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    Clinical Trial Results:
    Phase 1b/2, Multicenter, Open-label Study of Oprozomib and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma

    Summary
    EudraCT number
    		 2013-001169-18
    Trial protocol
    		 FR  
    Global end of trial date
    25 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jul 2020
    First version publication date
    09 Jul 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2012-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01832727
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Amgen: 20130408
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320-1799
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase 1b: - To determine the maximum tolerated dose (MTD) of oprozomib given orally, once daily, on 2 different schedules: 5 consecutive days every 14 days (bimonthly) or 2 consecutive days every 7 days (weekly) for a 14-day treatment cycle, both schedules given in combination with dexamethasone. - To evaluate safety and tolerability. Phase 2: - To estimate the overall response rate (ORR), defined as the proportion of subjects with the best overall response of stringent complete response (sCR), complete response (CR), near complete response (nCR), very good partial response (VGPR), and partial response (PR) as defined by the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) and modified European Group for Blood and Marrow Transplantation (EBMT) criteria. - To evaluate safety and tolerability.
    Protection of trial subjects
    The study was conducted in accordance with FDA and International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP), the Declaration of Helsinki, any applicable local health authority, and IRB or IEC requirements. This study was approved by a properly constituted IRB/IEC. Before the investigational drug was shipped to the investigator, the investigator or designee provided sponsor with a copy of the IRB/IEC approval letter stating that the study protocol and any subsequent amendments and ICFs have been reviewed and approved. The investigator was responsible for notifying his or her IRB/IEC of any significant AEs that are serious and/or unexpected. Subject medical information obtained as part of this study is confidential and was not disclosed to third parties, except as noted below. The subject may request in writing that medical information be given to his/her personal physician. The investigator/institution permits direct access to source data and documents for sponsor, its designee, the FDA, and other applicable regulatory authorities. The access may consist of study-related monitoring, audits, IRB/IEC reviews, and FDA/regulatory authority inspections. Before any study procedure was implemented, informed consent was documented by the use of a written informed consent form (ICF) approved by the IRB/IEC and signed and dated by the subject or the subject’s legally authorized representative at the time of consent. A copy of the signed ICF was given to the subject or subject’s legally authorized representative. The original signed ICF must be maintained by the investigator and available for inspection by sponsor, its designated representative, or regulatory authority at any time.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    United States: 58
    Worldwide total number of subjects
    65
    EEA total number of subjects
    7
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    33
    From 65 to 84 years
    30
    85 years and over
    2

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study was conducted at 18 centers in the United States and France.

    Pre-assignment
    Screening details
    		 Eighty-one subjects were screened; sixteen were not enrolled due to entry criteria violations.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 180 mg 5/14 Schedule (Phase 1b)
    Arm description
    		 Oprozomib 180 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oprozomib
    Investigational medicinal product code
    Other name
    OPZ , ONX 0912, oprozomib ER
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.

    Investigational medicinal product name
    Dexamthasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.

    Arm title
    		 Cohort 210 mg 5/14 Schedule (Phase 1b)
    Arm description
    		 Oprozomib 210 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 5/14 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oprozomib
    Investigational medicinal product code
    Other name
    OPZ , ONX 0912, oprozomib ER
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.

    Investigational medicinal product name
    Dexamthasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.

    Arm title
    		 Cohort 150/180 mg 5/14 Schedule (Phase 1b)
    Arm description
    		 Oprozomib 150 mg once daily treatment for 5 consecutive days (days 1, 2, 3, 4, and 5 of a 14-day cycle) followed by a step-up in oprozomib once daily dose to 180 mg starting in cycle 2 and moving forward. Dexamethasone 20 mg once daily was administered on days 1, 2, 8, and 9 of each 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oprozomib
    Investigational medicinal product code
    Other name
    OPZ , ONX 0912, oprozomib ER
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.

    Investigational medicinal product name
    Dexamthasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.

    Arm title
    		 Cohort 210 mg 2/7 Schedule (Phase 1b)
    Arm description
    		 Oprozomib 210 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 2/7 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamthasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.

    Investigational medicinal product name
    Oprozomib
    Investigational medicinal product code
    Other name
    OPZ , ONX 0912, oprozomib ER
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.

    Arm title
    		 Cohort 240 mg 2/7 Schedule (Phase 1b)
    Arm description
    		 Oprozomib 240 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oprozomib
    Investigational medicinal product code
    Other name
    OPZ , ONX 0912, oprozomib ER
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.

    Investigational medicinal product name
    Dexamthasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.

    Arm title
    		 Cohort 270 mg 2/7 Schedule (Phase 1b)
    Arm description
    		 Oprozomib 270 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Dexamthasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.

    Investigational medicinal product name
    Oprozomib
    Investigational medicinal product code
    Other name
    OPZ , ONX 0912, oprozomib ER
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.

    Arm title
    		 Cohort 300 mg 2/7 Schedule (Phase 1b)
    Arm description
    		 Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oprozomib
    Investigational medicinal product code
    Other name
    OPZ , ONX 0912, oprozomib ER
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.

    Investigational medicinal product name
    Dexamthasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.

    Arm title
    		 Cohort 330 mg 2/7 Schedule (Phase 1b)
    Arm description
    		 Oprozomib 330 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oprozomib
    Investigational medicinal product code
    Other name
    OPZ , ONX 0912, oprozomib ER
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.

    Investigational medicinal product name
    Dexamthasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.

    Arm title
    		 Phase 2 300 mg 2/7 Schedule
    Arm description
    		 The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oprozomib
    Investigational medicinal product code
    Other name
    OPZ , ONX 0912, oprozomib ER
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oprozomib tablets were supplied containing 60, 90, or 120 mg of oprozomib. Oprozomib extended release tablets were supplied containing 150, 180, 210, 240, or 270 mg of oprozomib. Both formulations were administered in a single dose on dosing days. The tablet formulation required multiple tablets to reach each dose on dosing days.

    Investigational medicinal product name
    Dexamthasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone was administered as 20 mg tablets in strengths of 4 and 6 mg taken orally. If a participant could not tolerate tablets or tablets were unavailable, 20 mg administered intravenously was substituted.

