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Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Relapsed or Relapsed and Refractory Multiple Myeloma

Sponsor
Pharmacyclics LLC. (Industry)
Overall Status
Completed
CT.gov ID
NCT01478581
Collaborator
(none)
92
Enrollment
11
Locations
4
Arms
77
Actual Duration (Months)
8.4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of this study is to determine the efficacy of PCI-32765, both as a single agent and in combination with dexamethasone, in subjects with relapsed or relapsed and refractory Multiple Myeloma (MM)

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

Bruton's tyrosine kinase (Btk) is an enzyme that is present in hematopoietic cells other than T cells and is necessary for downstream signal transduction from various hematopoietic receptors including the B cell receptor as well as some Fc, chemokine, and adhesion receptors, and is crucial for both B cell development and osteoclastogenesis. Although down-regulated in normal plasma cells, Btk is highly expressed in the malignant cells from many myeloma patients and some cell lines. PCI 32765 is a potent and specific inhibitor of Btk currently in Phase 2 clinical trials. The current study is designed and intended to determine the effects of PCI-32765 in subjects with MM.

Study Design

Study Type:
Interventional
Actual Enrollment :
92 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multicenter Phase 2 Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, in Subjects With Relapsed or Relapsed and Refractory Multiple Myeloma
Actual Study Start Date :
Mar 1, 2012
Actual Primary Completion Date :
Aug 1, 2018
Actual Study Completion Date :
Aug 1, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cohort 1

PCI-32765 420 mg per day

Drug: PCI-32765
Other Names:
  • Ibrutinib

    		•
    Experimental: Cohort 2

    PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week

    Drug: PCI-32765
    Other Names:
  • Ibrutinib

    • Drug: Dexamethasone
    Experimental: Cohort 3

    PCI-32765 840 mg per day

    Drug: PCI-32765
    Other Names:
  • Ibrutinib

    		•
    Experimental: Cohort 4

    PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week

    Drug: PCI-32765
    Other Names:
  • Ibrutinib

    • Drug: Dexamethasone

    Outcome Measures

    Primary Outcome Measures

    1. The Clinical Benefit Response (CBR) [From the date of first study treatment until disease progression per IMWG, up to 60 months]

      The clinical benefit response (CBR) rate, defined as the proportion of subjects who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) as assessed by the modified International Myeloma Working Group (IMWG) response criteria

    Secondary Outcome Measures

    1. To Evaluate the Efficacy of PCI-32765 by Assessing ORR [From the date of first study treatment until disease progression per IMWG, up to 60 months]

      The objective response rate, defined as the proportion of subjects who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR), as assessed by the modified International Myeloma Working Group (IMWG) response criteria.

    2. Pharmacokinetics (PK). (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Maximum Observed Plasma Concentration (Cmax) [Procedure was performed up to 60 weeks.]

      Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Maximum observed plasma concentration of ibrutinib during the dosing interval on Day 8.

    3. Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Time to Maximum Observed Plasma Concentration (Tmax). [Procedure was performed up to 60 weeks.]

      Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Time to corresponding maximum observed plasma concentration of ibrutinib during the dosing interval on Day 8.

    4. Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24h). [Procedure was performed up to 60 weeks.]

      Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Ibrutinib AUC0-24h calculated using linear trapezoidal summation after dosing from time 0 to 24 hours on Day 8.

    5. Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Terminal Elimination Half-life (t1/2,Term). [Procedure was performed up to 60 weeks.]

      Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Ibrutinib terminal elimination half-life associated with the terminal slope (λz) of the semi-logarithmic plasma concentration-time curve, calculated as 0.693/λz on Day 8.

    6. Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Accumulation Ratio for AUC0-24h (Acc. Ratio AUC0-24h) [Procedure was performed up to 60 weeks.]

      Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Acc. Ratio calculated as Day 8 ibrutinib AUC0-24h/ Day 1 ibrutinib AUC0-24h.

    7. Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Metabolite-to-Parent Ratio for Cmax (M/P Cmax) [Procedure was performed up to 60 weeks.]

      Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Calculated as (PCI-45227 Cmax/PCI-45227 molecular weight)/(ibrutinib Cmax/ibrutinib molecular weight) on Day 8.

    8. Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Metabolite-to-Parent Ratio for AUC0-24h (M/P AUC0-24h) [Procedure was performed up to 60 weeks.]

      Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Calculated as (PCI-45227 AUC0-24h/PCI-45227 molecular weight)/(ibrutinib AUC0-24h/ibrutinib molecular weight) on Day 8.

    9. Duration of Clinical Benefit Response (DCB) [From the date of first study treatment until disease progression per IMWG, up to 60 months]

      DCB is defined as the time from first observation of response to the time of disease progression.

    10. Duration of Response (DOR) [up to 3 Years]

      The time interval between the date of initial documentation of a response and the date of first documented evidence of progressive disease, death, or date of censoring for the subjects not progressed/died. The censoring date is the last adequate tumor assessment date.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Diagnosis of symptomatic MM with measurable disease, defined here as having at least one of the following:

    1. Serum monoclonal protein (M-protein) ≥0.5 g/dL as determined by serum protein electrophoresis (SPEP)

    2. Urine M-protein ≥200 mg/24 hrs

    3. Serum free light chain (FLC) assay: involved FLC level ≥10 mg/dL (≥100 mg/L) provided serum FLC ratio is abnormal

    • Relapsed or relapsed and refractory MM after receiving at least 2 but no more than 5 previous lines of therapy, 1 of which must be an immunomodulator.

