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A Dose Escalation/Expansion Study of LDK378 in Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase

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ClinicalTrials.gov Identifier: NCT01283516
Recruitment Status : Completed
First Posted : January 26, 2011
Results First Posted : August 11, 2014
Last Update Posted : March 15, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Tumors Characterized by Genetic Abnormalities of ALK
Intervention Drug: LDK378
Enrollment 304
Recruitment Details Study was considered completed when all patients discontinued ceritinib treatment, & all required follow-up was completed or patient died, was lost to follow-up or withdrew their consent to further participate in study or last patient on treatment was enrolled to a separate protocol to continue receiving ceritinib treatment, whichever came first.
Pre-assignment Details A total of 304 patients were treated with LDK378 in the study, including 59 patients from the dose-escalation phase (including 10 patients at 750 mg) and 245 patients from the expansion phase treated at LDK378 750 mg.
Arm/Group Title LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg
Hide Arm/Group Description Participants receiving 50 mg of LDK378 Participants receiving 100 mg of LDK378 Participants receiving 200 mg of LDK378 Participants receiving 300 mg of LDK378 Participants receiving 400 mg of LDK378 Participants receiving 500 mg of LDK378 Participants receiving 600 mg of LDK378 Participants receiving 700 mg of LDK378 Participants receiving 750 mg of LDK378.
Period Title: Overall Study
Started 2 [1] 2 3 3 14 10 10 5 255
Non-Small Cell Lung Cancer (NSCLC) 2 1 2 3 12 10 9 5 246
Dose-Determining Set (DDS) 2 1 3 3 14 8 10 5 8
Non-NSCLC 0 1 1 0 2 0 1 0 9 [2]
Completed 0 [3] 0 0 0 0 0 0 0 0
Not Completed 2 2 3 3 14 10 10 5 255
Reason Not Completed
Adverse Event             0             0             0             0             0             0             2             0             28
Death             0             0             0             0             0             1             0             1             12
Disease Progression             2             2             3             3             13             8             6             3             139
Withdrawal by Subject             0             0             0             0             1             0             1             0             36
Administrative problems             0             0             0             0             0             1             1             1             39
Lost to Follow-up             0             0             0             0             0             0             0             0             1
[1]
Started = Full Analysis Set and Safety Set
[2]
Small number of patients at 750 mg - non-NSCLC, assessment limited, not included in efficacy tables
[3]
Completed - see explanation in Recruitment Details.
Arm/Group Title LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg Total
Hide Arm/Group Description Participants receiving 50 mg of LDK378 Participants receiving 100 mg of LDK378 Participants receiving 200 mg of LDK378 Participants receiving 300 mg of LDK378 Participants receiving 400 mg of LDK378 Participants receiving 500 mg of LDK378 Participants receiving 600 mg of LDK378 Participants receiving 700 mg of LDK378 Participants receiving 750 mg of LDK378. Total of all reporting groups
Overall Number of Baseline Participants 2 2 3 3 14 10 10 5 255 304
Hide Baseline Analysis Population Description
Full Analysis Set (FAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least one dose of LDK378. Patients were classified according to the intended treatment dose group.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
46.5  (23.33) 30.5  (12.02) 53.7  (10.69) 58.7  (5.03) 48.7  (15.62) 55.0  (15.99) 54.6  (13.22) 56.4  (4.67) 51.9  (12.08) 52.0  (12.41)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
<65 years Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
2 2 2 3 12 7 7 5 215 255
>=65 years Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
0 0 1 0 2 3 3 0 40 49
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
Female
1
  50.0%
1
  50.0%
3
 100.0%
2
  66.7%
10
  71.4%
6
  60.0%
7
  70.0%
4
  80.0%
136
  53.3%
170
  55.9%
Male
1
  50.0%
1
  50.0%
0
   0.0%
1
  33.3%
4
  28.6%
4
  40.0%
3
  30.0%
1
  20.0%
119
  46.7%
134
  44.1%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Hispanic or Latino Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
0 0 1 0 0 1 3 1 26 32
Chinese Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
0 0 0 0 1 1 0 0 17 19
Indian (Indian subcontinent) Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
0 0 0 0 0 0 0 0 6 6
Mixed Ethnicity Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
0 0 0 0 1 0 1 0 1 3
Other Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
2 2 2 3 12 8 6 4 205 244
Predominant Race  
Measure Type: Number
Unit of measure:  Participants
Caucasian Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
2 2 2 2 12 8 8 3 160 199
Black Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
0 0 0 0 0 0 0 0 4 4
Asian Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
0 0 0 1 2 2 2 1 87 95
Native American Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
0 0 0 0 0 0 0 0 1 1
Pacific Islander Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
0 0 1 0 0 0 0 0 0 1
Other Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
0 0 0 0 0 0 0 1 3 4
Weight  
Mean (Standard Deviation)
Unit of measure:  Kilograms (kg)
Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
60.8  (19.80) 67.8  (5.94) 69.2  (17.20) 54.1  (9.70) 69.2  (15.91) 72.2  (18.74) 63.8  (13.23) 61.6  (16.05) 69.2  (15.64) 68.8  (15.61)
Height   [1] 
Mean (Standard Deviation)
Unit of measure:  Centimenters (cm)
Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 4 participants 254 participants 302 participants
169.0  (7.07) 178.0  (14.14) 161.3  (3.04) 164.6  (5.82) 169.9  (9.35) 166.4  (12.24) 165.1  (8.67) 163.6  (5.05) 167.5  (9.87) 167.5  (9.78)
[1]
Measure Analysis Population Description: Full Analysis Set (FAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least one dose of LDK378. Height was not collected for 1 patient each in the 700 mg arm and the 750 mg arm.
