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A Safety and Efficacy Study of INC280 and Gefitinib in Patients With EGFR Mutated, c-MET-amplified NSCLC Who Have Progressed After EGFRi Treatment

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01610336
Collaborator
(none)
161
Enrollment
31
Locations
11
Arms
97.7
Actual Duration (Months)
5.2
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study assessed the safety and efficacy of escalating doses INC280 when added to gefitinib in patients with lung cancer that were known to have dysregulation of the c-MET pathway and who had failed after benefiting on a prior treatment with either gefitinib or erlotinib.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

The Phase Ib dose escalation part was aimed at the determination of the MTD/RP2D of capmatinib in combination with 250 mg gefitinib in patients with NSCLC patients with epidermal growth factor receptor (EGFR) mutation and cMET dysregulation and showing disease progression following EGFR tyrosine-kinase inhibitor (EGFR TKI) therapy. Dose escalation started with a dose of 100 mg/day to a maximum of 1200 mg/day, as capsule or tablet formulation. Successive cohorts of patients were to receive increasing doses of capmatinib in combination with a 250 mg once daily (qd) dose of gefitinib until the MTD/RP2D of capmatinib had been determined. The Phase II dose expansion part consisted of 400 mg capmatinib twice daily (bid), as either capsules or tablets, in combination with 250 mg gefitinib.

Study Design

Study Type:
Interventional
Actual Enrollment :
161 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase IB/II, Open Label, Multicenter Study of INC280 Administered Orally in Combination With Gefitinib in Adult Patients With EGFR Mutated, c-MET-amplified Non-small Cell Lung Cancer Who Have Progressed After EGFR Inhibitor Treatment
Actual Study Start Date :
Apr 5, 2012
Actual Primary Completion Date :
Jun 10, 2016
Actual Study Completion Date :
May 27, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: INC280 100 mg Cap QD Phase Ib

cap=capsule; QD=once daily

Drug: INC280
During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.
Other Names:
  • Capmatinib

    • Drug: Gefitinib
    Gefitinib 250 mg taken once daily
    Experimental: INC280 200 mg Cap QD Phase Ib

    cap=capsule; QD=once daily

    Drug: INC280
    During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.
    Other Names:
  • Capmatinib

    • Drug: Gefitinib
    Gefitinib 250 mg taken once daily
    Experimental: INC280 400 mg Cap QD Phase Ib

    cap=capsule; QD=once daily

    Drug: INC280
    During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.
    Other Names:
  • Capmatinib

    • Drug: Gefitinib
    Gefitinib 250 mg taken once daily
    Experimental: INC280 800 mg Cap QD Phase Ib

    cap=capsule; QD=once daily

    Drug: INC280
    During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.
    Other Names:
  • Capmatinib

    • Drug: Gefitinib
    Gefitinib 250 mg taken once daily
    Experimental: INC280 200 mg Cap BID Phase Ib

    cap=capsule; BID=twice daily

    Drug: INC280
    During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.
    Other Names:
  • Capmatinib

    • Drug: Gefitinib
    Gefitinib 250 mg taken once daily
    Experimental: INC280 400 mg Cap BID Phase Ib

    cap=capsule; BID=twice daily

    Drug: INC280
    During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.
    Other Names:
  • Capmatinib

    • Drug: Gefitinib
    Gefitinib 250 mg taken once daily
    Experimental: INC280 600 mg Cap BID Phase Ib

    cap=capsule; BID=twice daily

    Drug: INC280
    During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.
    Other Names:
  • Capmatinib

    • Drug: Gefitinib
    Gefitinib 250 mg taken once daily
    Experimental: INC280 200 mg Tab BID Phase Ib

    tab=tablet; BID=twice daily

    Drug: INC280
    During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.
    Other Names:
  • Capmatinib

    • Drug: Gefitinib
    Gefitinib 250 mg taken once daily
    Experimental: INC280 400 mg Tab BID Phase Ib

    tab=tablet; BID=twice daily

    Drug: INC280
    During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.
    Other Names:
  • Capmatinib

    • Drug: Gefitinib
    Gefitinib 250 mg taken once daily
    Experimental: INC280 400 mg Cap BID Phase II

    cap=capsule; BID=twice daily

    Drug: INC280
    During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.
    Other Names:
  • Capmatinib

    • Drug: Gefitinib
    Gefitinib 250 mg taken once daily
    Experimental: INC280 400 mg Tab BID Phase II

    tab=tablet; BID=twice daily

    Drug: INC280
    During Phase Ib, INC280 was taken at escalating doses. During Phase II part, INC280 was taken at recommended Phase II dose.
    Other Names:
  • Capmatinib

    • Drug: Gefitinib
    Gefitinib 250 mg taken once daily

    Outcome Measures

    Primary Outcome Measures

    1. Phase Ib: Frequency of Dose Limiting Toxicities (DLTs) [Up to 215 weeks]

      A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.

    2. Phase II : Overall Response Rate (ORR) [Until disease progression, up to 60.8 weeks]

      Overall response rate is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), as per RECIST 1.1 (Overall Response (OR) = CR + PR). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

    Secondary Outcome Measures

    1. Phase Ib and II: Number of Participants With Adverse Events (AEs) [Up to 421 weeks]

      Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

    2. Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs) [Up to 421 weeks]

      Serious adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

    3. Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level [Up to 417 weeks]

      Number of patients with dose reductions of INC280 by dose level as a measure of tolerability.

    4. Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level [Up to 417 weeks]

      Number of patients with dose interruptions of gefitinib by dose level as a measure of tolerability

    5. Phase II: Overall Survival (OS) [From date of treatment until death due to any cause, up to 70.2 months]

      Overall survival is defined as the time from the start of treatment date to the date of death, due to any cause

    6. Phase II: Progression Free Survival (PFS) [Up to 60.8 months]

      Progression-free survivalis the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause.

    7. Phase II: Duration of Response (DoR) [Up to 23.2 months]

      Duration of overall response (DOR) is defined as the time between the date of first documented response (CR or PR) and the date of first documented disease progression or death due to underlying cancer.