    • Refractory myeloma (to most recent treatment) is defined as disease that is nonresponsive while on treatment or progressive disease within 60 days after the completion of preceding treatment. Nonresponsive disease is defined as either failure to achieve minimal response or development of progressive disease while on therapy.

    • Men and women ≥18 years of age.

    • ECOG performance status of ≤ 1.

    Exclusion Criteria:

    • Subject must not have primary refractory disease defined as disease that is nonresponsive in subjects who have never achieved a minor response (MR) or better with any therapy.

    • Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome, osteosclerotic myeloma, or Crow-Fukase syndrome.

    • Plasma cell leukemia.

    • Primary amyloidosis.

    • Certain exclusions on prior therapy.

    • ANC <0.75 x 10^9/L independent of growth factor support.

    • Platelets <50 x 10^9/L) independent of transfusion support.

    • AST or ALT ≥3.0 x upper limit of normal (ULN).

    • Total bilirubin >2.5 x ULN, unless due to Gilbert's syndrome.

    • Creatinine >2.5 mg/dL.

    • Unable to swallow capsules or disease significantly affecting gastrointestinal function.

    • Requires anti-coagulation with warfarin or a vitamin K antagonist. Requires treatment with strong CYP3A4/5 inhibitors.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 SITE-13 La Jolla California United States 92093
    2 SITE-5 Baltimore Maryland United States 21287
    3 SITE-4 Boston Massachusetts United States 02215
    4 SITE-8 Ann Arbor Michigan United States 48109
    5 SITE-2 Saint Louis Missouri United States 63110
    6 SITE-6 Hackensack New Jersey United States 07601
    7 SITE-10 New York New York United States 10029
    8 SITE-3 New York New York United States 10065
    9 SITE-1 Nashville Tennessee United States 37203
    10 SITE-11 Dallas Texas United States 75390
    11 SITE-9 Seattle Washington United States 98109

    Sponsors and Collaborators

    • Pharmacyclics LLC.

    Investigators

    None specified.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Pharmacyclics LLC.
    ClinicalTrials.gov Identifier:
    NCT01478581
    Other Study ID Numbers:
    • PCYC-1111-CA
    • PCI-32765
    First Posted:
    Nov 23, 2011
    Last Update Posted:
    Mar 10, 2020
    Last Verified:
    Oct 1, 2019
    Keywords provided by Pharmacyclics LLC.
    PCI-32765
    Multiple Myeloma
    Relapsed Refractory Multiple Myeloma
    Bruton's Tyrosine Kinase
    Additional relevant MeSH terms:
    Multiple Myeloma
    Neoplasms, Plasma Cell
    Dexamethasone

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail Simon 2-stage design . Stage 1 -13 subjects enrolled in cohort 1. For cohort 2,3, and 4, up to 18 subjects were enrolled in Stage 1. Cohort 4 was selected for expansion for enrollment of 43 subjects in Stage 2.
    Arm/Group Title PCI-32765 420 mg Per Day PCI-32765 560 mg Per Day, 40 mg Dexamethasone PCI-32765 840 mg Per Day PCI-32765 840 mg Per Day, 40 mg Dexamethasone
    Arm/Group Description PCI-32765 420 mg per day PCI-32765 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone PCI-32765 840 mg per day PCI-32765 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone
    Period Title: Overall Study
    STARTED 13 18 18 43
    COMPLETED 13 18 18 43
    NOT COMPLETED 0 0 0 0

    Baseline Characteristics

    Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4 Total
    Arm/Group Description PCI-32765 420 mg per day PCI-32765 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone PCI-32765 840 mg per day PCI-32765 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone Total of all reporting groups
    Overall Participants 13 18 18 43 92
    Age (years) [Median (Standard Deviation) ]
    Median (Standard Deviation) [years]
    62.0
    (7.57)
    65.5
    (8.44)
    65.5
    (7.52)
    65.0
    (7.40)
    65.0
    (7.63)
    Sex: Female, Male (Count of Participants)
    Female
    5
    38.5%
    9
    50%
    5
    27.8%
    17
    39.5%
    36
    39.1%
    Male
    8
    61.5%
    9
    50%
    13
    72.2%
    26
    60.5%
    56
    60.9%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    0
    0%
    0
    0%
    1
    5.6%
    6
    14%
    7
    7.6%
    Not Hispanic or Latino
    13
    100%
    18
    100%
    17
    94.4%
    34
    79.1%
    82
    89.1%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    3
    7%
    3
    3.3%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    0
    0%
    1
    5.6%
    0
    0%
    1
    1.1%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    2
    15.4%
    6
    33.3%
    4
    22.2%
    6
    14%
    18
    19.6%
    White
    10
    76.9%
    12
    66.7%
    12
    66.7%
    33
    76.7%
    67
    72.8%
    More than one race
    0
    0%
    0
    0%
    1
    5.6%
    0
    0%
    1
    1.1%
    Unknown or Not Reported
    1
    7.7%
    0
    0%
    0
    0%
    4
    9.3%
    5
    5.4%
    Region of Enrollment (participants) [Number]
    United States
    13
    100%
    18
    100%
    18
    100%
    43
    100%
    92
    100%