Body Mass Index   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 4 participants 254 participants 302 participants
21.1  (5.16) 21.8  (5.30) 26.5  (5.69) 20.2  (5.08) 24.0  (5.38) 25.9  (5.41) 23.1  (2.78) 24.3  (6.06) 24.5  (4.40) 24.4  (4.48)
[1]
Measure Analysis Population Description: Full Analysis Set (FAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least one dose of LDK378. Body Mass Index was not collected for 1 patient each in the 700 mg arm and the 750 mg arm.
WHO/ECOG Performance status   [1] 
Measure Type: Number
Unit of measure:  Participants
0:Fully active,in line with pre-disease activities Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
1 1 1 0 3 2 2 1 65 76
1: Able to carry out light work Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
1 1 2 3 8 7 7 3 161 193
2:Capable of self-care up & about >50% of the time Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
0 0 0 0 3 1 1 1 28 34
3: Limited self-care, confined to bed/chair >50% Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
0 0 0 0 0 0 0 0 1 1
[1]
Measure Description: The ECOG performance status is a scale used to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis.
Smoking History  
Measure Type: Number
Unit of measure:  Participants
Never Smoked Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
2 1 1 2 9 7 8 3 159 192
Ex-Smoker Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
0 1 2 1 5 3 2 2 88 104
Current Smoker Number Analyzed 2 participants 2 participants 3 participants 3 participants 14 participants 10 participants 10 participants 5 participants 255 participants 304 participants
0 0 0 0 0 0 0 0 8 8
1.Primary Outcome
Title Number of Participants With Dose Limiting Toxicities (DLTs)
Hide Description The maximum tolerated dose (MTD) was defined as the highest dose for a given schedule that was expected to cause DLTs in no more than 33% of patients during the first cycle of treatment. A patient with multiple occurrences of a DLT under one treatment is counted only once in the AE category for that treatment. MTD was determined at 750mg.
Time Frame 33 months
Hide Outcome Measure Data
Hide Analysis Population Description
Dose-determining Set (DDS) consists of all patients (NSCLC and non-NSCLC) from the safety set who either meet the minimum exposure criterion and have sufficient safety evaluations or have experienced a dose limiting toxicity (DLT) during Cycle 1 (including the PK run-in period). This constitutes all evaluable patients for the determination of MTD.
Arm/Group Title LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg
Hide Arm/Group Description:
Participants receiving 50 mg of LDK378
Participants receiving 100 mg of LDK378
Participants receiving 200 mg of LDK378
Participants receiving 300 mg of LDK378
Participants receiving 400 mg of LDK378
Participants receiving 500 mg of LDK378
Participants receiving 600 mg of LDK378
Participants receiving 700 mg of LDK378
Participants receiving 750 mg of LDK378.
Overall Number of Participants Analyzed 2 1 3 3 14 8 10 5 8
Measure Type: Number
Unit of Measure: Participants
Diarrhea 0 0 0 0 0 0 1 0 2
Vomiting 0 0 0 0 0 0 0 0 1
Alanine Aminotransferase Increased 0 0 0 0 1 0 0 0 0
Transaminases Increased 0 0 0 0 1 0 0 0 0
Dehydration 0 0 0 0 0 0 1 0 0
Hypophosphataemia 0 0 0 0 1 0 0 0 0
2.Secondary Outcome
Title Overall Response Rate (ORR) Based on Investigator Assessment
Hide Description Overall response rate (ORR) was defined as the percentage of participants with a best overall complete response (CR) or partial response (PR) per RECIST 1.0. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI. Both CR and PR had to be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR was the disappearance of all target lesions. PR was at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. Both CR and PR had to be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR = at least two determinations of CR, at least 4 weeks apart before progression. PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR).
Time Frame 275 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - NSCLC: Subset of Full Analysis Set including ALK-positive NSCLC patients who received at least one dose of LDK378 in the 750 mg dose group.
Arm/Group Title NSCLC With Prior ALKi (Arms 1A + 1B) NSCLC ALKi Naive (Arm 2) All NSCLC
Hide Arm/Group Description:
Patients with ALK-translocated NSCLC who were previously treated with an ALK inhibitor.
Patients with ALK-translocated NSCLC not previously treated with an ALK inhibitor.
all NSCLC patients.
Overall Number of Participants Analyzed 163 83 246
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of Participants
56.4
(48.5 to 64.2)
73.5
(62.7 to 82.6)
62.2
(55.8 to 68.3)
3.Secondary Outcome
Title Overall Response Rate Based on Blinded Independent Review Committee (BIRC) Assessment
Hide Description Overall response rate (ORR) was defined as the percentage of participants with a best overall complete response (CR) or partial response (PR) per RECIST 1.0. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI, CR was the disappearance of all target lesions. PR was at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. Both CR and PR had to be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response were first met. CR = at least two determinations of CR, at least 4 weeks apart before progression. PR = at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR).
Time Frame 275 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - NSCLC: Subset of Full Analysis Set including ALK-positive NSCLC patients who received at least one dose of LDK378 in the 750 mg dose group.