    Number of subjects in period 1
    		Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule
    Started
    9
    7
    3
    4
    4
    6
    8
    6
    18
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    9
    7
    3
    4
    4
    6
    8
    6
    18
         Adverse event, serious fatal
    -
    1
    -
    -
    1
    -
    -
    -
    -
         Physician decision
    1
    -
    -
    1
    -
    1
    -
    -
    -
         Consent withdrawn by subject
    1
    1
    -
    1
    -
    1
    -
    2
    1
         Adverse event, non-fatal
    4
    5
    1
    -
    -
    1
    2
    1
    9
         Study Terminated by Sponsor
    -
    -
    -
    -
    -
    -
    -
    1
    1
         Lost to follow-up
    -
    -
    -
    1
    -
    -
    -
    -
    -
         Disease Progression
    3
    -
    2
    1
    3
    3
    6
    2
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 180 mg 5/14 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 180 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 210 mg 5/14 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 210 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 5/14 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts.

    Reporting group title
    Cohort 150/180 mg 5/14 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 150 mg once daily treatment for 5 consecutive days (days 1, 2, 3, 4, and 5 of a 14-day cycle) followed by a step-up in oprozomib once daily dose to 180 mg starting in cycle 2 and moving forward. Dexamethasone 20 mg once daily was administered on days 1, 2, 8, and 9 of each 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 210 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 210 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 2/7 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts.

    Reporting group title
    Cohort 240 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 240 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 270 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 270 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 300 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 330 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 330 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Phase 2 300 mg 2/7 Schedule
    Reporting group description
    		 The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group values
    		 Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule Total
    Number of subjects
    		 9 7 3 4 4 6 8 6 18 65
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 5 4 2 1 4 2 4 5 6 33
        From 65 - < 75 years
    		 2 3 0 2 0 3 3 0 7 20
        >= 75 years
    		 2 0 1 1 0 1 1 1 5 12
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 65.8 ( 13.0 ) 64.1 ( 4.9 ) 67.3 ( 6.7 ) 68.5 ( 12.0 ) 53.8 ( 8.6 ) 66.7 ( 9.1 ) 65.6 ( 10.4 ) 59.7 ( 9.9 ) 68.9 ( 8.0 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 3 4 1 2 1 2 3 2 9 27
        Male
    		 6 3 2 2 3 4 5 4 9 38
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 0 1 0 0 1 0 2
        Not Hispanic or Latino
    		 9 7 3 4 2 6 8 5 11 55
        Not reported
    		 0 0 0 0 1 0 0 0 7 8
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0 0 0 0
        Asian
    		 1 0 0 0 0 0 0 0 0 1
        Black
    		 0 0 1 1 1 2 1 1 1 8
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0 0 0 0
        White
    		 8 7 2 3 2 4 7 4 10 47
        Other
    		 0 0 0 0 1 0 0 1 0 2
        Not reported
    		 0 0 0 0 0 0 0 0 7 7

    End points

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    End points reporting groups
    Reporting group title
    Cohort 180 mg 5/14 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 180 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 210 mg 5/14 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 210 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 5/14 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts.

    Reporting group title
    Cohort 150/180 mg 5/14 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 150 mg once daily treatment for 5 consecutive days (days 1, 2, 3, 4, and 5 of a 14-day cycle) followed by a step-up in oprozomib once daily dose to 180 mg starting in cycle 2 and moving forward. Dexamethasone 20 mg once daily was administered on days 1, 2, 8, and 9 of each 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 210 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 210 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 2/7 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts.

    Reporting group title
    Cohort 240 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 240 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 270 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 270 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 300 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 330 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 330 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Phase 2 300 mg 2/7 Schedule
    Reporting group description
    		 The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Subject analysis set title
    180 mg Oprozomib Tablet
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were administered 180 mg oprozomib tablets.

    Subject analysis set title
    210 mg Oprozomib Tablet
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were administered 210 mg oprozomib tablets.

    Subject analysis set title
    240 mg Oprozomib Tablet
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were administered 240 mg oprozomib tablets.

    Subject analysis set title
    270 mg Oprozomib Tablet
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were administered 270 mg oprozomib tablets.

    Subject analysis set title
    300 mg Oprozomib Tablet
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were administered 300 mg oprozomib tablets.

    Subject analysis set title
    150 mg Oprozomib ER Tablet
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were administered 150 mg extended release oprozomib tablets.

    Subject analysis set title
    300 mg Oprozomib ER Tablet
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were administered 300 mg extended release oprozomib tablets.

    Subject analysis set title
    330 mg Oprozomib ER Tablet
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants who were administered 330 mg extended release oprozomib tablets.

    Primary: Participants With Dose-Limiting Toxicities (DLT)

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    End point title
    		 Participants With Dose-Limiting Toxicities (DLT) [1]
    End point description
    Toxicities (graded per the Common Terminology Criteria for Adverse Events v 4.03) were considered DLTs if judged by the investigator to be related to oprozomib and occurred in the first 14 days of treatment, with treatment at the dose to be studied (i.e., Cycle 1 for continuous dosing or Cycle 2 for step-up dosing). A DLT was categorized as nonhematologic or hematologic. Examples include: • Any ≥ Grade 3 nonhematologic AE, with exceptions or qualifications such as Grade 3 nausea, vomiting, diarrhea, or constipation were considered a DLT only if lasting for > 7 days despite optimal supportive care • Grade 3 fatigue lasting > 14 days • Grade 4 neutropenia: absolute neutrophil count (ANC) < 500 cells/mcL lasting ≥ 7 days • Febrile neutropenia: Any single temperature ≥ 38.3°C or a sustained temperature of ≥ 38.0°C for over 1 hour with ≥Grade 3 neutropenia (ANC < 1000 cells/mcL) • Grade 3/4 thrombocytopenia • Others specified in the protocol
    End point type
    Primary
    End point timeframe
    Day 1 to Day 14 (Cycle 1) for continuous dosing and Day 15 to Day 28 (Cycle 2) for step-up dosing
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical reporting of safety outcomes was entirely descriptive, with no formal statistical testing performed.
    End point values
    		 Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule
    Number of subjects analysed
    9
    7
    3
    4
    4
    6
    8
    6
    18
    Units: participants
        Participants reporting >=1 DLT
    0
    3
    1
    0
    0
    2
    0
    2
    1
        Mental status changes
    0
    0
    1
    0
    0
    0
    0
    0
    0
        Alanine aminotransferase increased
    0
    1
    0
    0
    0
    0
    0
    0
    0
        Aspartate aminotransferase increased
    0
    1
    0
    0
    0
    0
    0
    0
    0
        Hypertension
    0
    1
    0
    0
    0
    0
    0
    0
    0
        Subarachnoid haemorrhage
    0
    1
    0
    0
    0
    0
    0
    0
    0
        Thrombocytopenia
    0
    1
    0
    0
    0
    1
    0
    0
    0
        Anaemia
    0
    0
    0
    0
    0
    0
    0
    0
    1
        Nausea
    0
    0
    0
    0
    0
    0
    0
    1
    0
        Upper respiratory tract infection
    0
    0
    0
    0
    0
    0
    0
    1
    0
        Vomiting
    0
    0
    0
    0
    0
    0
    0
    1
    0
        Pain in jaw
    0
    0
    0
    0
    0
    1
    0
    0
    0
    No statistical analyses for this end point

