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Trial record 38 of 50 for:    MK-2206

A Combination Therapy Study of MK-2206 and AZD6244 in Participants With Advanced Solid Tumors (MK-2206-010)

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ClinicalTrials.gov Identifier: NCT01021748
Recruitment Status : Completed
First Posted : November 30, 2009
Results First Posted : August 7, 2018
Last Update Posted : August 7, 2018
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Locally Advanced or Metastatic Solid Tumors
Interventions Drug: MK-2206
Drug: AZD6244
Enrollment 63
Recruitment Details  
Pre-assignment Details  
Arm/Group Title MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
Hide Arm/Group Description Participants received MK-2206 45 mg oral tablets once every other day (QOD) PLUS AZD6244 75 mg oral capsules once daily (QD) starting on Day 1 of each 28-day cycle. Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules twice daily (BID) starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets once weekly (QW) PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Period Title: Overall Study
Started 6 5 7 7 9 3 3 6 17
Treated 6 4 [1] 7 7 9 3 3 6 17
Completed 0 0 0 0 0 0 0 0 1
Not Completed 6 5 7 7 9 3 3 6 16
Reason Not Completed
Adverse Event             2             1             2             0             2             0             1             0             7
Physician Decision             1             0             1             1             0             0             1             1             2
Progressive Disease             3             3             4             6             7             3             0             5             6
Withdrawal by Subject             0             0             0             0             0             0             1             0             1
Not Treated             0             1             0             0             0             0             0             0             0
[1]
One participant was allocated, but not treated.
Arm/Group Title MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD Total
Hide Arm/Group Description Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Total of all reporting groups
Overall Number of Baseline Participants 6 4 7 7 9 3 3 6 17 62
Hide Baseline Analysis Population Description
The Baseline Analysis Population consisted of all participants who received at least one dose of study treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 6 participants 4 participants 7 participants 7 participants 9 participants 3 participants 3 participants 6 participants 17 participants 62 participants
55.0  (8.0) 50.0  (5.9) 48.9  (8.6) 56.6  (7.3) 56.1  (12.5) 44.3  (8.0) 63.0  (6.2) 54.3  (15.3) 64.7  (9.4) 56.8  (11.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 6 participants 4 participants 7 participants 7 participants 9 participants 3 participants 3 participants 6 participants 17 participants 62 participants
Female
4
  66.7%
3
  75.0%
4
  57.1%
2
  28.6%
5
  55.6%
2
  66.7%
2
  66.7%
2
  33.3%
12
  70.6%
36
  58.1%
Male
2
  33.3%
1
  25.0%
3
  42.9%
5
  71.4%
4
  44.4%
1
  33.3%
1
  33.3%
4
  66.7%
5
  29.4%
26
  41.9%
1.Primary Outcome
Title Number of Participants With a Dose-limiting Toxicity (DLT)
Hide Description Adverse events (AEs) were graded using Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. DLTs included: Grade 4 neutropenia lasting for ≥7 days; Grade 3 or Grade 4 neutropenia with fever >38.5ºC and/or infection requiring antibiotic or anti-fungal treatment; Grade 4 thrombocytopenia (≤25.0 x 10^9/L); Grade ≥3 non-hematologic toxicity with exceptions; Any drug-related AE, regardless of CTCAE Grade, leading to a dose modification of MK-2206 or AZD6244; Unresolved CTCAE Grade ≥3 drug-related toxicity requiring drug interruption for >14 days; ≥ Grade 3 signs or symptoms of glucose intolerance and accompanied by ≥ Grade 2 hyperglycemia (glucose >160 dL or 8.9 mmol/L); ≥ Grade 3 electrolyte abnormalities due to glucose intolerance and not attributable to another cause; Diagnosis of lactoacidosis or ketoacidosis; Persistent increases in corrected QT (QTc) interval (>60 msec from baseline and/or >500 msec); Clinically significant bradycardia.
Time Frame Cycle 1 (Up to 28 days)
Hide Outcome Measure Data
Hide Analysis Population Description
The population consisted of all participants who completed ≥ 80% of the first cycle of combination therapy unless interruption of study medication was due to toxicity (e.g. DLT).
Arm/Group Title MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
Hide Arm/Group Description:
Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Overall Number of Participants Analyzed 6 4 7 7 9 3 3 6 17
Measure Type: Number
Unit of Measure: Participants
0 2 2 1 3 0 2 0 3
2.Primary Outcome
Title Number of Participants Who Experienced at Least One Adverse Event (AE)
Hide Description An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening of a pre-existing condition which was temporally associated with the use of study drug was also an AE. The number of participants who experienced at least one AE is presented.