    Outcome Measures

    1. Primary Outcome
    Title The Clinical Benefit Response (CBR)
    Description The clinical benefit response (CBR) rate, defined as the proportion of subjects who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), or minimal response (MR) as assessed by the modified International Myeloma Working Group (IMWG) response criteria
    Time Frame From the date of first study treatment until disease progression per IMWG, up to 60 months

    Outcome Measure Data

    Analysis Population Description
    All treated population
    Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Arm/Group Description PCI-32765 420 mg per day PCI-32765 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone PCI-32765 840 mg per day PCI-32765 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone
    Measure Participants 13 18 18 43
    Count of Participants [Participants]
    1
    7.7%
    1
    5.6%
    0
    0%
    12
    27.9%
    2. Secondary Outcome
    Title To Evaluate the Efficacy of PCI-32765 by Assessing ORR
    Description The objective response rate, defined as the proportion of subjects who achieved stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR), as assessed by the modified International Myeloma Working Group (IMWG) response criteria.
    Time Frame From the date of first study treatment until disease progression per IMWG, up to 60 months

    Outcome Measure Data

    Analysis Population Description
    All treated population
    Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Arm/Group Description PCI-32765 420 mg per day PCI-32765 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone PCI-32765 840 mg per day PCI-32765 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone
    Measure Participants 13 18 18 43
    Count of Participants [Participants]
    0
    0%
    1
    5.6%
    0
    0%
    2
    4.7%
    3. Secondary Outcome
    Title Pharmacokinetics (PK). (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Maximum Observed Plasma Concentration (Cmax)
    Description Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Maximum observed plasma concentration of ibrutinib during the dosing interval on Day 8.
    Time Frame Procedure was performed up to 60 weeks.

    Outcome Measure Data

    Analysis Population Description
    All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.
    Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Arm/Group Description PCI-32765 420 mg per day PCI-32765 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone PCI-32765 840 mg per day PCI-32765 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone
    Measure Participants 13 16 18 43
    Mean (Standard Deviation) [ng/mL]
    157
    (126)
    103
    (96.7)
    219
    (159)
    166
    (200)
    4. Secondary Outcome
    Title Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Time to Maximum Observed Plasma Concentration (Tmax).
    Description Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Time to corresponding maximum observed plasma concentration of ibrutinib during the dosing interval on Day 8.
    Time Frame Procedure was performed up to 60 weeks.

    Outcome Measure Data

    Analysis Population Description
    All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.
    Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Arm/Group Description PCI-32765 420 mg per day PCI-32765 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone PCI-32765 840 mg per day PCI-32765 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone
    Measure Participants 13 16 18 43
    Mean (Standard Deviation) [hours]
    2.73
    (1.99)
    2.32
    (1.72)
    1.95
    (0.944)
    2.25
    (1.18)
    5. Secondary Outcome
    Title Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24h).
    Description Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Ibrutinib AUC0-24h calculated using linear trapezoidal summation after dosing from time 0 to 24 hours on Day 8.
    Time Frame Procedure was performed up to 60 weeks.

    Outcome Measure Data

    Analysis Population Description
    All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.
    Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Arm/Group Description PCI-32765 420 mg per day PCI-32765 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone PCI-32765 840 mg per day PCI-32765 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone
    Measure Participants 13 16 18 43
    Mean (Standard Deviation) [h∙ng/mL]
    1094
    (808)
    723
    (768)
    1423
    (1014)
    1230
    (1914)
    6. Secondary Outcome
    Title Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Terminal Elimination Half-life (t1/2,Term).
    Description Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Ibrutinib terminal elimination half-life associated with the terminal slope (λz) of the semi-logarithmic plasma concentration-time curve, calculated as 0.693/λz on Day 8.
    Time Frame Procedure was performed up to 60 weeks.

    Outcome Measure Data

    Analysis Population Description
    All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.
    Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Arm/Group Description PCI-32765 420 mg per day PCI-32765 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone PCI-32765 840 mg per day PCI-32765 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone
    Measure Participants 13 16 18 43
    Mean (Standard Deviation) [hours]
    7.76
    (1.39)
    6.95
    (0.821)
    8.42
    (2.85)
    6.90
    (1.81)
    7. Secondary Outcome
    Title Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Accumulation Ratio for AUC0-24h (Acc. Ratio AUC0-24h)
    Description Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Acc. Ratio calculated as Day 8 ibrutinib AUC0-24h/ Day 1 ibrutinib AUC0-24h.
    Time Frame Procedure was performed up to 60 weeks.

    Outcome Measure Data

    Analysis Population Description
    All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.
    Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Arm/Group Description PCI-32765 420 mg per day PCI-32765 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone PCI-32765 840 mg per day PCI-32765 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone
    Measure Participants 13 16 18 43
    Mean (Standard Deviation) [Ratio]
    2.75
    (3.36)
    1.90
    (1.64)
    1.88
    (1.41)
    1.31
    (0.830)
    8. Secondary Outcome
    Title Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Metabolite-to-Parent Ratio for Cmax (M/P Cmax)
    Description Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Calculated as (PCI-45227 Cmax/PCI-45227 molecular weight)/(ibrutinib Cmax/ibrutinib molecular weight) on Day 8.
    Time Frame Procedure was performed up to 60 weeks.