    Primary: Participants With Treatment-Emergent Adverse Events (TEAEs) During Phase 1b and 2

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    End point title
    		 Participants With Treatment-Emergent Adverse Events (TEAEs) During Phase 1b and 2 [2]
    End point description
    AE defined as any untoward medical occurrence in a clinical trial subject. Treatment-emergent adverse events were defined as adverse events that start on or after the first day of study treatment and within 30 days of the last day of study treatment. An adverse event that was present before the first administration of study treatment and subsequently worsens in severity during treatment was also considered to be treatment-emergent. Serious AE defined as AE that is fatal, life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v4.03) based on general guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE IP=investigational product
    End point type
    Primary
    End point timeframe
    Day 1 up to Week 282
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical reporting of safety outcomes was entirely descriptive, with no formal statistical testing performed.
    End point values
    		 Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule
    Number of subjects analysed
    9
    7
    3
    4
    4
    6
    8
    6
    18
    Units: participants
        >=1 TEAE
    9
    7
    3
    4
    4
    6
    8
    6
    18
        Grade >=3 (severe)
    8
    5
    2
    3
    3
    5
    6
    5
    16
        Serious AE
    4
    2
    2
    2
    1
    1
    3
    0
    9
        Leading to discontinuation of IP
    4
    6
    1
    0
    1
    1
    2
    1
    11
        Fatal AE
    0
    1
    0
    0
    1
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Participants With Treatment-Related, Treatment-Emergent Adverse Events (TEAEs) During Phase 1b and 2

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    End point title
    		 Participants With Treatment-Related, Treatment-Emergent Adverse Events (TEAEs) During Phase 1b and 2 [3]
    End point description
    AE defined as any untoward medical occurrence in a clinical trial participant. TEAEs were defined as AEs that start on or after the first day of study treatment and within 30 days of the last day of study treatment. An AE that was present before the first administration of study treatment and subsequently worsens in severity during treatment was also considered a TEAE. Investigator assessed AEs for relatedness to study drug. Serious AE defined as AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or other significant medical hazard. Severity of AEs assessed according to Common Terminology Criteria for Adverse Events (CTCAE, v4.03) based on the general guideline: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening or disabling; Grade 5: Death related to AE. IP=investigational product
    End point type
    Primary
    End point timeframe
    Day 1 up to Week 282
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical reporting of safety outcomes was entirely descriptive, with no formal statistical testing performed.
    End point values
    		 Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule
    Number of subjects analysed
    9
    7
    3
    4
    4
    6
    8
    6
    18
    Units: participants
        >=1 related TEAE
    9
    7
    3
    4
    4
    6
    8
    6
    18
        Grade >=3 (severe)
    8
    5
    2
    2
    2
    2
    4
    3
    14
        Serious AE
    3
    2
    0
    1
    0
    0
    2
    0
    3
        Leading to discontinuation of IP
    3
    6
    0
    0
    1
    1
    1
    1
    7
        Fatal AE
    0
    1
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Best Overall Response in Phase 2 as Assessed by Investigator

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    End point title
    		 Best Overall Response in Phase 2 as Assessed by Investigator [4] [5]
    End point description
    Disease response and progression were determined using the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC), except for minimal response (MR) and near complete response (nCR) which was based on the European Group for Blood and Marrow Transplantation (EBMT) criteria. Evaluations reported were assessed by the investigator for participants in Phase 2.
    End point type
    Primary
    End point timeframe
    Screening: Day 14 to Day -1; During study: Day 1 up to 13.16 months
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Formal statistics were not performed for the single arm reported in Phase 2
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The protocol specified that efficacy endpoints would be reported for the phase 2 treatment arm only.
    End point values
    		 Phase 2 300 mg 2/7 Schedule
    Number of subjects analysed
    18
    Units: participants
        Stringent Complete Response (sCR)
    0
        Complete Response (CR)
    1
        Near Complete Response (nCR)
    0
        Very Good Partial Response (VGPR)
    2
        Partial Response (PR)
    9
        Minimal Response (MR)
    1
        Stable Disease (SD)
    2
        Progressive Disease (PD)
    1
        Not Evaluable (NE)
    2
        Unknown
    0
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Achieved an Overall Response As Assessed by Investigator During Phase 2

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    End point title
    		 Percentage of Participants Who Achieved an Overall Response As Assessed by Investigator During Phase 2 [6] [7]
    End point description
    The overall response rate (ORR) was defined as the percentage of participants with the best overall response of stringent complete response (sCR), complete response (CR), near complete response (nCR), very good partial response (VGPR), and partial response (PR) as defined by the International Myeloma Working Group-Uniform Response Criteria (IMWG-URC) and modified European Group for Blood and Marrow Transplantation (EBMT) criteria.
    End point type
    Primary
    End point timeframe
    Day 14 to Day -1; During study: Day 1 up to 13.16 months
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Formal statistics were not performed for the single arm reported in Phase 2
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The protocol specified that efficacy endpoints would be reported for the phase 2 treatment arm only.
    End point values
    		 Phase 2 300 mg 2/7 Schedule
    Number of subjects analysed
    18
    Units: percentage of participants
        number (confidence interval 95%)
    66.7 (41.0 to 86.7)
    No statistical analyses for this end point

