.8%) 67
    General disorders
    Asthenia 15/95 (15.8%) 17 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 2 13/80 (16.3%) 15
    Catheter site erythema 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Catheter site haemorrhage 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Catheter site pain 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Catheter site related reaction 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Catheter thrombosis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/80 (0%) 0
    Chest discomfort 2/95 (2.1%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 3
    Chest pain 3/95 (3.2%) 4 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 2 0/6 (0%) 0 2/80 (2.5%) 2
    Chills 4/95 (4.2%) 4 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Cyst 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Facial pain 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Fatigue 51/95 (53.7%) 101 2/3 (66.7%) 6 3/3 (100%) 10 2/3 (66.7%) 2 3/6 (50%) 4 41/80 (51.3%) 79
    Feeling cold 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Gait disturbance 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Influenza like illness 3/95 (3.2%) 4 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 4
    Infusion related reaction 1/95 (1.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 2
    Infusion site haematoma 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Infusion site pain 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Injection site haematoma 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/80 (0%) 0
    Irritability 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Malaise 4/95 (4.2%) 6 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 4/80 (5%) 6
    Mass 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/80 (0%) 0
    Mucosal inflammation 4/95 (4.2%) 4 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/6 (16.7%) 1 2/80 (2.5%) 2
    Non-cardiac chest pain 1/95 (1.1%) 1 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Oedema peripheral 12/95 (12.6%) 17 1/3 (33.3%) 2 1/3 (33.3%) 2 1/3 (33.3%) 1 0/6 (0%) 0 9/80 (11.3%) 12
    Pain 4/95 (4.2%) 4 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 4/80 (5%) 4
    Pyrexia 12/95 (12.6%) 15 0/3 (0%) 0 1/3 (33.3%) 2 1/3 (33.3%) 2 0/6 (0%) 0 10/80 (12.5%) 11
    Swelling 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Vessel puncture site haematoma 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Immune system disorders
    Hypogammaglobulinaemia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Infections and infestations
    Bronchiectasis 1/95 (1.1%) 1 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Bronchitis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Cellulitis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Clostridium difficile colitis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Conjunctivitis infective 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Cystitis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Enterocolitis infectious 1/95 (1.1%) 1 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Escherichia urinary tract infection 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Eye infection 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Eyelid infection 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Gastroenteritis 1/95 (1.1%) 1 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Gingival infection 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Herpes zoster 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Hordeolum 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Infection 2/95 (2.1%) 2 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Influenza 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Localised infection 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Lower respiratory tract infection 14/95 (14.7%) 19 2/3 (66.7%) 4 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 11/80 (13.8%) 14
    Lung infection 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Nasopharyngitis 7/95 (7.4%) 8 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 7/80 (8.8%) 8
    Onychomycosis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Oral candidiasis 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 2/80 (2.5%) 2
    Orchitis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Pneumonia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Respiratory tract infection 3/95 (3.2%) 4 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 3
    Rhinitis 7/95 (7.4%) 13 0/3 (0%) 0 1/3 (33.3%) 3 0/3 (0%) 0 0/6 (0%) 0 6/80 (7.5%) 10
    Sepsis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Sinusitis 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Skin candida 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Skin infection 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Upper respiratory tract infection 14/95 (14.7%) 15 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 13/80 (16.3%) 14
    Urinary tract infection 6/95 (6.3%) 7 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 5/80 (6.3%) 6
    Viral infection 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Injury, poisoning and procedural complications
    Clavicle fracture 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Contusion 4/95 (4.2%) 4 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 4/80 (5%) 4
    Fall 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/80 (0%) 0
    Human bite 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Medical device site reaction 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Narcotic intoxication 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/80 (0%) 0
    Post-traumatic pain 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Procedural pain 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Rib fracture 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Road traffic accident 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Thermal burn 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Tooth fracture 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Investigations
    Alanine aminotransferase increased 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Aspartate aminotransferase increased 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Blood alkaline phosphatase increased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Blood creatinine increased 3/95 (3.2%) 4 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 3
    Blood magnesium decreased 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Blood potassium decreased 4/95 (4.2%) 5 0/3 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Blood pressure increased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Blood sodium decreased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Blood triglycerides increased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Body temperature increased 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    C-reactive protein increased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Electrocardiogram QT prolonged 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Eosinophil count increased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Gamma-glutamyltransferase increased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Haemoglobin decreased 2/95 (2.1%) 3 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 2 0/6 (0%) 0 1/80 (1.3%) 1