    Outcome Measure Data

    Analysis Population Description
    All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.
    Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Arm/Group Description PCI-32765 420 mg per day PCI-32765 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone PCI-32765 840 mg per day PCI-32765 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone
    Measure Participants 13 16 18 43
    Mean (Standard Deviation) [Ratio]
    0.952
    (0.464)
    1.47
    (0.632)
    1.39
    (1.36)
    1.39
    (0.746)
    9. Secondary Outcome
    Title Pharmacokinetics (PK) (Assessed by Sampling and Testing for Drug and Metabolite Levels at Designated Time Points). Mean Metabolite-to-Parent Ratio for AUC0-24h (M/P AUC0-24h)
    Description Ibrutinib and PCI-45227 concentrations were measurable following once-daily dosing of ibrutinib in subjects with MM. The following time-points were included: 0hr, 1hr, 2hr, 7hr, 24hr post-dose. Calculated as (PCI-45227 AUC0-24h/PCI-45227 molecular weight)/(ibrutinib AUC0-24h/ibrutinib molecular weight) on Day 8.
    Time Frame Procedure was performed up to 60 weeks.

    Outcome Measure Data

    Analysis Population Description
    All subjects who received at least one dose of study treatment and had evaluable pharmacokinetic data.
    Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Arm/Group Description PCI-32765 420 mg per day PCI-32765 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone PCI-32765 840 mg per day PCI-32765 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone
    Measure Participants 13 16 18 43
    Mean (Standard Deviation) [Ratio]
    1.44
    (0.567)
    2.21
    (0.985)
    1.90
    (1.35)
    1.96
    (0.923)
    10. Secondary Outcome
    Title Duration of Clinical Benefit Response (DCB)
    Description DCB is defined as the time from first observation of response to the time of disease progression.
    Time Frame From the date of first study treatment until disease progression per IMWG, up to 60 months

    Outcome Measure Data

    Analysis Population Description
    Clinical benefit responders.
    Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Arm/Group Description PCI-32765 420 mg per day PCI-32765 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone PCI-32765 840 mg per day PCI-32765 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone
    Measure Participants 1 1 0 12
    Median (Full Range) [Months]
    27.6
    3.7
    11.5
    11. Secondary Outcome
    Title Duration of Response (DOR)
    Description The time interval between the date of initial documentation of a response and the date of first documented evidence of progressive disease, death, or date of censoring for the subjects not progressed/died. The censoring date is the last adequate tumor assessment date.
    Time Frame up to 3 Years

    Outcome Measure Data

    Analysis Population Description
    Responders
    Arm/Group Title PCI-32765 420 mg Per Day PCI-32765 560 mg Per Day, 40 mg Dexamethasone PCI-32765 840 mg Per Day PCI-32765 840 mg Per Day, 40 mg Dexamethasone
    Arm/Group Description PCI-32765 420 mg per day PCI-32765 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone PCI-32765 840 mg per day PCI-32765 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone
    Measure Participants 0 1 0 2
    Median (95% Confidence Interval) [Month]
    3.7
    15.4