    8. Phase I: PK Parameters AUCtau of INC280 and Gefitinib [Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)]

      PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Area under the plasma concentration-time curve (AUC) from time zero to the end of dosing interval at steady state (tau), where tau=24 hours for once daily dosing and tau=12 hours for twice daily dosing

    9. Phase I: PK Parameters Cmax of INC280 and Gefitinib [Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)]

      PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Cmax is the maximum observed plasma concentration of INC280 and gefitinib

    10. Phase I: PK Parameters Tmax of INC280 and Gefitinib [Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)]

      PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Tmax is the time to reach maximum plasma concentration of INC280 and gefitinib

    11. Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib [Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)]

      PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Apparent systemic plasma clearance rate of INC280 and gefitinib

    12. Phase I: PK Parameters Half-life of INC280 and Gefitinib [Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose)(Cycle=28 days)]

      PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. The elimination half-life of INC280 and gefitinib associated with the terminal slope (Lamda_z) of a semi-logarithmic plasma concentration-time curve

    Other Outcome Measures

    1. Phase I: Percentage of Change From Baseline in C-MET H Score at Cycle 1 Day 15 [Baseline, Day 15 of cycle 1 (Cycle=28days)]

      Inhibition of c-MET signaling by pre- and post- treatment immunohistochemistry of p-c-MET

    Eligibility Criteria

    Criteria

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

    • Documented EGFR mutation

    • Documented c-MET dysregulation

    • Prior clinical benefit on EGFR inhibitors and then subsequent progression

    -≥ 18 year old

    • Life expectancy of ≥ 3 months

    • ECOG performance status ≤ 2

    Exclusion Criteria:

    • Unable to swallow tables once or twice daily

    • Previous treatment with c-MET inhibitor

    • Any unresolved toxicity from previous anticancer therapy greater than grade 1

    • History of cystic fibrosis

    • History of acute or chronic pancreatitis

    • Unable to undergo MRI or CT scans

    • Known history of HIV

    • Undergone a bone marrow or solid organ transplant

    • Clinically significant wound or lung tumor lesions with increased likelihood of bleeding

    • Pregnant or nursing

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Novartis Investigative Site Woolloongabba Queensland Australia 4102
    2 Novartis Investigative Site East Bentleigh Victoria Australia 3165
    3 Novartis Investigative Site Auckland Australia
    4 Novartis Investigative Site Leuven Belgium 3000
    5 Novartis Investigative Site Guangzhou Guangdong China 51000
    6 Novartis Investigative Site Shanghai Shanghai China 200433
    7 Novartis Investigative Site Beijing China 100039
    8 Novartis Investigative Site Guangzhou China 510060
    9 Novartis Investigative Site Strasbourg Cedex France 67091
    10 Novartis Investigative Site Toulouse Cedex 9 France 31059
    11 Novartis Investigative Site Frankfurt Germany 60590
    12 Novartis Investigative Site Freiburg Germany 79106
    13 Novartis Investigative Site Ramat Gan Israel 52621
    14 Novartis Investigative Site Milano MI Italy 20133
    15 Novartis Investigative Site Milano MI Italy 20141
    16 Novartis Investigative Site Modena MO Italy 41124
    17 Novartis Investigative Site Koto ku Tokyo Japan 135 8550
    18 Novartis Investigative Site Gyeonggi do Korea Korea, Republic of 10408
    19 Novartis Investigative Site Seoul Korea Korea, Republic of 05505
    20 Novartis Investigative Site Seoul Seocho Gu Korea, Republic of 06591
    21 Novartis Investigative Site Seoul Korea, Republic of 03080
    22 Novartis Investigative Site Seoul Korea, Republic of 06351
    23 Novartis Investigative Site Maastricht AZ Netherlands 5800
    24 Novartis Investigative Site Amsterdam Netherlands 1066 CX
    25 Novartis Investigative Site Rotterdam Netherlands 3015 GD
    26 Novartis Investigative Site Singapore Singapore 169610
    27 Novartis Investigative Site Barcelona Catalunya Spain 08035
    28 Novartis Investigative Site Madrid Spain 28034
    29 Novartis Investigative Site Tainan Taiwan 70403
    30 Novartis Investigative Site Taipei Taiwan 10002
    31 Novartis Investigative Site Bangkok Thailand 10400

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01610336
    Other Study ID Numbers:
    • CINC280X2202
    • 2011-002569-39
    First Posted:
    Jun 4, 2012
    Last Update Posted:
    Apr 8, 2021
    Last Verified:
    Mar 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    Yes
    Keywords provided by Novartis Pharmaceuticals
    EGFR
    c-MET
    Lung cancer
    Gefitinib
    Erlotinib
    Non-small cell lung cancer (NSCLC)
    lung adenocarcinoma
    large-cell lung carcinoma
    Additional relevant MeSH terms:
    Lung Neoplasms
    Carcinoma, Non-Small-Cell Lung
    Gefitinib

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title INC280 100 mg Cap QD Phase Ib INC280 200 mg Cap QD Phase Ib INC280 400 mg Cap QD Phase Ib INC280 800 mg Cap QD Phase Ib INC280 200 mg Cap BID Phase Ib INC280 400 mg Cap BID Phase Ib INC280 600 mg Cap BID Phase Ib INC280 200 mg Tab BID Phase Ib INC280 400 mg Tab BID Phase Ib INC280 400 mg Cap BID Phase II INC280 400 mg Tab BID Phase II
    Arm/Group Description cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily tab=tablet; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily
    Period Title: Overall Study
    STARTED 5 7 6 7 4 12 5 7 8 53 47
    COMPLETED 0 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 5 7 6 7 4 12 5 7 8 53 47

    Baseline Characteristics

    Arm/Group Title INC280 100 mg Cap QD Phase Ib INC280 200 mg Cap QD Phase Ib INC280 400 mg Cap QD Phase Ib INC280 800 mg Cap QD Phase Ib INC280 200 mg Cap BID Phase Ib INC280 400 mg Cap BID Phase Ib INC280 600 mg Cap BID Phase Ib INC280 200 mg Tab BID Phase Ib INC280 400 mg Tab BID Phase Ib INC280 400 mg Cap BID Phase II INC280 400 mg Tab BID Phase II Total
    Arm/Group Description cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily tab=tablet; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily Total of all reporting groups
    Overall Participants 5 7 6 7 4 12 5 7 8 53 47 161
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    57.8
    (11.05)
    60.4
    (15.27)
    59.5
    (6.89)
    51.3
    (8.88)
    64.5
    (8.89)
    55.9
    (10.81)
    61.0
    (8.46)
    60.9
    (12.86)
    58.4
    (5.01)
    58.6
    (10.50)
    62.8
    (9.32)
    59.7
    (10.20)
    Sex: Female, Male (Count of Participants)
    Female
    2
    40%
    5
    71.4%
    4
    66.7%
    5
    71.4%
    4
    100%
    4
    33.3%
    2
    40%
    5
    71.4%
    5
    62.5%
    33
    62.3%
    19
    40.4%
    88
    54.7%
    Male
    3
    60%
    2
    28.6%
    2
    33.3%
    2
    28.6%
    0
    0%
    8
    66.7%
    3
    60%
    2
    28.6%
    3
    37.5%
    20
    37.7%
    28
    59.6%
    73
    45.3%
    Race/Ethnicity, Customized (Number) [Number]
    Russian
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.1%
    1
    0.6%
    Mixed Ethnicity
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    2.1%
    1
    0.6%
    Not reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    4.3%
    2
    1.2%
    Unknown
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3
    6.4%
    3
    1.9%
    Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    8.3%
    0
    0%
    1
    14.3%
    0
    0%
    0
    0%
    5
    10.6%
    7
    4.3%
    Southeast Asian
    1
    20%
    1
    14.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    14.3%
    1
    12.5%
    0
    0%
    8
    17%
    12
    7.5%
    Other
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    25%
    2
    16.7%
    1
    20%
    2
    28.6%
    0
    0%
    0
    0%
    11
    23.4%
    17
    10.6%
    East Asian
    4
    80%
    6
    85.7%
    6
    100%
    7
    100%
    3
    75%
    9
    75%
    4
    80%
    3
    42.9%
    7
    87.5%
    53
    100%
    16
    34%
    118
    73.3%