    Heart rate decreased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Neutrophil count decreased 5/95 (5.3%) 11 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 4/80 (5%) 10
    Neutrophil count increased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Platelet count decreased 3/95 (3.2%) 5 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 5
    Protein total increased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Weight decreased 9/95 (9.5%) 10 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/6 (16.7%) 2 7/80 (8.8%) 7
    Weight increased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    White blood cell count decreased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Metabolism and nutrition disorders
    Decreased appetite 28/95 (29.5%) 44 2/3 (66.7%) 4 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 2 25/80 (31.3%) 38
    Dehydration 6/95 (6.3%) 6 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 5/80 (6.3%) 5
    Diabetes mellitus 1/95 (1.1%) 1 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Fluid intake reduced 1/95 (1.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 2
    Fluid overload 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/80 (0%) 0
    Gout 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Hypercalcaemia 1/95 (1.1%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 3
    Hyperglycaemia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Hyperphosphataemia 1/95 (1.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 2
    Hyperuricaemia 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Hypoalbuminaemia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Hypocalcaemia 5/95 (5.3%) 7 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 5/80 (6.3%) 7
    Hypoglycaemia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Hypokalaemia 8/95 (8.4%) 13 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 7/80 (8.8%) 12
    Hypomagnesaemia 4/95 (4.2%) 5 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 4/80 (5%) 5
    Hyponatraemia 3/95 (3.2%) 4 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 4
    Hypophosphataemia 2/95 (2.1%) 10 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 10
    Vitamin B12 deficiency 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Musculoskeletal and connective tissue disorders
    Arthralgia 12/95 (12.6%) 15 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 11/80 (13.8%) 14
    Back pain 12/95 (12.6%) 13 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 1/6 (16.7%) 1 10/80 (12.5%) 11
    Bone disorder 1/95 (1.1%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 3
    Bone pain 5/95 (5.3%) 6 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 2 0/6 (0%) 0 4/80 (5%) 4
    Coccydynia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Dactylitis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Fasciitis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Flank pain 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Groin pain 1/95 (1.1%) 1 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Joint range of motion decreased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Joint stiffness 1/95 (1.1%) 1 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Joint swelling 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Limb discomfort 1/95 (1.1%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 3
    Mobility decreased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Muscle spasms 10/95 (10.5%) 13 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 10/80 (12.5%) 13
    Muscle twitching 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Muscular weakness 4/95 (4.2%) 4 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 4/80 (5%) 4
    Musculoskeletal chest pain 10/95 (10.5%) 10 0/3 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 1/6 (16.7%) 1 7/80 (8.8%) 7
    Musculoskeletal pain 12/95 (12.6%) 17 0/3 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 0/6 (0%) 0 10/80 (12.5%) 15
    Musculoskeletal stiffness 3/95 (3.2%) 4 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 1/6 (16.7%) 1 1/80 (1.3%) 2
    Myalgia 5/95 (5.3%) 6 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 2 0/6 (0%) 0 4/80 (5%) 4
    Neck pain 1/95 (1.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 2
    Pain in extremity 15/95 (15.8%) 19 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 1/6 (16.7%) 1 13/80 (16.3%) 17
    Pain in jaw 2/95 (2.1%) 3 0/3 (0%) 0 1/3 (33.3%) 2 1/3 (33.3%) 1 0/6 (0%) 0 0/80 (0%) 0
    Rheumatoid arthritis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Spinal osteoarthritis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lipoma 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Nervous system disorders
    Ageusia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Areflexia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Balance disorder 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 1/80 (1.3%) 1
    Burning sensation 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Depressed level of consciousness 1/95 (1.1%) 1 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Dizziness 25/95 (26.3%) 33 3/3 (100%) 8 0/3 (0%) 0 1/3 (33.3%) 1 3/6 (50%) 3 18/80 (22.5%) 21
    Dizziness exertional 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Dysgeusia 13/95 (13.7%) 13 2/3 (66.7%) 2 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 10/80 (12.5%) 10
    Head discomfort 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Headache 23/95 (24.2%) 41 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 2 20/80 (25%) 38
    Hyperaesthesia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Hyperreflexia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Hypoaesthesia 8/95 (8.4%) 11 0/3 (0%) 0 2/3 (66.7%) 3 0/3 (0%) 0 1/6 (16.7%) 1 5/80 (6.3%) 7
    Hypogeusia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Hyporeflexia 2/95 (2.1%) 3 0/3 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Lethargy 6/95 (6.3%) 8 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 6/80 (7.5%) 8
    Memory impairment 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Neuralgia 8/95 (8.4%) 13 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 8/80 (10%) 13
    Neuropathy peripheral 28/95 (29.5%) 48 1/3 (33.3%) 1 2/3 (66.7%) 3 1/3 (33.3%) 2 0/6 (0%) 0 24/80 (30%) 42
    Paraesthesia 11/95 (11.6%) 17 0/3 (0%) 0 2/3 (66.7%) 5 1/3 (33.3%) 2 1/6 (16.7%) 1 7/80 (8.8%) 9
    Peripheral sensory neuropathy 15/95 (15.8%) 36 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 14/80 (17.5%) 35