    Secondary: PK Parameter for Oprozomib, Tablet and ER Formulation: Time to Maximum Serum Concentration on Cycle 1, Day 1

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    End point title
    		 PK Parameter for Oprozomib, Tablet and ER Formulation: Time to Maximum Serum Concentration on Cycle 1, Day 1
    End point description
    PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2. Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2. Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus predose on Day 2.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 180 mg Oprozomib Tablet 210 mg Oprozomib Tablet 240 mg Oprozomib Tablet 270 mg Oprozomib Tablet 300 mg Oprozomib Tablet 150 mg Oprozomib ER Tablet 300 mg Oprozomib ER Tablet 330 mg Oprozomib ER Tablet
    Number of subjects analysed
    9
    9
    4
    6
    5
    3
    19
    6
    Units: hour
        median (full range (min-max))
    1.0 (0.50 to 2.0)
    1.1 (0.50 to 6.0)
    1.0 (0.98 to 2.0)
    1.0 (0.50 to 2.0)
    2.0 (1.0 to 3.9)
    2.0 (1.1 to 4.0)
    1.0 (0.50 to 2.0)
    1.5 (0.47 to 4.0)
    No statistical analyses for this end point

    Secondary: PK Parameter for Oprozomib, Tablet and ER Formulation: Maximum Serum Concentration (Cmax) on Cycle 1, Day 1

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    End point title
    		 PK Parameter for Oprozomib, Tablet and ER Formulation: Maximum Serum Concentration (Cmax) on Cycle 1, Day 1
    End point description
    PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus predose on Day 2
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 180 mg Oprozomib Tablet 210 mg Oprozomib Tablet 240 mg Oprozomib Tablet 270 mg Oprozomib Tablet 300 mg Oprozomib Tablet 150 mg Oprozomib ER Tablet 300 mg Oprozomib ER Tablet 330 mg Oprozomib ER Tablet
    Number of subjects analysed
    9
    9
    4
    6
    5
    3
    19
    6
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    633 ( 192.1 )
    754 ( 91.7 )
    841 ( 73.8 )
    906 ( 69.3 )
    881 ( 37.8 )
    672 ( 54.5 )
    785 ( 63.7 )
    578 ( 80.1 )
    No statistical analyses for this end point

    Secondary: PK Parameter for Oprozomib, Tablet and ER Formulation: Area Under the Curve at the Last Quantifiable Concentration (AUClast) on Cycle 1, Day 1

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    End point title
    		 PK Parameter for Oprozomib, Tablet and ER Formulation: Area Under the Curve at the Last Quantifiable Concentration (AUClast) on Cycle 1, Day 1
    End point description
    The area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast) was estimated using the linear trapezoidal method. PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus predose on Day 2
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 180 mg Oprozomib Tablet 210 mg Oprozomib Tablet 240 mg Oprozomib Tablet 270 mg Oprozomib Tablet 300 mg Oprozomib Tablet 150 mg Oprozomib ER Tablet 300 mg Oprozomib ER Tablet 330 mg Oprozomib ER Tablet
    Number of subjects analysed
    9
    9
    4
    6
    5
    3
    19
    6
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    1140 ( 197.4 )
    1770 ( 104.7 )
    2170 ( 51.8 )
    1900 ( 68.9 )
    2530 ( 63.4 )
    1690 ( 16.1 )
    1740 ( 70.3 )
    1690 ( 70.8 )
    No statistical analyses for this end point

    Secondary: PK for Oprozomib, Tablet and ER Formulation: Area Under the Curve From Time 0 to Infinity (AUCinf) on Cycle 1 Day 1

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    End point title
    		 PK for Oprozomib, Tablet and ER Formulation: Area Under the Curve From Time 0 to Infinity (AUCinf) on Cycle 1 Day 1
    End point description
    The area under the plasma concentration-curve from time 0 to time infinity (AUCinf) was estimated using the linear trapezoidal method. PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus predose on Day 2 9999 = Not reported
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 180 mg Oprozomib Tablet 210 mg Oprozomib Tablet 240 mg Oprozomib Tablet 270 mg Oprozomib Tablet 300 mg Oprozomib Tablet 150 mg Oprozomib ER Tablet 300 mg Oprozomib ER Tablet 330 mg Oprozomib ER Tablet
    Number of subjects analysed
    7
    6
    4
    4
    5
    1
    15
    4
    Units: hr*ng/mL
        geometric mean (geometric coefficient of variation)
    947 ( 229.7 )
    1600 ( 127.2 )
    2180 ( 51.6 )
    1970 ( 88.8 )
    2550 ( 63.5 )
    9999 ( 9999 )
    1900 ( 77.7 )
    2150 ( 27.6 )
    No statistical analyses for this end point

    Secondary: PK Parameter for Oprozomib, Tablet and ER Formulation: Terminal Half-Life (t1/2,z) on Cycle 1, Day 1

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    End point title
    		 PK Parameter for Oprozomib, Tablet and ER Formulation: Terminal Half-Life (t1/2,z) on Cycle 1, Day 1
    End point description
    PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus predose on Day 2 9999 = Not reported
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 180 mg Oprozomib Tablet 210 mg Oprozomib Tablet 240 mg Oprozomib Tablet 270 mg Oprozomib Tablet 300 mg Oprozomib Tablet 150 mg Oprozomib ER Tablet 300 mg Oprozomib ER Tablet 330 mg Oprozomib ER Tablet
    Number of subjects analysed
    7
    6
    4
    4
    5
    1
    15
    4
    Units: hour
        geometric mean (geometric coefficient of variation)
    0.962 ( 40.6 )
    0.573 ( 29.4 )
    0.970 ( 79.2 )
    0.850 ( 29.5 )
    1.36 ( 80.1 )
    9999 ( 9999 )
    0.710 ( 40.7 )
    0.805 ( 40.1 )
    No statistical analyses for this end point

    Secondary: PK Parameter for Oprozomib, Tablet and ER Formulation: Apparent Drug Clearance After Oral Administration (CL/F) on Cycle 1, Day 1