    Outcome Measures

    1. Primary Outcome
    Title Phase Ib: Frequency of Dose Limiting Toxicities (DLTs)
    Description A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.
    Time Frame Up to 215 weeks

    Outcome Measure Data

    Analysis Population Description
    Safety Set: All patients in phase Ib who received at least one full or partial dose of INC280 or gefitinib.
    Arm/Group Title INC280 100 mg Cap QD Phase Ib INC280 200 mg Cap QD Phase Ib INC280 400 mg Cap QD Phase Ib INC280 800 mg Cap QD Phase Ib INC280 200 mg Cap BID Phase Ib INC280 400 mg Cap BID Phase Ib INC280 600 mg Cap BID Phase Ib INC280 200 mg Tab BID Phase Ib INC280 400 mg Tab BID Phase Ib
    Arm/Group Description cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily tab=tablet; BID=twice daily
    Measure Participants 3 7 6 5 4 10 1 7 7
    Cough
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    20%
    0
    0%
    0
    0%
    Dizziness
    0
    0%
    0
    0%
    0
    0%
    1
    14.3%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Dyspnoea
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    20%
    0
    0%
    0
    0%
    2. Primary Outcome
    Title Phase II : Overall Response Rate (ORR)
    Description Overall response rate is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), as per RECIST 1.1 (Overall Response (OR) = CR + PR). Complete Response (CR): Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm Partial Response (PR): At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
    Time Frame Until disease progression, up to 60.8 weeks

    Outcome Measure Data

    Analysis Population Description
    Full analysis set: all patients in phase II who receive at least one full or partial dose of INC280 or gefitinib.
    Arm/Group Title INC280 400 mg Cap BID Phase II INC280 400 mg Tab BID Phase II
    Arm/Group Description cap=capsule; BID=twice daily tab=tablet; BID=twice daily
    Measure Participants 53 47
    Count of Participants [Participants]
    12
    240%
    17
    242.9%
    3. Secondary Outcome
    Title Phase Ib and II: Number of Participants With Adverse Events (AEs)
    Description Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
    Time Frame Up to 421 weeks

    Outcome Measure Data

    Analysis Population Description
    Safety Set: All patients in phase Ib and II who received at least one full or partial dose of INC280 or gefitinib and and had at least one valid postbaseline safety assessment.
    Arm/Group Title INC280 100 mg Cap QD Phase Ib INC280 200 mg Cap QD Phase Ib INC280 400 mg Cap QD Phase Ib INC280 800 mg Cap QD Phase Ib INC280 200 mg Cap BID Phase Ib INC280 400 mg Cap BID Phase Ib INC280 600 mg Cap BID Phase Ib INC280 200 mg Tab BID Phase Ib INC280 400 mg Tab BID Phase Ib INC280 400 mg Cap BID Phase II INC280 400 mg Tab BID Phase II
    Arm/Group Description cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily tab=tablet; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily
    Measure Participants 5 7 6 7 4 12 5 7 8 53 47
    AEs
    5
    100%
    7
    100%
    6
    100%
    7
    100%
    4
    100%
    12
    100%
    5
    100%
    7
    100%
    8
    100%
    51
    96.2%
    47
    100%
    Grade 3/4 AEs
    3
    60%
    4
    57.1%
    2
    33.3%
    4
    57.1%
    2
    50%
    6
    50%
    4
    80%
    6
    85.7%
    4
    50%
    24
    45.3%
    35
    74.5%
    4. Secondary Outcome
    Title Phase Ib and II: Number of Participants With Serious Adverse Events (SAEs)
    Description Serious adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
    Time Frame Up to 421 weeks

    Outcome Measure Data

    Analysis Population Description
    Safety Set: All patients in phase Ib and II who received at least one full or partial dose of INC280 or gefitinib and and had at least one valid postbaseline safety assessment.
    Arm/Group Title INC280 100 mg Cap QD Phase Ib INC280 200 mg Cap QD Phase Ib INC280 400 mg Cap QD Phase Ib INC280 800 mg Cap QD Phase Ib INC280 200 mg Cap BID Phase Ib INC280 400 mg Cap BID Phase Ib INC280 600 mg Cap BID Phase Ib INC280 200 mg Tab BID Phase Ib INC280 400 mg Tab BID Phase Ib INC280 400 mg Cap BID Phase II INC280 400 mg Tab BID Phase II
    Arm/Group Description cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily tab=tablet; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily
    Measure Participants 5 7 6 7 4 12 5 7 8 53 47
    Count of Participants [Participants]
    1
    20%
    2
    28.6%
    2
    33.3%
    3
    42.9%
    0
    0%
    4
    33.3%
    3
    60%
    5
    71.4%
    3
    37.5%
    12
    22.6%
    19
    40.4%
    5. Secondary Outcome
    Title Phase Ib and II: Number of Patients With Dose Reductions of INC280 by Dose Level
    Description Number of patients with dose reductions of INC280 by dose level as a measure of tolerability.
    Time Frame Up to 417 weeks

    Outcome Measure Data

    Analysis Population Description
    Safety Set: All patients in phase Ib and II who received at least one full or partial dose of INC280 or gefitinib.
    Arm/Group Title INC280 100 mg Cap QD Phase Ib INC280 200 mg Cap QD Phase Ib INC280 400 mg Cap QD Phase Ib INC280 800 mg Cap QD Phase Ib INC280 200 mg Cap BID Phase Ib INC280 400 mg Cap BID Phase Ib INC280 600 mg Cap BID Phase Ib INC280 200 mg Tab BID Phase Ib INC280 400 mg Tab BID Phase Ib INC280 400 mg Cap BID Phase II INC280 400 mg Tab BID Phase II
    Arm/Group Description cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily tab=tablet; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily
    Measure Participants 5 7 6 7 4 12 5 7 8 53 47
    Without dose reductions
    5
    100%
    6
    85.7%
    5
    83.3%
    6
    85.7%
    1
    25%
    8
    66.7%
    1
    20%
    5
    71.4%
    5
    62.5%
    30
    56.6%
    23
    48.9%
    Only 1 dose reduction
    0
    0%
    1
    14.3%
    0
    0%
    1
    14.3%
    2
    50%
    2
    16.7%
    2
    40%
    0
    0%
    1
    12.5%
    13
    24.5%
    17
    36.2%
    2 dose reductions
    0
    0%
    0
    0%
    1
    16.7%
    0
    0%
    0
    0%
    1
    8.3%
    1
    20%
    1
    14.3%
    1
    12.5%
    6
    11.3%
    5
    10.6%
    3 dose reductions
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    25%
    0
    0%
    1
    20%
    0
    0%
    0
    0%
    1
    1.9%
    1
    2.1%
    >3 dose reductions
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    8.3%
    0
    0%
    1
    14.3%
    1
    12.5%
    3
    5.7%
    1
    2.1%
    6. Secondary Outcome
    Title Phase Ib and II: Number of Patients With Dose Interruptions of Gefitinib by Dose Level
    Description Number of patients with dose interruptions of gefitinib by dose level as a measure of tolerability
    Time Frame Up to 417 weeks