Arm/Group Title NSCLC With Prior ALKi (Arms 1A + 1B) NSCLC ALKi Naive (Arm 2) All NCSLC
Hide Arm/Group Description:
Patients with ALK-translocated NSCLC who were previously treated with an ALK inhibitor.
Patients with ALK-translocated NSCLC not previously treated with an ALK inhibitor.
all NSCLC patients.
Overall Number of Participants Analyzed 163 83 246
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
49.1
(41.2 to 57.0)
65.1
(53.8 to 75.2)
54.5
(48.0 to 60.8)
4.Secondary Outcome
Title Duration of Response (DOR) Based on Investigator Assessment
Hide Description Duration of response (DOR) was defined as the time from first documented response (partial response (PR) or complete response (CR)) to the date of first documented disease progression (PD) or death due to any cause, among patients with a confirmed PR or CR per RECIST 1.0.
Time Frame 275 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - NSCLC: Subset of Full Analysis Set including ALK-positive NSCLC patients who received at least one dose of LDK378 in the 750 mg dose group and had a confirmed overall complete response or partial response after initiation of LDK378.
Arm/Group Title NSCLC With Prior ALKi (Arms 1A + 1B) NSCLC ALKi Naive (Arm 2) All NSCLC
Hide Arm/Group Description:
Patients with ALK-translocated NSCLC who were previously treated with an ALK inhibitor.
Patients with ALK-translocated NSCLC not previously treated with an ALK inhibitor.
all NSCLC patients.
Overall Number of Participants Analyzed 92 61 153
Median (95% Confidence Interval)
Unit of Measure: months
8.25
(6.80 to 9.69)
14.19
(11.27 to 22.11)
10.12
(8.31 to 11.63)
5.Secondary Outcome
Title Duration of Response (DOR) Based on BIRC
Hide Description Duration of response (DOR) was defined as the time from first documented response (partial response (PR) or complete response (CR)) to the date of first documented disease progression (PD) or death due to any cause, among patients with a confirmed PR or CR per RECIST 1.0.
Time Frame 275 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - NSCLC: Subset of Full Analysis Set including ALK-positive NSCLC patients who received at least one dose of LDK378 in the 750 mg dose group and had a confirmed overall complete response or partial response after initiation of LDK378.
Arm/Group Title NSCLC With Prior ALKi (Arms 1A + 1B) NSCLC ALKi Naive (Arm 2) All NSCLC
Hide Arm/Group Description:
Patients with ALK-translocated NSCLC who were previously treated with an ALK inhibitor.
Patients with ALK-translocated NSCLC not previously treated with an ALK inhibitor.
all NSCLC patients.
Overall Number of Participants Analyzed 80 54 134
Median (95% Confidence Interval)
Unit of Measure: months
8.31
(5.98 to 12.42)
21.75
(14.06 to 31.11)
12.45
(8.77 to 16.56)
6.Secondary Outcome
Title Progression-free Survival Based on Investigator Assessment
Hide Description Progression-free survival (PFS) was defined as the time from the start date of study drug to the date of the first radiologically documented progressive disease (PD) per RECIST 1.0. or death due to any cause.
Time Frame 275 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - NSCLC: Subset of Full Analysis Set including ALK-positive NSCLC patients who received at least one dose of LDK378 in the 750 mg dose group.
Arm/Group Title NSCLC With Prior ALKi (Arms 1A + 1B) NSCLC ALKi Naive (Arm 2) All NSCLC
Hide Arm/Group Description:
Patients with ALK-translocated NSCLC who were previously treated with an ALK inhibitor.
Patients with ALK-translocated NSCLC not previously treated with an ALK inhibitor.
all NSCLC patients
Overall Number of Participants Analyzed 163 83 246
Median (95% Confidence Interval)
Unit of Measure: months
6.93
(5.55 to 8.48)
15.21
(12.12 to 19.48)
8.74
(6.93 to 10.97)
7.Secondary Outcome
Title Progression-free Survival Based on BIRC Assessment
Hide Description Progression-free survival (PFS) was defined as the time from the start date of study drug to the date of the first radiologically documented progressive disease (PD) per RECIST 1.0. or death due to any cause.
Time Frame 275 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) - NSCLC: Subset of Full Analysis Set including ALK-positive NSCLC patients who received at least one dose of LDK378 in the 750 mg dose group.
Arm/Group Title NSCLC With Prior ALKi (Arms 1A + 1B) NSCLC ALKi Naive (Arm 2) ALL NSCLC
Hide Arm/Group Description:
Patients with ALK-translocated NSCLC who were previously treated with an ALK inhibitor.
Patients with ALK-translocated NSCLC not previously treated with an ALK inhibitor
all NSCLC patients.
Overall Number of Participants Analyzed 163 83 246
Median (95% Confidence Interval)
Unit of Measure: months
6.97
(5.55 to 8.57)
19.32
(11.99 to 29.01)
9.53
(7.00 to 11.50)
8.Secondary Outcome
Title Primary Pharmacokinetics (PK) Parameter: AUC0-last
Hide Description The AUC from time zero to the last quantifiable concentration point (Tlast). Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378.