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    End point title
    		 PK Parameter for Oprozomib, Tablet and ER Formulation: Apparent Drug Clearance After Oral Administration (CL/F) on Cycle 1, Day 1
    End point description
    The apparent drug clearance after oral administration (CL/F) was calculated as the dose divided by AUCinf. PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus predose on Day 2 9999 = Not reported
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 180 mg Oprozomib Tablet 210 mg Oprozomib Tablet 240 mg Oprozomib Tablet 270 mg Oprozomib Tablet 300 mg Oprozomib Tablet 150 mg Oprozomib ER Tablet 300 mg Oprozomib ER Tablet 330 mg Oprozomib ER Tablet
    Number of subjects analysed
    7
    6
    4
    4
    5
    1
    15
    4
    Units: mL/hour
        geometric mean (geometric coefficient of variation)
    190000 ( 229.7 )
    131000 ( 127.2 )
    110000 ( 51.6 )
    137000 ( 88.8 )
    118000 ( 63.5 )
    9999 ( 9999 )
    157000 ( 77.7 )
    153000 ( 27.6 )
    No statistical analyses for this end point

    Secondary: PK Parameter for Oprozomib, Tablet and ER Formulation: Apparent Volume of Distribution After Oral Administration (Vz/F) on Cycle 1, Day 1

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    End point title
    		 PK Parameter for Oprozomib, Tablet and ER Formulation: Apparent Volume of Distribution After Oral Administration (Vz/F) on Cycle 1, Day 1
    End point description
    The apparent volume of distribution after oral administration (Vz/F) calculated as the dose divided by AUCinf times ƒz, where ƒz was the first-order terminal rate constant estimated via linear regression of the terminal log-linear phase. PK samples obtained on the following schedule: Phase 1b Continuous Dosing, Cycles 1 and 2: Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 8 hours post-dose plus pre-dose on Day 2 Phase 1b Step-up Dosing, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus pre-dose on Day 2 Phase 2, Day 1: pre-dose, post-dose at 15 and 30 minutes, 1, 2, 4, 6, and 7 hours post-dose plus predose on Day 2 9999 = Not reported
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 180 mg Oprozomib Tablet 210 mg Oprozomib Tablet 240 mg Oprozomib Tablet 270 mg Oprozomib Tablet 300 mg Oprozomib Tablet 150 mg Oprozomib ER Tablet 300 mg Oprozomib ER Tablet 330 mg Oprozomib ER Tablet
    Number of subjects analysed
    7
    6
    4
    4
    5
    1
    15
    4
    Units: mL
        geometric mean (geometric coefficient of variation)
    264000 ( 235.6 )
    108000 ( 106.7 )
    154000 ( 79.5 )
    168000 ( 138.9 )
    231000 ( 54.7 )
    9999 ( 9999 )
    161000 ( 69.0 )
    178000 ( 44.3 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Achieved a Clinical Benefit Response As Assessed by Investigator During Phase 2

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    End point title
    		 Percentage of Participants Who Achieved a Clinical Benefit Response As Assessed by Investigator During Phase 2 [8]
    End point description
    The clinical benefit rate (CBR) was defined as Overall Response Rate (ORR) plus Minimal Response (MR) as defined by the European Group for Blood and Marrow Transplantation (EBMT) criteria.
    End point type
    Secondary
    End point timeframe
    Day 14 to Day -1; During study: Day 1 up to 13.16 months
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The protocol specified that efficacy endpoints would be reported for the phase 2 treatment arm only.
    End point values
    		 Phase 2 300 mg 2/7 Schedule
    Number of subjects analysed
    18
    Units: percentage of participants
        number (confidence interval 95%)
    72.2 (46.5 to 90.3)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimates for Duration of Response (DOR) as Assessed by Investigator During Phase 2

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    End point title
    		 Kaplan-Meier Estimates for Duration of Response (DOR) as Assessed by Investigator During Phase 2 [9]
    End point description
    Duration of response was defined as the time from first evidence of partial response (PR) or better (i.e. best overall response) to confirmation of disease progression or death due to any cause. Durations were calculated for responders only. Medians and percentiles were estimated using the Kaplan-Meier method. 95% confidence intervals for medians and percentiles were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. 9999 = not estimable.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 13.16 months
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The protocol specified that efficacy endpoints would be reported for the phase 2 treatment arm only.
    End point values
    		 Phase 2 300 mg 2/7 Schedule
    Number of subjects analysed
    18
    Units: months
        median (confidence interval 95%)
    9999 (6.8 to 9999)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimates for Progression-free Survival (PFS) as Assessed by Investigator During Phase 2

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    End point title
    		 Kaplan-Meier Estimates for Progression-free Survival (PFS) as Assessed by Investigator During Phase 2 [10]
    End point description
    Progression-free survival (PFS) was defined as number of months between start of treatment and first evidence of documented disease progression or death (due to any cause), whichever occurs first. Disease progression was determined using IMWG-URC per investigator. The duration of PFS was right–censored for participants who met 1 of the following conditions: • 1) starting a new anticancer therapy before documentation of disease progression or death; • 2) death or disease progression immediately after more than 1 consecutively missed disease assessment visit or; • 3) alive without documentation of disease progression before the data cutoff date. 95% CIs for medians were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. 9999 = not estimable
    End point type
    Secondary
    End point timeframe
    Day 1 up to 14.1 months
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The protocol specified that efficacy endpoints would be reported for the phase 2 treatment arm only.
    End point values
    		 Phase 2 300 mg 2/7 Schedule
    Number of subjects analysed
    18
    Units: months
        median (confidence interval 95%)
    12.2 (3.5 to 9999)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate for Time to Progression (TTP) as Assessed by Investigator During Phase 2

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    End point title
    		 Kaplan-Meier Estimate for Time to Progression (TTP) as Assessed by Investigator During Phase 2 [11]
    End point description
    Time to progression (TTP) was defined as the number of months between the start of treatment to the first documentation of disease progression. Disease progression was determined using IMWG-URC as assessed by the investigator. The same censoring rules, except for death, as in analysis of PFS were applied in the calculation of TTP. Participants who died prior to progressive disease were censored at the date of last evaluable response assessment. 9999 = not estimable
    End point type
    Secondary
    End point timeframe
    Day 1 up to 14.1 months
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The protocol specified that efficacy endpoints would be reported for the phase 2 treatment arm only.
    End point values
    		 Phase 2 300 mg 2/7 Schedule
    Number of subjects analysed
    18
    Units: months
        median (confidence interval 95%)
    12.2 (3.5 to 9999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events - Day 1 up to Week 282
    Adverse event reporting additional description
    Mortality - Death that occurred from the first dose of study drug until the end of study. Adverse Events - From the first dose of study drug until 30 days after the last dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Cohort 180 mg 5/14 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 180 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 210 mg 5/14 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 210 mg treatment once daily for 5 consecutive days bimonthly (days 1, 2, 3, 4, and 5 of a 14-day cycle) with 20 mg dexamethasone once daily on days 1, 2, 8, and 9 (referred to as the 5/14 schedule). Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 5/14 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts.