    Outcome Measure Data

    Analysis Population Description
    Safety set: All patients in phase Ib and II who received at least one full or partial dose of INC280 or gefitinib.
    Arm/Group Title INC280 100 mg Cap QD Phase Ib INC280 200 mg Cap QD Phase Ib INC280 400 mg Cap QD Phase Ib INC280 800 mg Cap QD Phase Ib INC280 200 mg Cap BID Phase Ib INC280 400 mg Cap BID Phase Ib INC280 600 mg Cap BID Phase Ib INC280 200 mg Tab BID Phase Ib INC280 400 mg Tab BID Phase Ib mg Cap BID Phase II INC280 400 mg Tab BID Phase II
    Arm/Group Description cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily tab=tablet; BID=twice daily cap=capsule; BID=twice daily
    Measure Participants 5 7 6 7 4 12 5 7 8 53 47
    Without dose interruptions
    5
    100%
    5
    71.4%
    6
    100%
    4
    57.1%
    4
    100%
    6
    50%
    4
    80%
    4
    57.1%
    4
    50%
    42
    79.2%
    25
    53.2%
    With only one dose interruption
    0
    0%
    2
    28.6%
    0
    0%
    2
    28.6%
    0
    0%
    3
    25%
    0
    0%
    0
    0%
    2
    25%
    9
    17%
    16
    34%
    2 dose interruptions
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    8.3%
    0
    0%
    1
    14.3%
    0
    0%
    1
    1.9%
    4
    8.5%
    3 dose interruptions
    0
    0%
    0
    0%
    0
    0%
    1
    14.3%
    0
    0%
    2
    16.7%
    0
    0%
    0
    0%
    1
    12.5%
    0
    0%
    2
    4.3%
    >3 dose interruptions
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    20%
    2
    28.6%
    1
    12.5%
    1
    1.9%
    0
    0%
    7. Secondary Outcome
    Title Phase II: Overall Survival (OS)
    Description Overall survival is defined as the time from the start of treatment date to the date of death, due to any cause
    Time Frame From date of treatment until death due to any cause, up to 70.2 months

    Outcome Measure Data

    Analysis Population Description
    Full analysis set: all patients in phase II who receive at least one full or partial dose of INC280 or gefitinib.
    Arm/Group Title INC280 400 mg Cap BID Phase II INC280 400 mg Tab BID Phase II
    Arm/Group Description cap=capsule; BID=twice daily tab=tablet; BID=twice daily
    Measure Participants 53 47
    Median (95% Confidence Interval) [Months]
    12.3
    15.2
    8. Secondary Outcome
    Title Phase II: Progression Free Survival (PFS)
    Description Progression-free survivalis the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause.
    Time Frame Up to 60.8 months

    Outcome Measure Data

    Analysis Population Description
    Full analysis set: all patients in phase II who receive at least one full or partial dose of INC280 or gefitinib
    Arm/Group Title INC280 400 mg Cap BID Phase II INC280 400 mg Tab BID Phase II
    Arm/Group Description cap=capsule; BID=twice daily tab=tablet; BID=twice daily
    Measure Participants 53 47
    Median (95% Confidence Interval) [Months]
    5.1
    5.5
    9. Secondary Outcome
    Title Phase II: Duration of Response (DoR)
    Description Duration of overall response (DOR) is defined as the time between the date of first documented response (CR or PR) and the date of first documented disease progression or death due to underlying cancer.
    Time Frame Up to 23.2 months

    Outcome Measure Data

    Analysis Population Description
    Full analysis set subjects in phase II with confirmed complete response (CR) or partial response (PR)
    Arm/Group Title INC280 400 mg Cap BID Phase II INC280 400 mg Tab BID Phase II
    Arm/Group Description cap=capsule; BID=twice daily tab=tablet; BID=twice daily
    Measure Participants 12 17
    Median (95% Confidence Interval) [Months]
    5.6
    5.6
    10. Secondary Outcome
    Title Phase I: PK Parameters AUCtau of INC280 and Gefitinib
    Description PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Area under the plasma concentration-time curve (AUC) from time zero to the end of dosing interval at steady state (tau), where tau=24 hours for once daily dosing and tau=12 hours for twice daily dosing
    Time Frame Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set: all patients having at least one evaluable PK profile of INC280 and/or gefitinib. Patients were included on the estimation of this PK parameter if a sufficient number of blood samples was available.
    Arm/Group Title INC280 100 mg Cap QD Phase Ib INC280 200 mg Cap QD Phase Ib INC280 400 mg Cap QD Phase Ib INC280 800 mg Cap QD Phase Ib INC280 200 mg Cap BID Phase Ib INC280 400 mg Cap BID Phase Ib INC280 600 mg Cap BID Phase Ib INC280 200 mg Tab BID Phase Ib INC280 400 mg Tab BID Phase Ib
    Arm/Group Description cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily tab=tablet; BID=twice daily
    Measure Participants 4 7 5 3 4 10 2 7 7
    INC280
    4510
    (1960)
    9140
    (5550)
    29200
    (12700)
    30300
    (19800)
    9660
    (5780)
    21400
    (8420)
    37300
    (18800)
    13900
    (4470)
    28700
    (5460)
    Gefitinib
    7690
    (1400)
    8070
    (2080)
    7140
    (1830)
    12800
    8440
    (2360)
    8500
    (5330)
    7160
    (2040)
    7820
    (1130)
    11. Secondary Outcome
    Title Phase I: PK Parameters Cmax of INC280 and Gefitinib
    Description PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Cmax is the maximum observed plasma concentration of INC280 and gefitinib
    Time Frame Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set: all patients having at least one evaluable PK profile of INC280 and/or gefitinib. Patients were included on the estimation of this PK parameter if a sufficient number of blood samples was available.
    Arm/Group Title INC280 100 mg Cap QD Phase Ib INC280 200 mg Cap QD Phase Ib INC280 400 mg Cap QD Phase Ib INC280 800 mg Cap QD Phase Ib INC280 200 mg Cap BID Phase Ib INC280 400 mg Cap BID Phase Ib INC280 600 mg Cap BID Phase Ib INC280 200 mg Tab BID Phase Ib INC280 400 mg Tab BID Phase Ib
    Arm/Group Description cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily tab=tablet; BID=twice daily
    Measure Participants 4 7 6 4 4 10 2 7 7
    INC280
    826
    (521)
    1490
    (1430)
    4620
    (3060)
    6570
    (4360)
    1950
    (985)
    4220
    (2100)
    4840
    (1990)
    2550
    (676)
    6760
    (1740)
    Gefitinib
    417
    (42.9)
    378
    (85.2)
    405
    (144)
    357
    (225)
    480
    (191)
    464
    (209)
    255
    (158)
    479
    (167)
    355
    (74.1)
    12. Secondary Outcome
    Title Phase I: PK Parameters Tmax of INC280 and Gefitinib
    Description PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Tmax is the time to reach maximum plasma concentration of INC280 and gefitinib
    Time Frame Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set: all patients having at least one evaluable PK profile of INC280 and/or gefitinib. Patients were included on the estimation of this PK parameter if a sufficient number of blood samples was available.
    Arm/Group Title INC280 100 mg Cap QD Phase Ib INC280 200 mg Cap QD Phase Ib INC280 400 mg Cap QD Phase Ib INC280 800 mg Cap QD Phase Ib INC280 200 mg Cap BID Phase Ib INC280 400 mg Cap BID Phase Ib INC280 600 mg Cap BID Phase Ib INC280 200 mg Tab BID Phase Ib INC280 400 mg Tab BID Phase Ib
    Arm/Group Description cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily tab=tablet; BID=twice daily
    Measure Participants 4 7 6 4 4 10 2 7 7
    INC280
    1.96
    2.00
    2.00
    2.05
    1.50
    2.00
    5.00
    2.00
    1.08
    Gefitinib
    3.92
    6.00
    6.02
    5.94
    5.00
    6.00
    11.3
    6.00
    6.00
    13. Secondary Outcome
    Title Phase I: PK Parameters Apparent Systemic Plasma Clearance Rate of INC280 and Gefitinib
    Description PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. Apparent systemic plasma clearance rate of INC280 and gefitinib
    Time Frame Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose) (Cycle=28 days)