    Presyncope 3/95 (3.2%) 4 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 4
    Sensory loss 2/95 (2.1%) 3 0/3 (0%) 0 1/3 (33.3%) 2 1/3 (33.3%) 1 0/6 (0%) 0 0/80 (0%) 0
    Somnolence 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Syncope 3/95 (3.2%) 4 2/3 (66.7%) 3 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Tremor 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 1/80 (1.3%) 1
    Psychiatric disorders
    Abnormal dreams 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Anxiety 5/95 (5.3%) 5 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 4/80 (5%) 4
    Confusional state 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 1/80 (1.3%) 1
    Depressed mood 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Depression 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Insomnia 13/95 (13.7%) 15 0/3 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 1/6 (16.7%) 1 10/80 (12.5%) 12
    Libido decreased 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Mood altered 2/95 (2.1%) 2 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Nightmare 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Renal and urinary disorders
    Dysuria 2/95 (2.1%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 3
    Haematuria 1/95 (1.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 2
    Pollakiuria 2/95 (2.1%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 3
    Proteinuria 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Renal failure 1/95 (1.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 2 0/80 (0%) 0
    Renal impairment 3/95 (3.2%) 4 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 3
    Reproductive system and breast disorders
    Breast pain 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Epididymitis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Genital pain 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Testicular cyst 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Testicular pain 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Respiratory, thoracic and mediastinal disorders
    Atelectasis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Cough 21/95 (22.1%) 29 1/3 (33.3%) 1 2/3 (66.7%) 2 1/3 (33.3%) 2 1/6 (16.7%) 1 16/80 (20%) 23
    Dry throat 2/95 (2.1%) 2 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Dysphonia 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Dyspnoea 19/95 (20%) 25 2/3 (66.7%) 2 1/3 (33.3%) 5 2/3 (66.7%) 2 1/6 (16.7%) 2 13/80 (16.3%) 14
    Dyspnoea exertional 6/95 (6.3%) 9 1/3 (33.3%) 2 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 4/80 (5%) 6
    Emphysema 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Epistaxis 8/95 (8.4%) 9 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 8/80 (10%) 9
    Haemoptysis 1/95 (1.1%) 3 1/3 (33.3%) 3 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Hiccups 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Hypoxia 1/95 (1.1%) 1 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Nasal congestion 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Oropharyngeal pain 11/95 (11.6%) 11 1/3 (33.3%) 1 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 9/80 (11.3%) 9
    Pleural effusion 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Pneumothorax 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Productive cough 6/95 (6.3%) 7 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 6/80 (7.5%) 7
    Pulmonary oedema 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Rales 3/95 (3.2%) 3 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Rhinorrhoea 6/95 (6.3%) 7 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 2/6 (33.3%) 2 3/80 (3.8%) 4
    Sinus congestion 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Wheezing 3/95 (3.2%) 3 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Skin and subcutaneous tissue disorders
    Acne 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Alopecia 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Dermatitis allergic 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/80 (0%) 0
    Dry skin 7/95 (7.4%) 7 0/3 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 0/6 (0%) 0 5/80 (6.3%) 5
    Ecchymosis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Erythema 4/95 (4.2%) 5 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 3/80 (3.8%) 4
    Exfoliative rash 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Hyperhidrosis 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Ingrowing nail 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Night sweats 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Pain of skin 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/80 (0%) 0
    Pruritus 8/95 (8.4%) 9 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 7/80 (8.8%) 8
    Pruritus generalised 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Purpura 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Rash 13/95 (13.7%) 17 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 5 11/80 (13.8%) 12
    Rash erythematous 4/95 (4.2%) 4 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 3/80 (3.8%) 3
    Rash macular 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Rash maculo-papular 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Rash papular 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Rash pruritic 2/95 (2.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 2
    Skin disorder 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Skin lesion 1/95 (1.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 2
    Subcutaneous nodule 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Telangiectasia 1/95 (1.1%) 1 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/6 (0%) 0 0/80 (0%) 0
    Vascular disorders
    Haematoma 2/95 (2.1%) 2 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Hot flush 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1
    Hypertension 3/95 (3.2%) 3 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 2/80 (2.5%) 2
    Hypotension 5/95 (5.3%) 9 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 5/80 (6.3%) 9
    Orthostatic hypotension 2/95 (2.1%) 3 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/80 (2.5%) 3
    Phlebitis 4/95 (4.2%) 5 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 2/80 (2.5%) 3
    Thrombophlebitis 1/95 (1.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 2
    Vasculitis 1/95 (1.1%) 2 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 2
    Vein discolouration 1/95 (1.1%) 1 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/80 (1.3%) 1

    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 VP Drug Development
    Organization Kyowa Hakko Kirin Pharma, Inc.
    Phone 609-919-1100
    Email clinical.info@kyowa-kirin-pharma.com
    Responsible Party:
    Kyowa Hakko Kirin Pharma, Inc.
    ClinicalTrials.gov Identifier:
    NCT01063907
    Other Study ID Numbers:
    • 2478-INT-001
    • 2009-016223-56
    First Posted:
    Feb 5, 2010
    Last Update Posted:
    Dec 16, 2014
    Last Verified:
    Dec 1, 2014