Time Frame Up to approximately 23 months
Hide Outcome Measure Data
Hide Analysis Population Description
The population consisted of all participants who received at least one dose of study treatment.
Arm/Group Title MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
Hide Arm/Group Description:
Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Overall Number of Participants Analyzed 6 4 7 7 9 3 3 6 17
Measure Type: Number
Unit of Measure: Participants
6 4 7 7 9 3 3 6 17
3.Primary Outcome
Title Number of Participants Who Discontinued Study Treatment Due to an AE
Hide Description An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening of a pre-existing condition which was temporally associated with the use of study drug was also an AE. The number of participants who discontinued study treatment due to an AE is presented.
Time Frame Up to approximately 20 months
Hide Outcome Measure Data
Hide Analysis Population Description
The population consisted of all participants who received at least one dose of study treatment.
Arm/Group Title MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
Hide Arm/Group Description:
Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Overall Number of Participants Analyzed 6 4 7 7 9 3 3 6 17
Measure Type: Number
Unit of Measure: Participants
2 1 2 0 2 0 1 0 7
4.Secondary Outcome
Title Number of Participants With a Tumor Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
Hide Description Radiological evaluation (via computed tomography [CT] or magnetic resonance imaging [MRI]) of tumor response was assessed every 8 weeks post-treatment during Cycles 1-6, and per institutional standard of care in Cycle 7 and beyond. The best overall tumor response was the best response based on RECIST 1.1 recorded from the start of the study treatment until the end of treatment. Response categories included: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Participants whose tumor was not evaluable (NE) were missing a valid RECIST1.1 measurement at baseline. The best overall tumor response for participants is presented.
Time Frame Baseline and after every 8 weeks of treatment until documentation of objective response or disease progression (Up to 2 years)
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis population consisted of all participants with assessable disease at baseline or measureable disease at baseline per RECIST1.1.
Arm/Group Title MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
Hide Arm/Group Description:
Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Participants received MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
Overall Number of Participants Analyzed 6 3 7 7 9 3 2 6 13
Measure Type: Number
Unit of Measure: Participants
Complete Response 0 0 0 0 0 0 0 0 0
Partial Response 0 0 2 0 1 0 0 0 2
Stable Disease 4 0 1 3 3 3 2 4 10
Progressive Disease 2 3 4 4 5 0 0 2 1
Time Frame Up to approximately 23 months
Adverse Event Reporting Description The population consisted of all participants who received at least one dose of study treatment.
 
Arm/Group Title MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
Hide Arm/Group Description Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. Participants received MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle.
All-Cause Mortality
MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
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   4/6 (66.67%)      1/4 (25.00%)      6/7 (85.71%)      2/7 (28.57%)      6/9 (66.67%)      0/3 (0.00%)      2/3 (66.67%)      3/6 (50.00%)      5/17 (29.41%)    
Blood and lymphatic system disorders                   
Anaemia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 2/9 (22.22%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Cardiac disorders                   
Atrial flutter  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Eye disorders                   
Detachment of retinal pigment epithelium  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Gastrointestinal disorders                   
Abdominal pain  1  1/6 (16.67%)  1 0/4 (0.00%)  0 2/7 (28.57%)  2 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Constipation  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Diarrhoea  1  1/6 (16.67%)  2 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Dysphagia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Gastrointestinal haemorrhage  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  2 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Haemorrhoids  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Intestinal obstruction  1  1/6 (16.67%)  1 0/4 (0.00%)  0 2/7 (28.57%)  3 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Obstruction gastric  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Rectal haemorrhage  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Small intestinal obstruction  1  0/6 (0.00%)  0 1/4 (25.00%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Stomatitis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Vomiting  1  2/6 (33.33%)  2 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
General disorders                   
Fatigue  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Pyrexia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Infections and infestations                   
Clostridium difficile colitis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Hepatitis C  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Lower respiratory tract infection  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Meningitis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Pneumonia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Pyelonephritis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Injury, poisoning and procedural complications                   
Post procedural fistula  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Renal haematoma  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Investigations                   
Lipase increased  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                   
Malignant neoplasm progression  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Nervous system disorders                   
Complex partial seizures  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Renal and urinary disorders                   
Hydronephrosis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Renal failure acute  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Urinary retention  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                   