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set: all patients having at least one evaluable PK profile of INC280 and/or gefitinib. Patients were included on the estimation of this PK parameter if a sufficient number of blood samples was available.
    Arm/Group Title INC280 100 mg Cap QD Phase Ib INC280 200 mg Cap QD Phase Ib INC280 400 mg Cap QD Phase Ib INC280 800 mg Cap QD Phase Ib INC280 200 mg Cap BID Phase Ib INC280 400 mg Cap BID Phase Ib INC280 600 mg Cap BID Phase Ib INC280 200 mg Tab BID Phase Ib INC280 400 mg Tab BID Phase Ib
    Arm/Group Description cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily tab=tablet; BID=twice daily
    Measure Participants 4 7 5 3 4 10 2 7 7
    INC 280
    26.9
    (15.0)
    29.4
    (15.7)
    16.3
    (7.61)
    47.7
    (49.1)
    27.0
    (14.7)
    24.2
    (18.3)
    18.4
    (9.31)
    15.4
    (3.89)
    14.4
    (3.10)
    Gefitinib
    33.3
    (6.78)
    32.9
    (9.65)
    36.5
    (8.41)
    19.5
    30.8
    (8.61)
    41.0
    (24.1)
    36.9
    (8.81)
    32.5
    (4.99)
    14. Secondary Outcome
    Title Phase I: PK Parameters Half-life of INC280 and Gefitinib
    Description PK parameters were estimated from each individual plasma concentration-time profile using non-compartmental analysis. The elimination half-life of INC280 and gefitinib associated with the terminal slope (Lamda_z) of a semi-logarithmic plasma concentration-time curve
    Time Frame Cycle 1 day 15 (pre-dose, 0.5, 1, 2, 4, 6, 8 and 24 hours post dose)(Cycle=28 days)

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic analysis set: all patients having at least one evaluable PK profile of INC280 and/or gefitinib. Patients were included on the estimation of this PK parameter if a sufficient number of blood samples was available.
    Arm/Group Title INC280 100 mg Cap QD Phase Ib INC280 200 mg Cap QD Phase Ib INC280 400 mg Cap QD Phase Ib INC280 800 mg Cap QD Phase Ib INC280 200 mg Cap BID Phase Ib INC280 400 mg Cap BID Phase Ib INC280 600 mg Cap BID Phase Ib INC280 200 mg Tab BID Phase Ib INC280 400 mg Tab BID Phase Ib
    Arm/Group Description cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily tab=tablet; BID=twice daily
    Measure Participants 4 6 5 3 3 9 0 7 6
    INC280
    3.86
    (0.564)
    5.10
    (2.01)
    3.16
    (0.361)
    3.67
    (0.796)
    3.19
    (0.942)
    3.01
    (1.38)
    3.75
    (1.94)
    3.17
    (0.783)
    Gefitinib
    18.8
    26.9
    (4.63)
    36.3
    (8.20)
    37.8
    16.3
    (2.16)
    18.7
    (7.75)
    17.8
    (5.08)
    23.9
    15. Other Pre-specified Outcome
    Title Phase I: Percentage of Change From Baseline in C-MET H Score at Cycle 1 Day 15
    Description Inhibition of c-MET signaling by pre- and post- treatment immunohistochemistry of p-c-MET
    Time Frame Baseline, Day 15 of cycle 1 (Cycle=28days)

    Outcome Measure Data

    Analysis Population Description
    Full analysis set patients in phase Ib with p cMET H score measured. Few tumor samples were available since tumor biopsy was optional for this study.
    Arm/Group Title INC280 100 mg Cap QD Phase Ib INC280 200 mg Cap QD Phase Ib INC280 400 mg Cap QD Phase Ib INC280 800 mg Cap QD Phase Ib INC280 200 mg Cap BID Phase Ib INC280 400 mg Cap BID Phase Ib INC280 600 mg Cap BID Phase Ib INC280 200 mg Tab BID Phase Ib INC280 400 mg Tab BID Phase Ib INC280 400 mg Cap BID Phase II INC280 400 mg Tab BID Phase II
    Arm/Group Description cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; QD=once daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily tab=tablet; BID=twice daily cap=capsule; BID=twice daily tab=tablet; BID=twice daily
    Measure Participants 1 0 0 0 0 3 0 0 0 1 0
    Median (Full Range) [Percentage]
    -100
    -100
    -31