    Adverse Events

    Time Frame Five Years
    Adverse Event Reporting Description
    Arm/Group Title Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Arm/Group Description PCI-32765 420 mg per day PCI-32765 PCI-32765 560 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone PCI-32765 840 mg per day PCI-32765 PCI-32765 840 mg per day, 40 mg dexamethasone (oral) once per week PCI-32765 Dexamethasone
    All Cause Mortality
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/13 (15.4%) 1/18 (5.6%) 1/18 (5.6%) 1/43 (2.3%)
    Serious Adverse Events
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 6/13 (46.2%) 6/18 (33.3%) 7/18 (38.9%) 12/43 (27.9%)
    Blood and lymphatic system disorders
    Anaemia 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Cardiac disorders
    Atrial Fibrillation 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Palpitations 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Gastrointestinal disorders
    Diarrhoea 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Gastrointestinal Haemorrhage 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Vomiting 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Small Intestinal Haemorrhage 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    General disorders
    Chills 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Hernia Pain 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Pyrexia 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Infections and infestations
    Pneumonia 1/13 (7.7%) 0/18 (0%) 1/18 (5.6%) 4/43 (9.3%)
    Clostridium difficile infection 1/13 (7.7%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Aspergillus Infection 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Bacterial Sepsis 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Bronchopulmonary Aspergillosis 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Clostridium Difficile Colitis 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Device Related Infection 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Epiglottitis 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Escherichia Urinary Tract Infection 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Gastroenteritis 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Gastroenteritis Viral 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Herpes Zoster Disseminated 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Pyelonephritis 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Streptococcal Bacteraemia 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Urinary tract Infection 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Injury, poisoning and procedural complications
    Fall 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Seroma 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Wound Secretion 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Investigations
    Lipase Increased 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Metabolism and nutrition disorders
    Hyperglycaemia 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Hyponatraemia 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Musculoskeletal and connective tissue disorders
    Bone Lesion 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Bone Pain 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Groin Pain 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Pathological Fracture 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Plasma cell myeloma 1/13 (7.7%) 1/18 (5.6%) 1/18 (5.6%) 0/43 (0%)
    Nervous system disorders
    Syncope 1/13 (7.7%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Cerebrovascular Accident 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Ischaemic Stroke 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Encephalopathy 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Renal and urinary disorders
    Acute Kidney Injury 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Renal Failure 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Pleural Effusion 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Respiratory Failure 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Vascular disorders
    Haematoma 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Hypotension 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Other (Not Including Serious) Adverse Events
    Cohort 1 Cohort 2 Cohort 3 Cohort 4
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 12/13 (92.3%) 18/18 (100%) 17/18 (94.4%) 43/43 (100%)
    Blood and lymphatic system disorders
    Anemia 4/13 (30.8%) 6/18 (33.3%) 6/18 (33.3%) 12/43 (27.9%)
    Thrombocytopenia 5/13 (38.5%) 5/18 (27.8%) 4/18 (22.2%) 9/43 (20.9%)
    Neutropenia 1/13 (7.7%) 0/18 (0%) 3/18 (16.7%) 1/43 (2.3%)
    Increased tendency to bruise 1/13 (7.7%) 0/18 (0%) 1/18 (5.6%) 2/43 (4.7%)
    Lymphopenia 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Febrile neutropenia 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Leukocytosis 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Bandaemia 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Cardiac disorders
    Palpitations 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Tachycardia 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Angina pectoris 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Atrial fibrillation 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Atrial flutter 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Bradycardia 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Extrasystoles 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Myocardial ischaemia 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Supraventricular extrasystoles 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Ear and labyrinth disorders
    Ear Pain 0/13 (0%) 0/18 (0%) 2/18 (11.1%) 1/43 (2.3%)
    Hypoacusis 0/13 (0%) 1/18 (5.6%) 1/18 (5.6%) 1/43 (2.3%)
    Ear Discomfort 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 1/43 (2.3%)
    Tinnitus 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 1/43 (2.3%)
    Deafness unilateral 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Ear Congestion 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Otorrhoea 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Tympanic membrane disorder 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Tympanic membrane perforation 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Endocrine disorders
    Cushingoid 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Goitre 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Eye disorders
    Vision Blurred 1/13 (7.7%) 1/18 (5.6%) 2/18 (11.1%) 4/43 (9.3%)
    Eye haemorrhage 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Eye irritation 0/13 (0%) 0/18 (0%) 2/18 (11.1%) 0/43 (0%)
    Abnormal sensation in eye 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Asthenopia 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Cataract 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Choroidal infarction 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Conjunctival hyperaemia 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Dry eye 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Eye discharge 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Eye pain 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Eye Pruritus 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Eyelid disorder 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Eyelid oedema 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Glaucoma 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Iritis 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Lacrimation increased 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Ophthalmoplegia 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Retinal haemorrhage 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Uveitis 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Vitreous floaters 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Gastrointestinal disorders