Pleural effusion  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Pneumonitis  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Skin and subcutaneous tissue disorders                   
Dermatitis acneiform  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Rash  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Vascular disorders                   
Haemorrhage  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Superior vena cava syndrome  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Vena cava thrombosis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
MK-2206 45 mg QOD + AZD6244 75 mg QD MK-2206 45 mg QOD + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 50 mg BID MK-2206 90 mg QW + AZD6244 75 mg QD MK-2206 90 mg QW + AZD6244 75 mg BID MK-2206 90 mg QW + AZD6244 100 mg QD MK-2206 90 mg QW + AZD6244 150 mg QD MK-2206 100 mg QW + AZD6244 100 mg QD MK-2206 135 mg QW + AZD6244 100 mg QD
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   6/6 (100.00%)      4/4 (100.00%)      7/7 (100.00%)      7/7 (100.00%)      9/9 (100.00%)      3/3 (100.00%)      2/3 (66.67%)      6/6 (100.00%)      17/17 (100.00%)    
Blood and lymphatic system disorders                   
Anaemia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 2/7 (28.57%)  2 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Leukopenia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  3 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Lymphopenia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/17 (11.76%)  7
Neutropenia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 2/7 (28.57%)  3 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/17 (11.76%)  2
Thrombocytopenia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Cardiac disorders                   
Arrhythmia supraventricular  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 0/17 (0.00%)  0
Atrioventricular block first degree  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Bradycardia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/17 (11.76%)  2
Left ventricular dysfunction  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Palpitations  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Tachycardia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 0/17 (0.00%)  0
Ear and labyrinth disorders                   
Auricular swelling  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Tinnitus  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Eye disorders                   
Amblyopia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Blepharitis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Cataract  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Cataract subcapsular  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Conjunctival haemorrhage  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Conjunctivitis  1  0/6 (0.00%)  0 1/4 (25.00%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Detachment of macular retinal pigment epithelium  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Dry eye  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  2
Eye pain  1  0/6 (0.00%)  0 1/4 (25.00%)  1 0/7 (0.00%)  0 1/7 (14.29%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Eye pruritus  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Eye swelling  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Eyelid oedema  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Lacrimation increased  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 3/17 (17.65%)  3
Macular fibrosis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Macular pigmentation  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Maculopathy  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Ocular hypertension  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Periorbital oedema  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/17 (11.76%)  2
Photophobia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Retinal detachment  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Retinal pigment epitheliopathy  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Scleral hyperaemia  1  0/6 (0.00%)  0 1/4 (25.00%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Vision blurred  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  2 0/7 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  2 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Visual impairment  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Gastrointestinal disorders                   
Abdominal discomfort  1  0/6 (0.00%)  0 0/4 (0.00%)  0 2/7 (28.57%)  3 0/7 (0.00%)  0 1/9 (11.11%)  1 1/3 (33.33%)  1 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Abdominal distension  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 2/9 (22.22%)  2 2/3 (66.67%)  2 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Abdominal pain  1  2/6 (33.33%)  2 0/4 (0.00%)  0 2/7 (28.57%)  3 1/7 (14.29%)  1 3/9 (33.33%)  3 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  2
Abdominal pain lower  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Abdominal pain upper  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Ascites  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Constipation  1  1/6 (16.67%)  1 0/4 (0.00%)  0 1/7 (14.29%)  1 2/7 (28.57%)  2 2/9 (22.22%)  2 2/3 (66.67%)  2 1/3 (33.33%)  1 1/6 (16.67%)  1 2/17 (11.76%)  2
Diarrhoea  1  3/6 (50.00%)  8 3/4 (75.00%)  3 3/7 (42.86%)  7 3/7 (42.86%)  6 5/9 (55.56%)  6 3/3 (100.00%)  5 0/3 (0.00%)  0 2/6 (33.33%)  4 14/17 (82.35%)  20
Dry mouth  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 4/17 (23.53%)  6
Dyspepsia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 3/9 (33.33%)  3 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 1/17 (5.88%)  1
Eructation  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Faecal incontinence  1  1/6 (16.67%)  2 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Flatulence  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Gastrointestinal haemorrhage  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Haemorrhoids  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Lip ulceration  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Mouth ulceration  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Nausea  1  2/6 (33.33%)  2 1/4 (25.00%)  1 5/7 (71.43%)  6 4/7 (57.14%)  5 1/9 (11.11%)  1 1/3 (33.33%)  1 2/3 (66.67%)  3 3/6 (50.00%)  3 8/17 (47.06%)  13
Odynophagia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Oesophageal pain  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 0/17 (0.00%)  0