    Reporting group title
    Cohort 210 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 210 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason. This was the first cohort to enroll participants into the 2/7 schedule. The Cohort Safety Review Committee (CSRC) reviewed safety data and made dose adjustments for oprozomib in 30 mg increments for all cohorts.

    Reporting group title
    Cohort 240 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 240 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 270 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 270 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 300 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 330 mg 2/7 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 330 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Cohort 150/180 mg 5/14 Schedule (Phase 1b)
    Reporting group description
    		 Oprozomib 150 mg once daily treatment for 5 consecutive days (days 1, 2, 3, 4, and 5 of a 14-day cycle) followed by a step-up in oprozomib once daily dose to 180 mg starting in cycle 2 and moving forward. Dexamethasone 20 mg once daily was administered on days 1, 2, 8, and 9 of each 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Reporting group title
    Phase 2 300 mg 2/7 Schedule
    Reporting group description
    		 The Cohort Safety Review Committee (CSRC) determined this dose as the recommended phase 2 dose (RP2D). Oprozomib 300 mg once daily on Days 1, 2, 8, and 9 of a 14-day treatment cycle in combination with 20 mg dexamethasone once daily on Days 1, 2, 8, and 9 of a 14-day cycle. Treatment was administered in 14-day cycles until disease progression, unacceptable toxicity, or study treatment discontinuation for any reason.