    Adverse Events

    Time Frame Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of 8 years.
    Adverse Event Reporting Description Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
    Arm/Group Title 100 mg Cap QD (Ph Ib) 200 mg Cap QD (Ph Ib) 400 mg Cap QD (Ph Ib) 800 mg Cap QD (Ph Ib) 200 mg Cap BID (Ph Ib) 400 mg Cap BID (Ph Ib) 600 mg Cap BID (Ph Ib) 200 mg Tab BID (Ph Ib) 400 mg Tab BID (Ph Ib) 400 mg Cap BID (Ph II) 400 mg Tab BID (Ph II)
    Arm/Group Description 100 mg Cap QD (Ph Ib) 200 mg Cap QD (Ph Ib) 400 mg Cap QD (Ph Ib) 800 mg Cap QD (Ph Ib) 200 mg Cap BID (Ph Ib) 400 mg Cap BID (Ph Ib) 600 mg Cap BID (Ph Ib) 200 mg Tab BID (Ph Ib) 400 mg Tab BID (Ph Ib) 400 mg Cap BID (Ph II) 400 mg Tab BID (Ph II)
    All Cause Mortality
    100 mg Cap QD (Ph Ib) 200 mg Cap QD (Ph Ib) 400 mg Cap QD (Ph Ib) 800 mg Cap QD (Ph Ib) 200 mg Cap BID (Ph Ib) 400 mg Cap BID (Ph Ib) 600 mg Cap BID (Ph Ib) 200 mg Tab BID (Ph Ib) 400 mg Tab BID (Ph Ib) 400 mg Cap BID (Ph II) 400 mg Tab BID (Ph II)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/5 (20%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 1/12 (8.3%) 3/5 (60%) 0/7 (0%) 1/8 (12.5%) 6/53 (11.3%) 2/47 (4.3%)
    Serious Adverse Events
    100 mg Cap QD (Ph Ib) 200 mg Cap QD (Ph Ib) 400 mg Cap QD (Ph Ib) 800 mg Cap QD (Ph Ib) 200 mg Cap BID (Ph Ib) 400 mg Cap BID (Ph Ib) 600 mg Cap BID (Ph Ib) 200 mg Tab BID (Ph Ib) 400 mg Tab BID (Ph Ib) 400 mg Cap BID (Ph II) 400 mg Tab BID (Ph II)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/5 (20%) 2/7 (28.6%) 2/6 (33.3%) 3/7 (42.9%) 0/4 (0%) 4/12 (33.3%) 3/5 (60%) 5/7 (71.4%) 3/8 (37.5%) 12/53 (22.6%) 19/47 (40.4%)
    Blood and lymphatic system disorders
    Febrile neutropenia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Thrombocytopenia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Cardiac disorders
    Angina pectoris 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Atrial fibrillation 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Cardiac disorder 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Myocardial infarction 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Pericardial effusion 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Gastrointestinal disorders
    Abdominal pain 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Gastritis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Ileus 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Intestinal perforation 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Vomiting 0/5 (0%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    General disorders
    Asthenia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Oedema peripheral 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 2/47 (4.3%)
    Hepatobiliary disorders
    Cholecystitis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Hepatic function abnormal 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Infections and infestations
    Cellulitis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 2/47 (4.3%)
    Device related infection 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Erysipelas 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Klebsiella infection 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Peritonitis bacterial 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Pneumonia 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 1/8 (12.5%) 4/53 (7.5%) 2/47 (4.3%)
    Pneumonia mycoplasmal 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Septic shock 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Tracheobronchitis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Upper respiratory tract infection 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Injury, poisoning and procedural complications
    Femur fracture 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Fibula fracture 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Hip fracture 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Investigations
    Alanine aminotransferase increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Aspartate aminotransferase increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Bilirubin conjugated increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Blood bilirubin increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Blood pressure decreased 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Hypoalbuminaemia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Hyponatraemia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Musculoskeletal and connective tissue disorders
    Back pain 0/5 (0%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Muscular weakness 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant pleural effusion 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Metastases to central nervous system 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Peritumoural oedema 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Nervous system disorders
    Cerebrovascular accident 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Dizziness 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Haemorrhage intracranial 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Headache 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Intracranial pressure increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 2/53 (3.8%) 0/47 (0%)
    Somnolence 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Spinal cord compression 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Renal and urinary disorders
    Acute kidney injury 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Cough 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Dyspnoea 1/5 (20%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 2/5 (40%) 0/7 (0%) 2/8 (25%) 1/53 (1.9%) 1/47 (2.1%)
    Dyspnoea exertional 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Haemoptysis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Pneumonitis 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Pneumothorax 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Pulmonary embolism 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 3/47 (6.4%)
    Respiratory failure 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Vascular disorders
    Haematoma 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Orthostatic hypotension 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Other (Not Including Serious) Adverse Events
    100 mg Cap QD (Ph Ib) 200 mg Cap QD (Ph Ib) 400 mg Cap QD (Ph Ib) 800 mg Cap QD (Ph Ib) 200 mg Cap BID (Ph Ib) 400 mg Cap BID (Ph Ib) 600 mg Cap BID (Ph Ib) 200 mg Tab BID (Ph Ib) 400 mg Tab BID (Ph Ib) 400 mg Cap BID (Ph II) 400 mg Tab BID (Ph II)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/5 (100%) 7/7 (100%) 6/6 (100%) 7/7 (100%) 4/4 (100%) 12/12 (100%) 4/5 (80%) 6/7 (85.7%) 7/8 (87.5%) 49/53 (92.5%) 47/47 (100%)
    Blood and lymphatic system disorders
    Anaemia 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 2/4 (50%) 1/12 (8.3%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 18/53 (34%) 4/47 (8.5%)
    Leukopenia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 5/53 (9.4%) 0/47 (0%)
    Neutropenia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 4/53 (7.5%) 0/47 (0%)
    Cardiac disorders
    Cardiac failure congestive 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Tachycardia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Ear and labyrinth disorders
    Hypoacusis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 2/47 (4.3%)
    Tinnitus 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 1/47 (2.1%)
    Eye disorders
    Dry eye 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 2/47 (4.3%)
    Eye irritation 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Lacrimation increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 2/7 (28.6%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Photopsia 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Vision blurred 1/5 (20%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Visual acuity reduced 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Gastrointestinal disorders
    Abdominal discomfort 0/5 (0%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Abdominal distension 0/5 (0%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 3/53 (5.7%) 1/47 (2.1%)