Time Frame PK run-in of Dose Escalation phase
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 & had at least 1 evaluable PK sample
Arm/Group Title LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg
Hide Arm/Group Description:
Participants receiving 50 mg of LDK378
Participants receiving 100 mg of LDK378
Participants receiving 200 mg of LDK378
Participants receiving 300 mg of LDK378
Participants receiving 400 mg of LDK378
Participants receiving 500 mg of LDK378
Participants receiving 600 mg of LDK378
Participants receiving 700 mg of LDK378
Participants receiving 750 mg of LDK378.
Overall Number of Participants Analyzed 2 2 3 3 14 10 10 5 252
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
366 [1] 
(NA%)
938
(24.3%)
1460
(62.9%)
7470
(46.5%)
4070
(81.8%)
5140
(141.7%)
8180
(57.4%)
9210
(111.7%)
7870
(127.3%)
[1]
N/A = not estimable
9.Secondary Outcome
Title Primary Pharmacokinetics (PK) Parameter: AUC0-24h
Hide Description Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. AUC0 - 24 is the AUC calculated to 24 hour. Cycle 1 Day 1 = C1D1; Cycle 1 Day 8 = C1D8; Cycle 2 Day 1 = C2D1. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter AUC0-24.
Time Frame PK run-in of dose escalation phase, Cycle 1 Day 8 of dose escalation phase, Cycle 1, Day 1 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 & had at least 1 evaluable PK sample
Arm/Group Title LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg
Hide Arm/Group Description:
Participants receiving 50 mg of LDK378
Participants receiving 100 mg of LDK378
Participants receiving 200 mg of LDK378
Participants receiving 300 mg of LDK378
Participants receiving 400 mg of LDK378
Participants receiving 500 mg of LDK378
Participants receiving 600 mg of LDK378
Participants receiving 700 mg of LDK378
Participants receiving 750 mg of LDK378.
Overall Number of Participants Analyzed 2 2 3 3 14 10 10 5 252
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
PK Run-in dose escalation phase Number Analyzed 1 participants 2 participants 2 participants 3 participants 12 participants 8 participants 9 participants 4 participants 10 participants
226 [1] 
(NA%)
467
(10.7%)
703
(55.6%)
3440
(44.7%)
1920
(78.0%)
2350
(87.9%)
3590
(53.4%)
3450
(137.9%)
3390
(121.4%)
C1D8: dose escalation phase Number Analyzed 2 participants 2 participants 3 participants 2 participants 9 participants 9 participants 7 participants 2 participants 8 participants
435
(42.1%)
1520
(41.1%)
4150
(32.2%)
7660
(402.8%)
7680
(77.4%)
12300
(37.4%)
14700
(71.7%)
35200
(0.800%)
13900
(74.8%)
C1D1 dose escalation phase for 750mg Number Analyzed 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 73 participants
3340
(111.9%)
C2D1 dose escalation & expansion phases Number Analyzed 1 participants 1 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 23 participants
376 [1] 
(NA%)
894 [1] 
(NA%)
22600
(37.1%)
[1]
N/A = not estimable
10.Secondary Outcome
Title Primary Pharmacokinetics (PK) Parameter: Tmax
Hide Description Tmax is the time to reach Cmax. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Cycle 1 Day 1 = C1D1; Cycle 1 Day 8 = C1D8; Cycle 2 Day 1 = C2D1. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter Tmax.
Time Frame PK run-in of dose escalation phase, Cycle 1 Day 8 of dose escalation phase, Cycle 1, Day 1 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 & had at least 1 evaluable PK sample
Arm/Group Title LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg
Hide Arm/Group Description:
Participants receiving 50 mg of LDK378
Participants receiving 100 mg of LDK378
Participants receiving 200 mg of LDK378
Participants receiving 300 mg of LDK378
Participants receiving 400 mg of LDK378
Participants receiving 500 mg of LDK378
Participants receiving 600 mg of LDK378
Participants receiving 700 mg of LDK378
Participants receiving 750 mg of LDK378.
Overall Number of Participants Analyzed 2 2 3 3 14 10 10 5 252
Median (Full Range)
Unit of Measure: hour
PK run-in dose escalation phase Number Analyzed 1 participants 2 participants 2 participants 3 participants 12 participants 8 participants 9 participants 4 participants 10 participants
5.95
(5.95 to 5.95)
15.0
(6.00 to 24.0)
5.08
(4.17 to 6.00)
4.00
(4.00 to 5.95)
4.99
(2.97 to 6.73)
3.98
(3.00 to 23.5)
6.00
(3.00 to 24.1)
6.00
(4.00 to 25.0)
6.02
(3.95 to 23.8)
C1D8 dose escalation phase Number Analyzed 2 participants 2 participants 3 participants 3 participants 13 participants 9 participants 9 participants 5 participants 8 participants
2.46
(2.00 to 2.92)
3.49
(3.00 to 3.98)
3.00
(2.98 to 7.95)
4.00
(3.00 to 7.18)
6.08
(2.98 to 24.0)
3.95
(1.93 to 6.00)
4.00
(0.00 to 23.6)
5.97
(2.00 to 24.0)
5.03
(3.00 to 7.95)
C1D1 dose escalation phase for 750mg Number Analyzed 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 208 participants
6.00
(1.13 to 24.0)
C2D1 dose escalation & dose expansion phases Number Analyzed 2 participants 1 participants 3 participants 0 participants 0 participants 0 participants 0 participants 0 participants 133 participants
5.00
(4.00 to 6.00)
2.08
(2.08 to 2.08)
8.00
(4.00 to 23.9)
6.00
(0.00 to 22.6)
11.Secondary Outcome
Title Primary Pharmacokinetics (PK) Parameter: Cmax
Hide Description Cmax is the maximum observed concentration. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter Cmax.