    Serious adverse events
    		 Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 9 (44.44%)
    2 / 7 (28.57%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    3 / 8 (37.50%)
    0 / 6 (0.00%)
    2 / 3 (66.67%)
    9 / 18 (50.00%)
         number of deaths (all causes)
    0
    1
    0
    1
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone lesion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 18 (16.67%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 180 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 5/14 Schedule (Phase 1b) Cohort 210 mg 2/7 Schedule (Phase 1b) Cohort 240 mg 2/7 Schedule (Phase 1b) Cohort 270 mg 2/7 Schedule (Phase 1b) Cohort 300 mg 2/7 Schedule (Phase 1b) Cohort 330 mg 2/7 Schedule (Phase 1b) Cohort 150/180 mg 5/14 Schedule (Phase 1b) Phase 2 300 mg 2/7 Schedule
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    7 / 7 (100.00%)
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    6 / 6 (100.00%)
    8 / 8 (100.00%)
    6 / 6 (100.00%)
    3 / 3 (100.00%)
    18 / 18 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasma cell myeloma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    5
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Flushing
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Haematoma
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Hot flush
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    0
    0
    Hypertension
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
         occurrences all number
    3
    3
    1
    2
    4
    1
    5
    5
    1
    Hypotension
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    2
    1
    0
    1
    0
    0
    0
    0
    3
    Orthostatic hypotension
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    0
    0
    Phlebitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Post thrombotic syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Thrombosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Venous thrombosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Surgical and medical procedures
    Joint surgery
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Medical device implantation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    8 / 18 (44.44%)
         occurrences all number
    3
    1
    0
    0
    0
    1
    1
    0
    32
    Chest discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    1
    0
    0
    Chills
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    2 / 3 (66.67%)
    3 / 18 (16.67%)
         occurrences all number
    2
    0
    0
    1
    0
    1
    4
    3
    4
    Discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Facial pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    6 / 9 (66.67%)
    4 / 7 (57.14%)
    2 / 4 (50.00%)
    2 / 4 (50.00%)
    4 / 6 (66.67%)
    7 / 8 (87.50%)
    6 / 6 (100.00%)
    2 / 3 (66.67%)
    7 / 18 (38.89%)
         occurrences all number
    13
    5
    8
    3
    9
    21
    12
    4
    16
    Feeling abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    0
    0
    1
    Feeling jittery
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Gait disturbance
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    2
    4
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Nodule
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Oedema
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    2
    2
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    5 / 18 (27.78%)
         occurrences all number
    1
    1
    3
    0
    0
    1
    2
    2
    5
    Pain
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    2 / 3 (66.67%)
    5 / 18 (27.78%)
         occurrences all number
    3
    0
    0
    2
    1
    1
    0
    8
    7
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Breast disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Erectile dysfunction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Uterine prolapse
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Vaginal prolapse
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    6 / 18 (33.33%)
         occurrences all number
    1
    1
    0
    3
    3
    1
    0
    2
    9
    Dysphonia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    2 / 18 (11.11%)
         occurrences all number
    4
    1
    1
    0
    2
    1
    3
    2
    4
    Dyspnoea exertional
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    2
    Epistaxis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    2
    1
    0
    0
    0
    0
    Haemoptysis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Hiccups
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    3
    2
    0
    1
    0
    0
    0
    0
    5
    Hypoxia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    2 / 3 (66.67%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    2
    0
    Nasal congestion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    2
    Orthopnoea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Pleuritic pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Pulmonary embolism
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Respiratory failure
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    Rhonchi
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Sinus congestion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    2
    Sneezing
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    4
    Anxiety
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    1
    1
    1
    0
    0
    1
    0
    0
    3
    Bruxism
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Confusional state
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    Disorientation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    4 / 18 (22.22%)
         occurrences all number
    2
    2
    0
    1
    3
    4
    3
    0
    8
    Irritability
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    3
    Mental disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    1
    Mental status changes
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Thinking abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    3
    0
    1
    1
    2
    3
    0
    0
    Aspartate aminotransferase decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    3
    0
    0
    1
    1
    2
    0
    0
    Blood alkaline phosphatase decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    0
    0
    0
    0
    Blood creatinine decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    3
    2
    0
    1
    0
    3
    0
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    1
    Blood phosphorus increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Blood pressure abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Blood urea decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Blood uric acid decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Cardiac murmur
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    International normalised ratio increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    2
    1
    2
    0
    1
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    0
    0
    1
    Platelet count decreased
         subjects affected / exposed
    2 / 9 (22.22%)
    2 / 7 (28.57%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    3
    5
    0
    3
    0
    0
    2
    0
    1
    Protein total increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    4
    White blood cell count decreased
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    2
    1
    1
    0
    0
    1
    0
    0
    White blood cell count increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    Animal scratch
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Concussion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Contusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Fall
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    0
    0
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Laceration
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    1
    0
    Muscle strain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Thermal burn
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Wound
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Arrhythmia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Bundle branch block right
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Diastolic dysfunction
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    0
    0
    3
    0
    0
    1
    Pericardial effusion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    2
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Cognitive disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Dizziness
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    3
    1
    0
    1
    1
    3
    5
    0
    7
    Dysgeusia
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 7 (28.57%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    3 / 8 (37.50%)
    3 / 6 (50.00%)
    0 / 3 (0.00%)
    4 / 18 (22.22%)
         occurrences all number
    2
    2
    1
    4
    1
    4
    67
    0
    4
    Head discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    3 / 8 (37.50%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    6 / 18 (33.33%)
         occurrences all number
    1
    2
    2
    1
    2
    10
    2
    0
    9
    Hypoaesthesia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    1
    1
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    1
    Memory impairment
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    0
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Seizure
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Tremor
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 9 (33.33%)
    2 / 7 (28.57%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    5 / 8 (62.50%)
    3 / 6 (50.00%)
    1 / 3 (33.33%)
    8 / 18 (44.44%)
         occurrences all number
    17
    2
    1
    1
    0
    9
    7
    1
    21
    Leukopenia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Lymphopenia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    9
    1
    2
    0
    4
    0
    1
    0
    0
    Microcytic anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Neutropenia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 7 (28.57%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    4 / 18 (22.22%)
         occurrences all number
    8
    2
    2
    2
    7
    7
    2
    1
    11
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Ear congestion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Ear discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Middle ear effusion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Otorrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Tinnitus
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    5
    Vertigo
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    15
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Vision blurred
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    1
    1
    0
    0
    0
    2
    2
    0
    5
    Visual impairment
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Vitreous floaters
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    2
    Abdominal distension
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    7 / 18 (38.89%)
         occurrences all number
    1
    0
    0
    0
    0
    36
    24
    0
    11
    Abdominal pain
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    6 / 18 (33.33%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    1
    0
    15
    Abdominal pain upper
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    4 / 18 (22.22%)
         occurrences all number
    3
    1
    0
    0
    0
    1
    1
    0
    7
    Abdominal rigidity
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Anal incontinence
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Constipation
         subjects affected / exposed
    2 / 9 (22.22%)
    2 / 7 (28.57%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    4 / 8 (50.00%)
    5 / 6 (83.33%)
    1 / 3 (33.33%)
    10 / 18 (55.56%)
         occurrences all number
    3
    2
    2
    12
    1
    15
    16
    1
    26
    Dental caries
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    8 / 9 (88.89%)
    6 / 7 (85.71%)
    4 / 4 (100.00%)
    3 / 4 (75.00%)
    6 / 6 (100.00%)
    7 / 8 (87.50%)
    5 / 6 (83.33%)
    2 / 3 (66.67%)
    14 / 18 (77.78%)
         occurrences all number
    26
    23
    21
    13
    53
    76
    35
    4
    71
    Diverticulum
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    1
    0
    Dyspepsia
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    6 / 18 (33.33%)