    Abdominal pain 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%) 1/12 (8.3%) 1/5 (20%) 1/7 (14.3%) 2/8 (25%) 1/53 (1.9%) 4/47 (8.5%)
    Abdominal pain upper 0/5 (0%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 1/7 (14.3%) 2/8 (25%) 1/53 (1.9%) 4/47 (8.5%)
    Constipation 3/5 (60%) 2/7 (28.6%) 0/6 (0%) 0/7 (0%) 1/4 (25%) 1/12 (8.3%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 5/53 (9.4%) 11/47 (23.4%)
    Diarrhoea 1/5 (20%) 1/7 (14.3%) 0/6 (0%) 2/7 (28.6%) 3/4 (75%) 4/12 (33.3%) 1/5 (20%) 1/7 (14.3%) 3/8 (37.5%) 7/53 (13.2%) 15/47 (31.9%)
    Dry mouth 1/5 (20%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 2/47 (4.3%)
    Duodenal ulcer 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Dyspepsia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 3/47 (6.4%)
    Dysphagia 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Gastric ulcer 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Gastritis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 2/47 (4.3%)
    Gastrooesophageal reflux disease 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Gingival bleeding 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 3/53 (5.7%) 1/47 (2.1%)
    Mouth ulceration 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 2/53 (3.8%) 0/47 (0%)
    Nausea 2/5 (40%) 2/7 (28.6%) 3/6 (50%) 6/7 (85.7%) 2/4 (50%) 1/12 (8.3%) 1/5 (20%) 5/7 (71.4%) 3/8 (37.5%) 7/53 (13.2%) 26/47 (55.3%)
    Stomatitis 1/5 (20%) 1/7 (14.3%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 3/47 (6.4%)
    Vomiting 2/5 (40%) 3/7 (42.9%) 2/6 (33.3%) 7/7 (100%) 1/4 (25%) 1/12 (8.3%) 1/5 (20%) 2/7 (28.6%) 3/8 (37.5%) 10/53 (18.9%) 10/47 (21.3%)
    General disorders
    Asthenia 0/5 (0%) 1/7 (14.3%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 1/5 (20%) 2/7 (28.6%) 1/8 (12.5%) 3/53 (5.7%) 4/47 (8.5%)
    Chest discomfort 1/5 (20%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 1/47 (2.1%)
    Face oedema 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Fatigue 1/5 (20%) 1/7 (14.3%) 1/6 (16.7%) 1/7 (14.3%) 0/4 (0%) 2/12 (16.7%) 1/5 (20%) 1/7 (14.3%) 2/8 (25%) 10/53 (18.9%) 17/47 (36.2%)
    Generalised oedema 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Influenza like illness 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Mucosal inflammation 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Non-cardiac chest pain 1/5 (20%) 2/7 (28.6%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 8/53 (15.1%) 4/47 (8.5%)
    Oedema 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 2/8 (25%) 0/53 (0%) 3/47 (6.4%)
    Oedema peripheral 0/5 (0%) 0/7 (0%) 2/6 (33.3%) 1/7 (14.3%) 1/4 (25%) 4/12 (33.3%) 2/5 (40%) 3/7 (42.9%) 2/8 (25%) 15/53 (28.3%) 21/47 (44.7%)
    Pain 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 1/53 (1.9%) 0/47 (0%)
    Peripheral swelling 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 3/47 (6.4%)
    Pyrexia 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 1/4 (25%) 2/12 (16.7%) 1/5 (20%) 1/7 (14.3%) 1/8 (12.5%) 2/53 (3.8%) 4/47 (8.5%)
    Infections and infestations
    Cellulitis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 3/47 (6.4%)
    Conjunctivitis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 2/47 (4.3%)
    Cystitis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 3/7 (42.9%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Ear infection 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Eye infection 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Folliculitis 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Gastroenteritis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Infected dermal cyst 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Influenza 0/5 (0%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Localised infection 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Nasopharyngitis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 2/12 (16.7%) 1/5 (20%) 1/7 (14.3%) 0/8 (0%) 5/53 (9.4%) 1/47 (2.1%)
    Paronychia 2/5 (40%) 1/7 (14.3%) 2/6 (33.3%) 0/7 (0%) 2/4 (50%) 4/12 (33.3%) 0/5 (0%) 2/7 (28.6%) 3/8 (37.5%) 7/53 (13.2%) 10/47 (21.3%)
    Periodontitis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 1/47 (2.1%)
    Pneumonia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Rhinitis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Skin infection 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Upper respiratory tract infection 1/5 (20%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 2/53 (3.8%) 4/47 (8.5%)
    Urinary tract infection 0/5 (0%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 4/47 (8.5%)
    Injury, poisoning and procedural complications
    Hand fracture 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Skin abrasion 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Tracheal haemorrhage 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Wound complication 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Investigations
    Alanine aminotransferase increased 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 1/7 (14.3%) 1/4 (25%) 2/12 (16.7%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 13/53 (24.5%) 5/47 (10.6%)
    Amylase increased 2/5 (40%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 1/4 (25%) 4/12 (33.3%) 0/5 (0%) 2/7 (28.6%) 1/8 (12.5%) 7/53 (13.2%) 11/47 (23.4%)
    Aspartate aminotransferase increased 1/5 (20%) 0/7 (0%) 1/6 (16.7%) 1/7 (14.3%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 10/53 (18.9%) 7/47 (14.9%)
    Bilirubin conjugated increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 5/53 (9.4%) 0/47 (0%)
    Blood albumin decreased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 2/53 (3.8%) 0/47 (0%)
    Blood alkaline phosphatase increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 1/4 (25%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 2/53 (3.8%) 4/47 (8.5%)
    Blood bilirubin increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 5/12 (41.7%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 8/53 (15.1%) 4/47 (8.5%)
    Blood creatinine increased 0/5 (0%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 3/12 (25%) 1/5 (20%) 2/7 (28.6%) 0/8 (0%) 9/53 (17%) 8/47 (17%)
    Blood glucose increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Blood iron decreased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Blood phosphorus increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Crystal urine present 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Gamma-glutamyltransferase increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 3/53 (5.7%) 5/47 (10.6%)
    Haemoglobin decreased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 3/53 (5.7%) 0/47 (0%)
    Lipase increased 1/5 (20%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 2/12 (16.7%) 1/5 (20%) 1/7 (14.3%) 0/8 (0%) 5/53 (9.4%) 10/47 (21.3%)
    Neutrophil count decreased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Protein total increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Protein urine present 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 2/5 (40%) 0/7 (0%) 0/8 (0%) 2/53 (3.8%) 0/47 (0%)
    Urinary sediment present 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Urine analysis abnormal 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Urine bilirubin increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Urine ketone body present 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Urobilinogen urine increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Weight decreased 0/5 (0%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 1/7 (14.3%) 2/8 (25%) 0/53 (0%) 4/47 (8.5%)
    Weight increased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 3/47 (6.4%)
    White blood cell count decreased 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 2/53 (3.8%) 1/47 (2.1%)
    White blood cells urine positive 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 2/5 (40%) 2/7 (28.6%) 1/6 (16.7%) 4/7 (57.1%) 1/4 (25%) 1/12 (8.3%) 3/5 (60%) 3/7 (42.9%) 3/8 (37.5%) 13/53 (24.5%) 19/47 (40.4%)
    Hyperamylasaemia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 8/53 (15.1%) 0/47 (0%)