Time Frame PK run-in of dose escalation phase, Cycle 1 Day 8 of dose escalation phase, Cycle 1, Day 1 of dose escalation ion phase, Cycle 2 Day 1 of dose escalation & expansion phases
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 & had at least 1 evaluable PK sample
Arm/Group Title LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg
Hide Arm/Group Description:
Participants receiving 50 mg of LDK378
Participants receiving 100 mg of LDK378
Participants receiving 200 mg of LDK378
Participants receiving 300 mg of LDK378
Participants receiving 400 mg of LDK378
Participants receiving 500 mg of LDK378
Participants receiving 600 mg of LDK378
Participants receiving 700 mg of LDK378
Participants receiving 750 mg of LDK378.
Overall Number of Participants Analyzed 2 2 3 3 14 10 10 5 252
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
PK Run-in dose escalation phase Number Analyzed 1 participants 2 participants 2 participants 3 participants 12 participants 8 participants 9 participants 4 participants 10 participants
13.1 [1] 
(NA%)
29.3
(10.1%)
40.2
(88.5%)
198
(41.5%)
120
(80.9%)
153
(86.5%)
212
(59.7%)
206
(145.6%)
186
(126.9%)
C1D8 dose escalation phase Number Analyzed 2 participants 2 participants 3 participants 3 participants 13 participants 9 participants 9 participants 5 participants 8 participants
25.1
(37.5%)
76.7
(20.9%)
212
(18.0%)
381
(167.5%)
419
(69.7%)
641
(40.0%)
688
(68.3%)
1140
(37.7%)
674
(76.2%)
C1D1 dose escalation phase for 750mg Number Analyzed 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 208 participants
203
(100.9%)
C2D1 dose escalation & dose expansion phases Number Analyzed 2 participants 1 participants 3 participants 0 participants 0 participants 0 participants 0 participants 0 participants 133 participants
21.9
(9.4%)
53.5 [1] 
(NA%)
229
(120.7%)
1010
(44.8%)
[1]
N/A = not estimable
12.Secondary Outcome
Title Secondary Pharmacokinetics (PK) Parameter: T1/2
Hide Description T1/2 is the elimination half-life associated with the terminal slope (λz) of a semi logarithmic concentration-time curve (time). Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378.
Time Frame PK Run-in dose escalation phase
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 & had at least 1 evaluable PK sample
Arm/Group Title LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg
Hide Arm/Group Description:
Participants receiving 50 mg of LDK378
Participants receiving 100 mg of LDK378
Participants receiving 200 mg of LDK378
Participants receiving 300 mg of LDK378
Participants receiving 400 mg of LDK378
Participants receiving 500 mg of LDK378
Participants receiving 600 mg of LDK378
Participants receiving 700 mg of LDK378
Participants receiving 750 mg of LDK378.
Overall Number of Participants Analyzed 1 1 1 3 10 7 6 3 9
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: hour
19.5 [1] 
(NA%)
19.4 [1] 
(NA%)
33.2 [1] 
(NA%)
30.1
(10.0%)
30.7
(39.1%)
31.1
(11.1%)
37.6
(24.6%)
38.9
(98.4%)
40.6
(34.7%)
[1]
N/A = not estimable
13.Secondary Outcome
Title Secondary Pharmacokinetics (PK) Parameter: CL/F
Hide Description CL/F is the apparent total body clearance of drug from the plasma
Time Frame PK Run-in dose escalation phase
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 & had at least 1 evaluable PK sample
Arm/Group Title LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg
Hide Arm/Group Description:
Participants receiving 50 mg of LDK378
Participants receiving 100 mg of LDK378
Participants receiving 200 mg of LDK378
Participants receiving 300 mg of LDK378
Participants receiving 400 mg of LDK378
Participants receiving 500 mg of LDK378
Participants receiving 600 mg of LDK378
Participants receiving 700 mg of LDK378
Participants receiving 750 mg of LDK378.
Overall Number of Participants Analyzed 1 1 1 2 5 3 2 2 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Litres/hour
126 [1] 
(NA%)
116 [1] 
(NA%)
77.5 [1] 
(NA%)
44.5
(36.8%)
95.9
(58.6%)
147.0
(170.3%)
46.3
(9.6%)
66.6
(35.8%)
88.5
(162.5%)
[1]
N/A = not estimable
14.Secondary Outcome
Title Secondary Pharmacokinetics (PK) Parameter: Vz/F
Hide Description Vz/F is the apparent volume of distribution during terminal phase (associated with Lambda_z)
Time Frame PK Run-in dose escalation phase
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 & had at least 1 evaluable PK sample
Arm/Group Title LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg
Hide Arm/Group Description:
Participants receiving 50 mg of LDK378
Participants receiving 100 mg of LDK378
Participants receiving 200 mg of LDK378
Participants receiving 300 mg of LDK378
Participants receiving 400 mg of LDK378
Participants receiving 500 mg of LDK378
Participants receiving 600 mg of LDK378
Participants receiving 700 mg of LDK378
Participants receiving 750 mg of LDK378.