Oral pain  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Proctalgia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Rectal haemorrhage  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 1/17 (5.88%)  1
Stomatitis  1  2/6 (33.33%)  2 1/4 (25.00%)  2 1/7 (14.29%)  1 0/7 (0.00%)  0 5/9 (55.56%)  7 1/3 (33.33%)  1 0/3 (0.00%)  0 1/6 (16.67%)  2 3/17 (17.65%)  4
Varices oesophageal  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Vomiting  1  2/6 (33.33%)  2 1/4 (25.00%)  1 7/7 (100.00%)  10 4/7 (57.14%)  4 0/9 (0.00%)  0 0/3 (0.00%)  0 2/3 (66.67%)  4 3/6 (50.00%)  3 4/17 (23.53%)  4
General disorders                   
Asthenia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Axillary pain  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Chest discomfort  1  1/6 (16.67%)  2 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Chest pain  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Chills  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Face oedema  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 0/17 (0.00%)  0
Fatigue  1  3/6 (50.00%)  6 1/4 (25.00%)  1 4/7 (57.14%)  11 3/7 (42.86%)  4 3/9 (33.33%)  6 2/3 (66.67%)  4 1/3 (33.33%)  1 3/6 (50.00%)  4 11/17 (64.71%)  15
Influenza like illness  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Localised oedema  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Malaise  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Mucosal inflammation  1  0/6 (0.00%)  0 0/4 (0.00%)  0 3/7 (42.86%)  7 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 7/17 (41.18%)  10
Oedema  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Oedema peripheral  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 1/7 (14.29%)  1 1/9 (11.11%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Pain  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Pyrexia  1  0/6 (0.00%)  0 1/4 (25.00%)  1 1/7 (14.29%)  1 1/7 (14.29%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  2
Infections and infestations                   
Cystitis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Ear infection  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  2 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Eyelid infection  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Infection  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Lower respiratory tract infection  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  2 0/7 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 1/6 (16.67%)  2 0/17 (0.00%)  0
Nasopharyngitis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Oral candidiasis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Oral herpes  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Paronychia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  2 0/7 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 2/17 (11.76%)  3
Pharyngitis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Rhinitis  1  1/6 (16.67%)  1 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Sinusitis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Upper respiratory tract infection  1  0/6 (0.00%)  0 1/4 (25.00%)  1 1/7 (14.29%)  1 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Urinary tract infection  1  0/6 (0.00%)  0 0/4 (0.00%)  0 2/7 (28.57%)  2 0/7 (0.00%)  0 1/9 (11.11%)  1 1/3 (33.33%)  1 1/3 (33.33%)  1 0/6 (0.00%)  0 4/17 (23.53%)  5
Injury, poisoning and procedural complications                   
Accidental overdose  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Contusion  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Fall  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  2
Laceration  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Nail injury  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Post-traumatic neck syndrome  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Tooth fracture  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Investigations                   
Activated partial thromboplastin time prolonged  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Alanine aminotransferase increased  1  1/6 (16.67%)  2 1/4 (25.00%)  7 1/7 (14.29%)  1 1/7 (14.29%)  2 2/9 (22.22%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 3/17 (17.65%)  7
Aspartate aminotransferase increased  1  1/6 (16.67%)  2 1/4 (25.00%)  3 0/7 (0.00%)  0 1/7 (14.29%)  3 2/9 (22.22%)  3 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 4/17 (23.53%)  6
Blood albumin decreased  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Blood alkaline phosphatase increased  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 3/7 (42.86%)  3 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Blood bilirubin increased  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  2
Blood creatine phosphokinase increased  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  10 0/7 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 3/17 (17.65%)  3
Blood creatinine increased  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 1/17 (5.88%)  1
Blood glucose increased  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Blood potassium decreased  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Blood urea increased  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Culture urine positive  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Electrocardiogram QT prolonged  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Electrocardiogram T wave amplitude decreased  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Haemoglobin  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  2
Lymphocyte count decreased  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  3
Neutrophil count decreased  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Weight decreased  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
White blood cell count decreased  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Metabolism and nutrition disorders                   
Decreased appetite  1  1/6 (16.67%)  1 1/4 (25.00%)  1 3/7 (42.86%)  3 1/7 (14.29%)  1 1/9 (11.11%)  1 0/3 (0.00%)  0 2/3 (66.67%)  2 1/6 (16.67%)  1 4/17 (23.53%)  8
Dehydration  1  1/6 (16.67%)  1 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Hyperglycaemia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 2/7 (28.57%)  5 1/9 (11.11%)  3 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 2/17 (11.76%)  2