    Diarrhoea 5/13 (38.5%) 8/18 (44.4%) 10/18 (55.6%) 26/43 (60.5%)
    Nausea 6/13 (46.2%) 5/18 (27.8%) 7/18 (38.9%) 11/43 (25.6%)
    Constipation 1/13 (7.7%) 4/18 (22.2%) 2/18 (11.1%) 5/43 (11.6%)
    Gastrooesophageal Reflux Disease 0/13 (0%) 2/18 (11.1%) 3/18 (16.7%) 6/43 (14%)
    Vomiting 2/13 (15.4%) 1/18 (5.6%) 4/18 (22.2%) 4/43 (9.3%)
    Abdominal Pain 3/13 (23.1%) 2/18 (11.1%) 2/18 (11.1%) 3/43 (7%)
    Dyspepsia 1/13 (7.7%) 0/18 (0%) 2/18 (11.1%) 7/43 (16.3%)
    Abdominal Discomfort 0/13 (0%) 1/18 (5.6%) 1/18 (5.6%) 3/43 (7%)
    Abdominal Distension 0/13 (0%) 2/18 (11.1%) 0/18 (0%) 3/43 (7%)
    Abdominal Pain Upper 2/13 (15.4%) 0/18 (0%) 0/18 (0%) 3/43 (7%)
    Flatulence 0/13 (0%) 2/18 (11.1%) 1/18 (5.6%) 1/43 (2.3%)
    Toothache 1/13 (7.7%) 0/18 (0%) 1/18 (5.6%) 2/43 (4.7%)
    Stomatitis 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 2/43 (4.7%)
    Aphthous ulcer 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 1/43 (2.3%)
    Colitis 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Dry Mouth 0/13 (0%) 0/18 (0%) 2/18 (11.1%) 0/43 (0%)
    Dysphagia 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 1/43 (2.3%)
    Abdominal tenderness 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Anal incontinence 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Angina bullosa haemorrhagica 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Dental caries 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Faeces soft 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Frequent bowel movements 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Gingival pain 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Haematochezia 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Haemorrhoidal haemorrhage 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Haemorrhoids 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Hiatus hernia 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Hypoaesthesia oral 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Irritable bowel syndrome 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Lip blister 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Melaena 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Mouth haemorrhage 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Odynophagia 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Oral Discomfort 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Oral mucosa erosion 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Oral pain 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Parotid gland enlargement 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Tongue eruption 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Tooth disorder 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Tooth loss 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Small intestinal haemorrhage 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    General disorders
    Fatigue 3/13 (23.1%) 7/18 (38.9%) 9/18 (50%) 21/43 (48.8%)
    Pyrexia 4/13 (30.8%) 1/18 (5.6%) 3/18 (16.7%) 7/43 (16.3%)
    Oedema Peripheral 1/13 (7.7%) 2/18 (11.1%) 3/18 (16.7%) 5/43 (11.6%)
    Asthenia 0/13 (0%) 2/18 (11.1%) 1/18 (5.6%) 5/43 (11.6%)
    Malaise 0/13 (0%) 1/18 (5.6%) 2/18 (11.1%) 4/43 (9.3%)
    Pain 0/13 (0%) 0/18 (0%) 2/18 (11.1%) 3/43 (7%)
    Chills 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 3/43 (7%)
    Peripheral swelling 1/13 (7.7%) 0/18 (0%) 2/18 (11.1%) 1/43 (2.3%)
    Chest pain 1/13 (7.7%) 0/18 (0%) 1/18 (5.6%) 1/43 (2.3%)
    Feeling jittery 2/13 (15.4%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Chest discomfort 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 1/43 (2.3%)
    Feeling abnormal 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Injection site bruising 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 1/43 (2.3%)
    Crepitations 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Facial pain 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Hernia pain 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Non-cardiac chest pain 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Oedema 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Systemic inflammatory response syndrome 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Unevaluable event 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Hepatobiliary disorders
    Hyperbilirubinaemia 0/13 (0%) 0/18 (0%) 0/18 (0%) 4/43 (9.3%)
    Cholelithiasis 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Hepatic function abnormal 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Hepatic steatosis 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Immune system disorders
    Food allergy 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Infections and infestations
    Upper Respiratory Tract Infection 3/13 (23.1%) 2/18 (11.1%) 7/18 (38.9%) 8/43 (18.6%)
    Urinary Tract Infection 0/13 (0%) 2/18 (11.1%) 3/18 (16.7%) 5/43 (11.6%)
    Cellulitis 0/13 (0%) 0/18 (0%) 2/18 (11.1%) 4/43 (9.3%)
    Localised Infection 0/13 (0%) 1/18 (5.6%) 2/18 (11.1%) 2/43 (4.7%)
    Sinusitis 1/13 (7.7%) 1/18 (5.6%) 1/18 (5.6%) 2/43 (4.7%)
    Influenza 1/13 (7.7%) 1/18 (5.6%) 1/18 (5.6%) 1/43 (2.3%)
    Oral candidiasis 0/13 (0%) 1/18 (5.6%) 1/18 (5.6%) 2/43 (4.7%)
    Paronychia 0/13 (0%) 0/18 (0%) 0/18 (0%) 4/43 (9.3%)
    Ear Infection 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 2/43 (4.7%)
    Herpes Zoster 1/13 (7.7%) 0/18 (0%) 1/18 (5.6%) 1/43 (2.3%)
    Pneumonia 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 2/43 (4.7%)
    Bronchitis 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Candida infection 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 1/43 (2.3%)
    Clostridium difficile colitis 0/13 (0%) 1/18 (5.6%) 1/18 (5.6%) 0/43 (0%)
    Clostridium difficile infection 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Fungal infection 1/13 (7.7%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Nasopharyngitis 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Parainfluenzae virus infection 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Bronchopulmonary aspergillosis 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Chronic sinusitis 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Corona virus infection 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Diverticulitis 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Ear infection staphylococcal 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Epididymitis 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Epiglottitis 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Eye infection 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Gastroenteritis viral 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Helicobacter infection 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Herpes simplex 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Measles 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Oral herpes 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Otitis externa 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Otitis media 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Pyelonephritis 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Rash pustular 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Rhinovirus infection 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Skin infection 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Systemic candida 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Tooth infection 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Viral upper respiratory tract infection 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Wound infection 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Conjunctivitis 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Injury, poisoning and procedural complications