Overall Number of Participants Analyzed 1 1 1 2 5 3 2 2 3
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Litre
3540 [1] 
(NA%)
3250 [1] 
(NA%)
3720 [1] 
(NA%)
1880
(50.7%)
3470
(74.4%)
6230
(218.9%)
1990
(4.3%)
2340
(56.5%)
4230
(164.4%)
[1]
N/A = not estimable
15.Secondary Outcome
Title Secondary Pharmacokinetics (PK) Parameter: CLss/F
Hide Description CLss/F is the apparent total body clearance of drug from the plasma. There was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter CLss/F.
Time Frame Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 & had at least 1 evaluable PK sample
Arm/Group Title LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg
Hide Arm/Group Description:
Participants receiving 50 mg of LDK378
Participants receiving 100 mg of LDK378
Participants receiving 200 mg of LDK378
Participants receiving 300 mg of LDK378
Participants receiving 400 mg of LDK378
Participants receiving 500 mg of LDK378
Participants receiving 600 mg of LDK378
Participants receiving 700 mg of LDK378
Participants receiving 750 mg of LDK378.
Overall Number of Participants Analyzed 2 2 3 3 14 10 10 5 252
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: Litres/hour
C1D8: dose escalation phase Number Analyzed 2 participants 2 participants 3 participants 2 participants 9 participants 9 participants 7 participants 2 participants 8 participants
115
(42.1%)
65.8
(41.1%)
48.2
(32.2%)
39.2
(402.8%)
52.1
(77.4%)
40.7
(37.4%)
40.8
(71.7%)
19.9
(0.8%)
53.9
(74.8%)
C2D1:dose escalation & dose expansion phases Number Analyzed 1 participants 1 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 23 participants
133 [1] 
(NA%)
112 [1] 
(NA%)
33.2
(37.1%)
[1]
N/A = not estimable
16.Secondary Outcome
Title Secondary Pharmacokinetics (PK) Parameter: Racc
Hide Description Racc is the accumulation ratio calculated using AUCtau values obtained from a dosing interval at steady-state divided by AUCtau at day 1 or PK run-in phase. AUCtau is the AUC calculated to the end of the dosing interval, tau. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. Blood samples for PK analysis of LDK378 were collected during the study from patients receiving LDK378. However, there was no PK sampling during C1D1 and C2D1 except for 750 mg dose to compute PK parameter Racc.
Time Frame Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic Analysis Set (PAS) consisted of all patients (including NSCLC and non-NSCLC) who received at least 1 dose of LDK378 & had at least 1 evaluable PK sample
Arm/Group Title LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg
Hide Arm/Group Description:
Participants receiving 50 mg of LDK378
Participants receiving 100 mg of LDK378
Participants receiving 200 mg of LDK378
Participants receiving 300 mg of LDK378
Participants receiving 400 mg of LDK378
Participants receiving 500 mg of LDK378
Participants receiving 600 mg of LDK378
Participants receiving 700 mg of LDK378
Participants receiving 750 mg of LDK378.
Overall Number of Participants Analyzed 2 2 3 3 14 10 10 5 252
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: unitless
C1D8: dose escalation phase Number Analyzed 1 participants 2 participants 2 participants 2 participants 7 participants 7 participants 6 participants 2 participants 8 participants
2.56 [1] 
(NA%)
3.25
(53.5%)
6.62
(17.6%)
1.83
(215.9%)
3.80
(124.7%)
6.08
(71.5%)
3.55
(51.7%)
6.84
(89.4%)
4.68
(72.1%)
C2D1: dose escalation & dose expansion phases Number Analyzed 1 participants 1 participants 0 participants 0 participants 0 participants 0 participants 0 participants 0 participants 9 participants
1.67 [1] 
(NA%)
1.77 [1] 
(NA%)
6.20
(58.5%)
[1]
N/A = not estimable
Time Frame Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV), at least 30 days following the last dose of study treatment . All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 5 years.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg All Participants
Hide Arm/Group Description Participants receiving 50 mg of LDK378 Participants receiving 100 mg of LDK378 Participants receiving 200 mg of LDK378 Participants receiving 300 mg of LDK378 Participants receiving 400 mg of LDK378 Participants receiving 500 mg of LDK378 Participants receiving 600 mg of LDK378 Participants receiving 700 mg of LDK378 Participants receiving 750 mg of LDK378. All participants enrolled in the study
All-Cause Mortality
LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg All Participants
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 (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg All Participants
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 (%) Affected / at Risk (%)
Total   0/2 (0.00%)   1/2 (50.00%)   1/3 (33.33%)   1/3 (33.33%)   7/14 (50.00%)   4/10 (40.00%)   7/10 (70.00%)   3/5 (60.00%)   145/255 (56.86%)   169/304 (55.59%) 
Blood and lymphatic system disorders                     
Anaemia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Febrile Neutropenia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Cardiac disorders                     
Acute Myocardial Infarction  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Angina Pectoris  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Atrial Fibrillation  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  3/304 (0.99%) 
Cardiac Failure Congestive  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Cardiac Tamponade  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Cardio-Respiratory Arrest  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Pericardial Effusion  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  6/255 (2.35%)  7/304 (2.30%) 
Pericarditis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  5/255 (1.96%)  5/304 (1.64%) 
Stress Cardiomyopathy  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Supraventricular Extrasystoles  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Congenital, familial and genetic disorders                     
Atrial Septal Defect  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Ear and labyrinth disorders                     
Hearing Impaired  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Eye disorders                     
Cataract  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Diabetic Retinopathy  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Gastrointestinal disorders                     
Abdominal Pain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Abdominal Pain Upper  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Constipation  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  2/255 (0.78%)  3/304 (0.99%) 
Diarrhoea  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  3/255 (1.18%)  3/304 (0.99%) 
Dyspepsia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Dysphagia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Gastric Ulcer  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Gastritis Haemorrhagic  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Ileus  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Intestinal Perforation  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Intra-Abdominal Haemorrhage  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Nausea  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  6/255 (2.35%)  6/304 (1.97%) 
Oesophagitis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Pancreatitis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Stomatitis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Subileus  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Upper Gastrointestinal Haemorrhage  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Vomiting  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  1/10 (10.00%)  0/5 (0.00%)  3/255 (1.18%)  6/304 (1.97%) 
General disorders                     