         occurrences all number
    3
    1
    0
    5
    1
    10
    0
    0
    19
    Eructation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    0
    0
    0
    Faeces soft
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Flatulence
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Functional gastrointestinal disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Gastrointestinal motility disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Gastrointestinal sounds abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    3 / 8 (37.50%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    0
    0
    3
    4
    2
    0
    5
    Gingival bleeding
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Glossodynia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Hypoaesthesia oral
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Ileus
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Large intestine polyp
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Lip haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    8 / 9 (88.89%)
    7 / 7 (100.00%)
    4 / 4 (100.00%)
    3 / 4 (75.00%)
    5 / 6 (83.33%)
    7 / 8 (87.50%)
    6 / 6 (100.00%)
    3 / 3 (100.00%)
    12 / 18 (66.67%)
         occurrences all number
    26
    22
    23
    26
    16
    62
    67
    5
    56
    Oral disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Periodontal disease
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Retching
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    0
    0
    1
    Toothache
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Vomiting
         subjects affected / exposed
    6 / 9 (66.67%)
    5 / 7 (71.43%)
    4 / 4 (100.00%)
    3 / 4 (75.00%)
    2 / 6 (33.33%)
    2 / 8 (25.00%)
    5 / 6 (83.33%)
    3 / 3 (100.00%)
    8 / 18 (44.44%)
         occurrences all number
    16
    19
    11
    3
    25
    6
    11
    5
    22
    Hepatobiliary disorders
    Hepatitis cholestatic
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Angioedema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Blister
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Chronic papillomatous dermatitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Dermatitis allergic
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    Drug eruption
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Dry skin
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    2
    0
    0
    Ecchymosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Hair texture abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    3
    0
    1
    Miliaria
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Nail ridging
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    6
    2
    0
    7
    Onychomadesis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Rash
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    2
    0
    0
    Rash macular
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Rash maculo-papular
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Skin lesion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Dysuria
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    1
    Haematuria
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Nocturia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    1
    Renal failure
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Urinary hesitation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    3 / 6 (50.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    3
    0
    0
    Arthritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Back pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    2
    0
    1
    Bone pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    2
    Exostosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Joint stiffness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Joint swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Limb discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    6 / 18 (33.33%)
         occurrences all number
    2
    0
    0
    0
    0
    5
    0
    1
    11
    Muscular weakness
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    3 / 6 (50.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    7
    2
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    2
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    3 / 6 (50.00%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    3
    0
    2
    Neck pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    0
    0
    0
    Osteonecrosis of jaw
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    0
    1
    3
    2
    1
    1
    Pain in jaw
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    1
    Candida infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    Cellulitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Diverticulitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    1
    Genital herpes
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Haemophilus infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Herpes virus infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Herpes zoster
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Hordeolum
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    2
    Sepsis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    0
    1
    Tinea cruris
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Tooth abscess
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Tooth infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    3 / 6 (50.00%)
    3 / 8 (37.50%)
    5 / 6 (83.33%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    0
    1
    6
    3
    9
    0
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    1
    0
    0
    0
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Cell death
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    4
    Decreased appetite
         subjects affected / exposed
    5 / 9 (55.56%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    3 / 4 (75.00%)
    0 / 6 (0.00%)
    2 / 8 (25.00%)
    2 / 6 (33.33%)
    2 / 3 (66.67%)
    5 / 18 (27.78%)
         occurrences all number
    5
    1
    0
    32
    0
    2
    2
    3
    5
    Dehydration
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    2
    1
    0
    0
    2
    1
    2
    Diabetes mellitus
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    2
    Fluid overload
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Hypercalcaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    1 / 6 (16.67%)
    2 / 8 (25.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    6
    2
    2
    6
    1
    2
    0
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    1
    Hypermagnesaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 7 (14.29%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    7
    1
    1
    2
    0
    2
    1
    0
    2
    Hypocalcaemia
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 8 (12.50%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    7
    1
    0
    0
    2
    1
    2
    0
    0
    Hypoglycaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    4 / 9 (44.44%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 8 (12.50%)
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    2 / 18 (11.11%)
         occurrences all number
    6
    1
    0
    1
    0
    1
    2
    1
    3
    Hypomagnesaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    1
    2
    11
    0
    3
    0
    3
    Hyponatraemia
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 7 (14.29%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    0 / 3 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    6
    2
    0
    1
    0
    0
    2
    0
    5
    Hypophosphataemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 8 (0.00%)
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    1 / 18 (5.56%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    2
    1
    1
    Hypovolaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Iron deficiency
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 18 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Lactic acidosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Malnutrition
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 7 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Mar 2013
    Study 2012-001 was amended to implement a new starting dose for Oprozomib Tablets for both dosing schedules based on dose-escalation data from ongoing Study 2011-001. Other key changes: 1. Global change: Starting dose of 150 mg was changed to 210 mg for both oprozomib dosing schedules. This update was made based on dose-escalation data from ongoing Study 2011-001 from both tablet and product-in-capsule (PIC) formulations. 2. Global change: Changed units for absolute neutrophil count (ANC) and platelet counts from [value] *10^9/L to standard units, [value] cells/mcL. 3. Study Synopsis (Test Product, Dose, and Mode of Administration): Removed specific dexamethasone oral tablet strengths (4 mg and 6 mg). This text did not appear in the protocol body. 4. Section 1.4.1: Added dose rationale for 210 mg starting dose of Oprozomib Tablets based on preliminary safety results from Study 2011-001, PK data demonstrating comparable exposures between the tablet and capsule, and rationale for the combination of oprozomib with low-dose dexamethasone as a means to reduce gastrointestinal (GI) toxicity. 5. Section 3.4, Appendix A and Appendix B (footnote 1): Added that subjects continuing on study treatment and whose disease has not progressed 1 year after starting study treatment will reduce the frequency of their visits (on Day 1 of their next scheduled cycle) to every 4 weeks instead of every 2 weeks, with adequate drug supply for 2 cycles of treatment. Also clarified that disease response will be assessed every 8 weeks (4 cycles) after 1 year on therapy. 6. Section 4.1: Clarified in Inclusion Criterion #5 that bilirubin must be . 1.5 times the upper limit of normal (ULN) in the absence of Gilbert's disease or hemolysis. 7. Section 4.2: Clarified in Exclusion Criterion #3 that glucocorticoid therapy within 14 days prior to randomization that exceeds a cumulative dose of 160 mg of dexamethasone or equivalent is not allowed. OTHER CHANGES
    25 Jun 2013
    Study 2012-001 was amended to incorporate FDA requested changes/additions, specifically with regard to the definition of dose-limiting toxicities as applied to the Phase 1b component of the study and the incorporation of specific guidelines for the Prophylaxis and Management of Tumor Lysis Syndrome (TLS). 1. Study Synopsis (Study Design) and Section 6.3 Dose-Limiting Toxicity: The text was edited to classify Grade >= 4 abnormalities in serum creatinine or electrolytes as DLTs; Grade >= 3 acute kidney injury defined as creatinine > 3 * baseline or > 4.0 mg/dL of any duration is to be considered a DLT; and occurrence of Grade >= 3 nausea, vomiting, constipation or diarrhea of > 7 days duration in spite of optimal management, including a 5-HT3 antagonist and aprepitant for nausea and vomiting, and loperamide (e.g., Imodium) and diphenoxylate/atropine (e.g. Lomotil) for diarrhea is to be considered a DLT. 2. Sections 6.5 and 6.6.1: Text was added to provide guidance for monitoring/prophylaxis and treatment of tumor lysis syndrome. Administrative updates, editorial changes, and style and formatting revisions have been made to improve clarity and consistency throughout the document. Other significant changes. Changes in sections of the protocol body were also made in the protocol synopsis and elsewhere in the document.
    26 Jun 2014
    The key changes in Amendment 3 are listed below: 1. Addition of the new Oprozomib ER formulation Tablets 2. Addition of the step-up dosing for dose escalation 3. Addition of additional clinic visits for safety assessments 4. Addition of PK and PD assessments based on new dosing and formulation 5. Addition of assessments of orthostatic hypotension and management 6. Updates to safety and efficacy information from oprozomib studies 7. Updates to Inclusion/Exclusion criteria 8. Updates to phototoxicity risk with oprozomib Administrative updates, editorial changes, and style and formatting revisions have been made to improve clarity and consistency throughout the document. Changes in sections of the protocol body were also made in the protocol synopsis and elsewhere in the document, as applicable. Changes in the schedules of assessments have been updated to be current with the revised study plan and assessment schedule.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31229804
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