    Contusion 2/13 (15.4%) 2/18 (11.1%) 1/18 (5.6%) 3/43 (7%)
    Fall 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 5/43 (11.6%)
    Laceration 0/13 (0%) 0/18 (0%) 2/18 (11.1%) 2/43 (4.7%)
    Skin abrasion 0/13 (0%) 0/18 (0%) 0/18 (0%) 3/43 (7%)
    Foot fracture 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Muscle strain 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Accidental overdose 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Dental restoration failure 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Eye contusion 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    infusion related reaction 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Joint injury 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Limb injury 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Muscle rupture 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Post procedural contusion 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Post procedural haemorrhage 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Pubis fracture 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Spinal compression fracture 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Testicular injury 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Tibia fracture 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Wrist fracture 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Investigations
    Blood Creatinine Increased 0/13 (0%) 2/18 (11.1%) 1/18 (5.6%) 3/43 (7%)
    Weight Decreased 1/13 (7.7%) 2/18 (11.1%) 0/18 (0%) 3/43 (7%)
    Blood lactate dehydrogenase increased 2/13 (15.4%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Aspartate aminotransferase increased 0/13 (0%) 2/18 (11.1%) 0/18 (0%) 0/43 (0%)
    Breath sounds abnormal 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Neutrophil count decreased 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Blood alkaline phosphatase decreased 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Blood bilirubin increased 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Blood chloride increased 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Blood creatine phosphokinase increased 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Body temperature increased 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Cardiac murmur 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Heart rate irregular 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Lymphocyte count increased 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Medical observation abnormal 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Neutrophil count increased 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Red blood cell count decreased 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Weight increased 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    White blood cell count increased 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Metabolism and nutrition disorders
    Decreased Appetite 2/13 (15.4%) 4/18 (22.2%) 2/18 (11.1%) 6/43 (14%)
    Hypokalaemia 3/13 (23.1%) 2/18 (11.1%) 1/18 (5.6%) 5/43 (11.6%)
    Hyperuricaemia 3/13 (23.1%) 1/18 (5.6%) 1/18 (5.6%) 4/43 (9.3%)
    Hyponatraemia 2/13 (15.4%) 0/18 (0%) 1/18 (5.6%) 5/43 (11.6%)
    Hypocalcaemia 3/13 (23.1%) 1/18 (5.6%) 1/18 (5.6%) 2/43 (4.7%)
    Dehydration 0/13 (0%) 2/18 (11.1%) 1/18 (5.6%) 3/43 (7%)
    Hypercalcaemia 1/13 (7.7%) 2/18 (11.1%) 2/18 (11.1%) 1/43 (2.3%)
    Hypomagnesaemia 1/13 (7.7%) 1/18 (5.6%) 0/18 (0%) 4/43 (9.3%)
    Hyperglycaemia 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 3/43 (7%)
    Hypoalbuminaemia 2/13 (15.4%) 1/18 (5.6%) 0/18 (0%) 1/43 (2.3%)
    Hypophosphataemia 3/13 (23.1%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Hyperlipidaemia 1/13 (7.7%) 1/18 (5.6%) 0/18 (0%) 1/43 (2.3%)
    Hyperphosphataemia 2/13 (15.4%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Hypoglycaemia 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Hyperkalaemia 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Hypermagnesaemia 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Iron deficiency 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Musculoskeletal and connective tissue disorders
    Muscle Spasms 4/13 (30.8%) 6/18 (33.3%) 3/18 (16.7%) 10/43 (23.3%)
    Pain In Extremity 1/13 (7.7%) 5/18 (27.8%) 0/18 (0%) 11/43 (25.6%)
    Back Pain 1/13 (7.7%) 5/18 (27.8%) 3/18 (16.7%) 7/43 (16.3%)
    Musculoskeletal Pain 1/13 (7.7%) 2/18 (11.1%) 2/18 (11.1%) 1/43 (2.3%)
    Musculoskeletal Chest Pain 1/13 (7.7%) 4/18 (22.2%) 0/18 (0%) 1/43 (2.3%)
    Myalgia 0/13 (0%) 2/18 (11.1%) 0/18 (0%) 3/43 (7%)
    Arthralgia 3/13 (23.1%) 4/18 (22.2%) 4/18 (22.2%) 8/43 (18.6%)
    Bone pain 0/13 (0%) 0/18 (0%) 2/18 (11.1%) 1/43 (2.3%)
    Muscular weakness 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 2/43 (4.7%)
    Flank pain 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Groin pain 1/13 (7.7%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Neck pain 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Pain in jaw 1/13 (7.7%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Arthritis 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Bursitis 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Chondropathy 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Coccydynia 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Intervertebral disc protrusion 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Joint Stiffness 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Limb discomfort 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Limb mass 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Muscle oedema 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Musculoskeletal stiffness 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Osteolysis 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Osteonecrosis of jaw 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Soft tissue mass 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Spinal osteoarthritis 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Spinal pain 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Synovitis 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Bladder cancer recurrent 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Haemangioma of skin 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Lipoma 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Squamous cell carcinoma 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Nervous system disorders
    Dizziness 2/13 (15.4%) 4/18 (22.2%) 2/18 (11.1%) 10/43 (23.3%)
    Headache 2/13 (15.4%) 2/18 (11.1%) 4/18 (22.2%) 3/43 (7%)
    Peripheral Sensory Neuropathy 1/13 (7.7%) 2/18 (11.1%) 1/18 (5.6%) 1/43 (2.3%)
    Dysgeusia 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 3/43 (7%)
    Neuropathy peripheral 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 3/43 (7%)
    Syncope 1/13 (7.7%) 1/18 (5.6%) 0/18 (0%) 1/43 (2.3%)