Asthenia  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  3/304 (0.99%) 
Chest Pain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Drug Withdrawal Syndrome  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Fatigue  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Gait Disturbance  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
General Physical Health Deterioration  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  6/255 (2.35%)  6/304 (1.97%) 
Multi-Organ Failure  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Non-Cardiac Chest Pain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  4/255 (1.57%)  4/304 (1.32%) 
Pain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  2/304 (0.66%) 
Pyrexia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  4/255 (1.57%)  4/304 (1.32%) 
Hepatobiliary disorders                     
Bile Duct Obstruction  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Cholecystitis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Drug-Induced Liver Injury  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Gallbladder Fistula  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Gallbladder Oedema  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Gallbladder Perforation  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Hepatitis Cholestatic  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Infections and infestations                     
Appendicitis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Appendicitis Perforated  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Bacterial Sepsis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Bronchitis  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  3/304 (0.99%) 
Cellulitis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Cranial Nerve Infection  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Diverticulitis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Empyema  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  2/304 (0.66%) 
Gastroenteritis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  1/255 (0.39%)  2/304 (0.66%) 
Infection  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Ludwig Angina  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Lung Infection  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Neutropenic Sepsis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Oral Candidiasis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Peritonitis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Pneumonia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  19/255 (7.45%)  20/304 (6.58%) 
Pneumonia Bacterial  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Pulmonary Tuberculosis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Respiratory Tract Infection  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Sepsis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  3/255 (1.18%)  3/304 (0.99%) 
Septic Shock  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Urinary Tract Infection  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Injury, poisoning and procedural complications                     
Compression Fracture  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Eye Injury  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Facial Bones Fracture  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Pelvic Fracture  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Spinal Fracture  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Toxicity To Various Agents  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Upper Limb Fracture  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Investigations                     
Alanine Aminotransferase Increased  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  5/255 (1.96%)  6/304 (1.97%) 
Amylase Increased  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Aspartate Aminotransferase Increased  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  3/255 (1.18%)  4/304 (1.32%) 
Blood Creatinine Increased  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Blood Urea Increased  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Ejection Fraction Decreased  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Lipase Increased  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Oxygen Saturation Decreased  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Platelet Count Decreased  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Transaminases Increased  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  2/304 (0.66%) 
Metabolism and nutrition disorders                     
Decreased Appetite  1  0/2 (0.00%)  1/2 (50.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  3/304 (0.99%) 
Dehydration  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  4/255 (1.57%)  5/304 (1.64%) 
Diabetic Ketoacidosis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Hypercalcaemia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Hyperglycaemia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  6/255 (2.35%)  6/304 (1.97%) 
Hyperkalaemia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Hyperuricaemia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Hypomagnesaemia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Hyponatraemia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Musculoskeletal and connective tissue disorders                     
Arthralgia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  1/5 (20.00%)  2/255 (0.78%)  3/304 (0.99%) 
Back Pain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Bone Pain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Fracture Pain  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Muscular Weakness  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Musculoskeletal Pain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  1/255 (0.39%)  2/304 (0.66%) 
Neck Pain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Tendon Disorder  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                     
Basal Cell Carcinoma  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Malignant Neoplasm Of Thorax  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Malignant Pleural Effusion  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Metastases To Central Nervous System  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Metastases To Meninges  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Nervous system disorders                     
Amnesia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Ataxia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  3/255 (1.18%)  3/304 (0.99%) 
Brain Oedema  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Cauda Equina Syndrome  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Central Nervous System Necrosis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Cognitive Disorder  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Depressed Level Of Consciousness  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Dizziness  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Dysarthria  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Epilepsy  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Generalised Tonic-Clonic Seizure  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Haemorrhage Intracranial  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Headache  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  5/255 (1.96%)  5/304 (1.64%) 
Hemiparesis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Hydrocephalus  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Loss Of Consciousness  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Migraine  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Nervous System Disorder  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Paraplegia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Seizure  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  16/255 (6.27%)  18/304 (5.92%) 