    Hyperglycaemia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 2/53 (3.8%) 4/47 (8.5%)
    Hyperkalaemia 1/5 (20%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Hypoalbuminaemia 0/5 (0%) 0/7 (0%) 0/6 (0%) 2/7 (28.6%) 3/4 (75%) 7/12 (58.3%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 23/53 (43.4%) 12/47 (25.5%)
    Hypocalcaemia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 1/5 (20%) 1/7 (14.3%) 0/8 (0%) 8/53 (15.1%) 3/47 (6.4%)
    Hypochloraemia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 2/53 (3.8%) 0/47 (0%)
    Hypokalaemia 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 1/4 (25%) 2/12 (16.7%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 7/53 (13.2%) 4/47 (8.5%)
    Hypomagnesaemia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 2/47 (4.3%)
    Hyponatraemia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 1/5 (20%) 2/7 (28.6%) 0/8 (0%) 6/53 (11.3%) 1/47 (2.1%)
    Hypophosphataemia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 3/53 (5.7%) 1/47 (2.1%)
    Hypoproteinaemia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 2/5 (40%) 0/7 (0%) 0/8 (0%) 5/53 (9.4%) 0/47 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 1/53 (1.9%) 3/47 (6.4%)
    Back pain 0/5 (0%) 4/7 (57.1%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 4/53 (7.5%) 4/47 (8.5%)
    Bone pain 0/5 (0%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 2/53 (3.8%) 1/47 (2.1%)
    Flank pain 1/5 (20%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Gouty arthritis 0/5 (0%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Joint swelling 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 1/53 (1.9%) 0/47 (0%)
    Ligament pain 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Muscle spasms 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 2/4 (50%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 1/8 (12.5%) 1/53 (1.9%) 3/47 (6.4%)
    Muscle tightness 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Muscular weakness 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 1/7 (14.3%) 1/8 (12.5%) 2/53 (3.8%) 0/47 (0%)
    Musculoskeletal chest pain 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 2/53 (3.8%) 1/47 (2.1%)
    Musculoskeletal pain 1/5 (20%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 2/12 (16.7%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 3/53 (5.7%) 3/47 (6.4%)
    Myalgia 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 2/47 (4.3%)
    Neck pain 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Pain in extremity 1/5 (20%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 1/47 (2.1%)
    Rhabdomyolysis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Nervous system disorders
    Cognitive disorder 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Depressed level of consciousness 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Dizziness 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 2/7 (28.6%) 2/4 (50%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 2/8 (25%) 6/53 (11.3%) 3/47 (6.4%)
    Dyskinesia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Facial spasm 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Headache 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 1/12 (8.3%) 1/5 (20%) 1/7 (14.3%) 3/8 (37.5%) 3/53 (5.7%) 8/47 (17%)
    Hypoaesthesia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 1/53 (1.9%) 1/47 (2.1%)
    Nervous system disorder 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 2/12 (16.7%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Neuropathy peripheral 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 2/47 (4.3%)
    Paraesthesia 0/5 (0%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Taste disorder 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Tremor 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 2/53 (3.8%) 0/47 (0%)
    Psychiatric disorders
    Anxiety 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Depression 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Insomnia 1/5 (20%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 1/4 (25%) 0/12 (0%) 1/5 (20%) 3/7 (42.9%) 1/8 (12.5%) 7/53 (13.2%) 2/47 (4.3%)
    Renal and urinary disorders
    Azotaemia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Dysuria 0/5 (0%) 1/7 (14.3%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 3/47 (6.4%)
    Haematuria 1/5 (20%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 5/53 (9.4%) 2/47 (4.3%)
    Haemoglobinuria 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Pollakiuria 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Proteinuria 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 2/53 (3.8%) 0/47 (0%)
    Respiratory, thoracic and mediastinal disorders
    Aspiration 1/5 (20%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Chronic obstructive pulmonary disease 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Cough 0/5 (0%) 0/7 (0%) 2/6 (33.3%) 1/7 (14.3%) 1/4 (25%) 3/12 (25%) 3/5 (60%) 0/7 (0%) 1/8 (12.5%) 14/53 (26.4%) 8/47 (17%)
    Dysphonia 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Dyspnoea 1/5 (20%) 0/7 (0%) 1/6 (16.7%) 2/7 (28.6%) 1/4 (25%) 4/12 (33.3%) 1/5 (20%) 1/7 (14.3%) 2/8 (25%) 3/53 (5.7%) 9/47 (19.1%)
    Haemoptysis 1/5 (20%) 0/7 (0%) 1/6 (16.7%) 1/7 (14.3%) 1/4 (25%) 1/12 (8.3%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 8/53 (15.1%) 2/47 (4.3%)
    Interstitial lung disease 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Nasal dryness 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Oropharyngeal pain 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 1/4 (25%) 1/12 (8.3%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 4/53 (7.5%) 0/47 (0%)
    Productive cough 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 4/47 (8.5%)
    Pulmonary embolism 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Rhinorrhoea 1/5 (20%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Tachypnoea 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 2/4 (50%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 1/53 (1.9%) 0/47 (0%)
    Skin and subcutaneous tissue disorders
    Acne 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 3/47 (6.4%)
    Decubitus ulcer 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Dermatitis acneiform 1/5 (20%) 2/7 (28.6%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 4/7 (57.1%) 1/8 (12.5%) 0/53 (0%) 5/47 (10.6%)
    Dermatosis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Dry skin 0/5 (0%) 2/7 (28.6%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 1/53 (1.9%) 4/47 (8.5%)
    Pruritus 3/5 (60%) 1/7 (14.3%) 0/6 (0%) 1/7 (14.3%) 1/4 (25%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 2/53 (3.8%) 5/47 (10.6%)
    Rash 2/5 (40%) 3/7 (42.9%) 0/6 (0%) 2/7 (28.6%) 2/4 (50%) 4/12 (33.3%) 1/5 (20%) 2/7 (28.6%) 3/8 (37.5%) 7/53 (13.2%) 15/47 (31.9%)
    Rash macular 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Rash maculo-papular 1/5 (20%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Rash vesicular 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Skin fissures 0/5 (0%) 0/7 (0%) 1/6 (16.7%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Urticaria 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 1/47 (2.1%)
    Vascular disorders
    Deep vein thrombosis 0/5 (0%) 0/7 (0%) 0/6 (0%) 1/7 (14.3%) 0/4 (0%) 0/12 (0%) 1/5 (20%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Hypotension 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Orthostatic hypotension 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 1/7 (14.3%) 0/8 (0%) 0/53 (0%) 0/47 (0%)
    Peripheral vascular disorder 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 0/12 (0%) 0/5 (0%) 0/7 (0%) 1/8 (12.5%) 0/53 (0%) 0/47 (0%)
    Phlebitis 0/5 (0%) 0/7 (0%) 0/6 (0%) 0/7 (0%) 0/4 (0%) 1/12 (8.3%) 0/5 (0%) 0/7 (0%) 0/8 (0%) 0/53 (0%) 0/47 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.

    Results Point of Contact

    Name/Title Study Director
    Organization Novartis Pharmaceuticals
    Phone 862-778-8300
    Email novartis.email@novartis.com
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01610336
    Other Study ID Numbers:
    • CINC280X2202
    • 2011-002569-39
    First Posted:
    Jun 4, 2012
    Last Update Posted:
    Apr 8, 2021
    Last Verified:
    Mar 1, 2021