Hyperphosphataemia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Hypoalbuminaemia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  2 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Hypocalcaemia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  2 1/7 (14.29%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Hypokalaemia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 3/17 (17.65%)  3
Hypomagnesaemia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Hyponatraemia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  2
Hypophosphataemia  1  0/6 (0.00%)  0 1/4 (25.00%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  4
Musculoskeletal and connective tissue disorders                   
Back pain  1  0/6 (0.00%)  0 0/4 (0.00%)  0 2/7 (28.57%)  2 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 3/17 (17.65%)  3
Bone pain  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Flank pain  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 2/6 (33.33%)  3 0/17 (0.00%)  0
Joint swelling  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Muscle spasms  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  2 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Muscle twitching  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Musculoskeletal discomfort  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 2/9 (22.22%)  5 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Musculoskeletal pain  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  3 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Myalgia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Neck pain  1  0/6 (0.00%)  0 0/4 (0.00%)  0 2/7 (28.57%)  4 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 1/17 (5.88%)  1
Pain in extremity  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                   
Tumour pain  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Nervous system disorders                   
Brachial plexopathy  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Cognitive disorder  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Convulsion  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Dizziness  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/6 (33.33%)  5 1/17 (5.88%)  1
Dysgeusia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 2/9 (22.22%)  2 1/3 (33.33%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 2/17 (11.76%)  3
Headache  1  0/6 (0.00%)  0 1/4 (25.00%)  1 1/7 (14.29%)  2 2/7 (28.57%)  3 0/9 (0.00%)  0 1/3 (33.33%)  1 1/3 (33.33%)  1 1/6 (16.67%)  1 5/17 (29.41%)  6
Hypoaesthesia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Lethargy  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 1/17 (5.88%)  1
Migraine  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Paraesthesia  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Sciatica  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Somnolence  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Psychiatric disorders                   
Affective disorder  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Depression  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 3/17 (17.65%)  3
Renal and urinary disorders                   
Bladder spasm  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Dysuria  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  3 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/17 (0.00%)  0
Haematuria  1  1/6 (16.67%)  1 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Hydronephrosis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  2 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Micturition urgency  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 1/7 (14.29%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Pollakiuria  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Proteinuria  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Urinary hesitation  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Urinary incontinence  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Urinary retention  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Urinary tract pain  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Reproductive system and breast disorders                   
Vaginal haemorrhage  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Vulvovaginal discomfort  1  0/6 (0.00%)  0 0/4 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Vulvovaginal dryness  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Vulvovaginal pain  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                   
Allergic cough  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Cough  1  1/6 (16.67%)  1 0/4 (0.00%)  0 1/7 (14.29%)  1 1/7 (14.29%)  1 3/9 (33.33%)  3 1/3 (33.33%)  2 2/3 (66.67%)  2 2/6 (33.33%)  4 3/17 (17.65%)  3
Dry throat  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Dysphonia  1  0/6 (0.00%)  0 2/4 (50.00%)  2 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/17 (11.76%)  2
Dyspnoea  1  1/6 (16.67%)  2 0/4 (0.00%)  0 2/7 (28.57%)  3 0/7 (0.00%)  0 1/9 (11.11%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 2/6 (33.33%)  2 4/17 (23.53%)  5
Dyspnoea exertional  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Epistaxis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 1/6 (16.67%)  1 0/17 (0.00%)  0
Haemoptysis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/6 (33.33%)  3 0/17 (0.00%)  0
Nasal congestion  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Nasal dryness  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Nasal inflammation  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Oropharyngeal pain  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 2/7 (28.57%)  2 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/17 (11.76%)  2
Paranasal sinus hypersecretion  1  1/6 (16.67%)  1 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/17 (0.00%)  0
Pleural effusion  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  2 0/17 (0.00%)  0
Pleuritic pain  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/9 (11.11%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/17 (0.00%)  0
Pneumonitis  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  2
Productive cough  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Rhinitis allergic  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  1
Rhinorrhoea  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 1/17 (5.88%)  1
Skin and subcutaneous tissue disorders                   
Acne  1  0/6 (0.00%)  0 0/4 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/9 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/17 (5.88%)  2
Alopecia  1  0/6 (0.00%)  0 0/4 (0.00%)  0