    Disturbance in attention 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Hypoaesthesia 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Psychomotor hyperactivity 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Tremor 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Aphasia 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Ataxia 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Balance disorder 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Burning sensation 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Drooling 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Dysarthria 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Ischaemic stroke 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Lethargy 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Migraine with aura 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Neuralgia 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Presyncope 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Sciatica 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Sinus headache 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Psychiatric disorders
    Insomnia 1/13 (7.7%) 5/18 (27.8%) 1/18 (5.6%) 13/43 (30.2%)
    Anxiety 0/13 (0%) 0/18 (0%) 2/18 (11.1%) 5/43 (11.6%)
    Mood swings 0/13 (0%) 0/18 (0%) 0/18 (0%) 3/43 (7%)
    Confusional state 1/13 (7.7%) 1/18 (5.6%) 0/18 (0%) 1/43 (2.3%)
    Irritability 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 3/43 (7%)
    Depression 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Adjustment disorder with depressed mood 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Affect lability 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Agitation 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Claustrophobia 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Depressed mood 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Hallucination 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Restlessness 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Sleep disorder 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Renal and urinary disorders
    Dysuria 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 2/43 (4.7%)
    Renal impairment 0/13 (0%) 1/18 (5.6%) 1/18 (5.6%) 1/43 (2.3%)
    Pollakiuria 0/13 (0%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Urinary incontinence 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 1/43 (2.3%)
    Chronic kidney disease 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Haematuria 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Incontinence 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Nephrolithiasis 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Nocturia 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Urinary retention 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Reproductive system and breast disorders
    Breast ulceration 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Scrotal pain 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Uterine cyst 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Vulvovaginal pain 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Respiratory, thoracic and mediastinal disorders
    Cough 4/13 (30.8%) 3/18 (16.7%) 2/18 (11.1%) 12/43 (27.9%)
    Dyspnoea 2/13 (15.4%) 4/18 (22.2%) 2/18 (11.1%) 6/43 (14%)
    Epistaxis 1/13 (7.7%) 4/18 (22.2%) 1/18 (5.6%) 7/43 (16.3%)
    Oropharyngeal Pain 1/13 (7.7%) 2/18 (11.1%) 2/18 (11.1%) 4/43 (9.3%)
    Rhinorrhoea 2/13 (15.4%) 2/18 (11.1%) 0/18 (0%) 4/43 (9.3%)
    Nasal Congestion 0/13 (0%) 2/18 (11.1%) 2/18 (11.1%) 2/43 (4.7%)
    Productive cough 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 3/43 (7%)
    Wheezing 1/13 (7.7%) 0/18 (0%) 2/18 (11.1%) 1/43 (2.3%)
    Pleural effusion 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 2/43 (4.7%)
    Dysphonia 0/13 (0%) 2/18 (11.1%) 0/18 (0%) 0/43 (0%)
    Dyspnoea exertional 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Respiratory tract congestion 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Sinus congestion 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Sneezing 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 1/43 (2.3%)
    Acute respiratory failure 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Haemoptysis 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Interstitial lung disease 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Nasal cyst 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Nasal discomfort 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Nasal dryness 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Paranasal sinus discomfort 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Pulmonary mass 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Rales 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Respiratory failure 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Rhinitis allergic 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Sinus pain 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Tachypnoea 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Upper-airway cough syndrome 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Skin and subcutaneous tissue disorders
    Dry Skin 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 4/43 (9.3%)
    Hyperhidrosis 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 4/43 (9.3%)
    Pruritus 1/13 (7.7%) 0/18 (0%) 1/18 (5.6%) 3/43 (7%)
    Rash Maculo-Papular 0/13 (0%) 1/18 (5.6%) 1/18 (5.6%) 3/43 (7%)
    Ecchymosis 0/13 (0%) 0/18 (0%) 0/18 (0%) 4/43 (9.3%)
    Erythema 0/13 (0%) 0/18 (0%) 0/18 (0%) 3/43 (7%)
    Night sweats 0/13 (0%) 2/18 (11.1%) 1/18 (5.6%) 0/43 (0%)
    Skin exfoliation 0/13 (0%) 2/18 (11.1%) 0/18 (0%) 1/43 (2.3%)
    Skin fissures 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 2/43 (4.7%)
    Petechiae 1/13 (7.7%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Rash 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 1/43 (2.3%)
    Skin mass 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 1/43 (2.3%)
    Actinic keratosis 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Alopecia 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Blister 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Blood blister 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Cold sweat 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Dermatitis acneiform 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Hirsutism 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Nail bed inflammation 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Nail growth abnormal 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Onychoclasis 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Papule 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Precancerous skin lesion 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Pruritus generalised 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Rash erythematous 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Rash macular 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Rash papular 0/13 (0%) 1/18 (5.6%) 0/18 (0%) 0/43 (0%)
    Rash pruritic 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Skin ulcer 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Skin warm 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Telangiectasia 1/13 (7.7%) 0/18 (0%) 0/18 (0%) 0/43 (0%)
    Vitiligo 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Vascular disorders
    Hypotension 1/13 (7.7%) 1/18 (5.6%) 1/18 (5.6%) 4/43 (9.3%)
    Hypertension 0/13 (0%) 1/18 (5.6%) 1/18 (5.6%) 2/43 (4.7%)
    Flushing 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)
    Haematoma 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Hot flush 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Orthostatic hypotension 0/13 (0%) 0/18 (0%) 1/18 (5.6%) 0/43 (0%)
    Pallor 0/13 (0%) 0/18 (0%) 0/18 (0%) 1/43 (2.3%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Bernhard Hauns, Medical Monitor
    Organization Pharmacyclics Switzerland GmbH
    Phone +41 52 556 0800
    Email bhauns@pcyc.com
    Responsible Party:
    Pharmacyclics LLC.
    ClinicalTrials.gov Identifier:
    NCT01478581
    Other Study ID Numbers:
    • PCYC-1111-CA
    • PCI-32765
    First Posted:
    Nov 23, 2011
    Last Update Posted:
    Mar 10, 2020
    Last Verified:
    Oct 1, 2019