Somnolence  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Speech Disorder  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Spinal Cord Compression  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Syncope  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Toxic Encephalopathy  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Psychiatric disorders                     
Anxiety  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Confusional State  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Mental Disorder  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Mental Status Changes  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Renal and urinary disorders                     
Acute Kidney Injury  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Azotaemia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Calculus Ureteric  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Renal Failure  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Reproductive system and breast disorders                     
Pelvic Pain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Respiratory, thoracic and mediastinal disorders                     
Acute Respiratory Failure  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Atelectasis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Chronic Obstructive Pulmonary Disease  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Dyspnoea  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  15/255 (5.88%)  16/304 (5.26%) 
Epistaxis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  1/5 (20.00%)  0/255 (0.00%)  1/304 (0.33%) 
Haemoptysis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Hiccups  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Hypoxia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Interstitial Lung Disease  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Lung Infiltration  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Obstructive Airways Disorder  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Pleural Effusion  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  3/255 (1.18%)  3/304 (0.99%) 
Pleuritic Pain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Pneumonia Aspiration  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  2/304 (0.66%) 
Pneumonitis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  9/255 (3.53%)  9/304 (2.96%) 
Pneumothorax  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  4/255 (1.57%)  5/304 (1.64%) 
Pulmonary Embolism  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  3/255 (1.18%)  4/304 (1.32%) 
Respiratory Distress  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  1/5 (20.00%)  0/255 (0.00%)  2/304 (0.66%) 
Respiratory Failure  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  6/255 (2.35%)  8/304 (2.63%) 
Skin and subcutaneous tissue disorders                     
Pruritus  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Vascular disorders                     
Deep Vein Thrombosis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Embolism  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Thrombophlebitis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  1/304 (0.33%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (19.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
LDK378 50 mg LDK378 100 mg LDK378 200 mg LDK378 300 mg LDK378 400 mg LDK378 500 mg LDK378 600 mg LDK378 700 mg LDK378 750 mg All Participants
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 (%) Affected / at Risk (%)
Total   2/2 (100.00%)   2/2 (100.00%)   3/3 (100.00%)   3/3 (100.00%)   14/14 (100.00%)   10/10 (100.00%)   10/10 (100.00%)   5/5 (100.00%)   254/255 (99.61%)   303/304 (99.67%) 
Blood and lymphatic system disorders                     
Anaemia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  2/14 (14.29%)  2/10 (20.00%)  3/10 (30.00%)  0/5 (0.00%)  32/255 (12.55%)  40/304 (13.16%) 
Leukocytosis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  2/255 (0.78%)  3/304 (0.99%) 
Cardiac disorders                     
Arrhythmia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  1/5 (20.00%)  2/255 (0.78%)  3/304 (0.99%) 
Atrial Fibrillation  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  2/304 (0.66%) 
Bradycardia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  5/255 (1.96%)  6/304 (1.97%) 
Sinus Bradycardia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  4/255 (1.57%)  5/304 (1.64%) 
Sinus Tachycardia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  3/304 (0.99%) 
Tachycardia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  6/255 (2.35%)  7/304 (2.30%) 
Ear and labyrinth disorders                     
Tinnitus  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  1/5 (20.00%)  7/255 (2.75%)  8/304 (2.63%) 
Vertigo  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  7/255 (2.75%)  8/304 (2.63%) 
Eye disorders                     
Blepharospasm  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  4/255 (1.57%)  5/304 (1.64%) 
Diplopia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  3/304 (0.99%) 
Eyelid Ptosis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Photopsia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/14 (14.29%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  5/304 (1.64%) 
Visual Impairment  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  17/255 (6.67%)  17/304 (5.59%) 
Vitreous Floaters  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  1/5 (20.00%)  1/255 (0.39%)  3/304 (0.99%) 
Gastrointestinal disorders                     
Abdominal Discomfort  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  18/255 (7.06%)  19/304 (6.25%) 
Abdominal Distension  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  2/10 (20.00%)  0/5 (0.00%)  9/255 (3.53%)  13/304 (4.28%) 
Abdominal Pain  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  1/14 (7.14%)  3/10 (30.00%)  2/10 (20.00%)  1/5 (20.00%)  102/255 (40.00%)  111/304 (36.51%) 
Abdominal Pain Lower  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  3/255 (1.18%)  4/304 (1.32%) 
Abdominal Pain Upper  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/14 (14.29%)  1/10 (10.00%)  0/10 (0.00%)  1/5 (20.00%)  64/255 (25.10%)  68/304 (22.37%) 
Ascites  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  3/304 (0.99%) 
Constipation  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  3/14 (21.43%)  3/10 (30.00%)  4/10 (40.00%)  2/5 (40.00%)  90/255 (35.29%)  103/304 (33.88%) 
Dental Caries  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  4/255 (1.57%)  5/304 (1.64%) 
Diarrhoea  1  0/2 (0.00%)  0/2 (0.00%)  2/3 (66.67%)  1/3 (33.33%)  9/14 (64.29%)  7/10 (70.00%)  8/10 (80.00%)  4/5 (80.00%)  221/255 (86.67%)  252/304 (82.89%) 
Dyspepsia  1  1/2 (50.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  2/10 (20.00%)  4/10 (40.00%)  1/5 (20.00%)  35/255 (13.73%)  43/304 (14.14%) 
Dysphagia  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  2/10 (20.00%)  0/10 (0.00%)  0/5 (0.00%)  7/255 (2.75%)  10/304 (3.29%) 
Flatulence  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  11/255 (4.31%)  12/304 (3.95%) 
Gastrointestinal Disorder  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  2/304 (0.66%) 
Gastrointestinal Pain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  2/304 (0.66%) 
Gastrooesophageal Reflux Disease  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  1/10 (10.00%)  0/5 (0.00%)  20/255 (7.84%)  22/304 (7.24%) 
Haemorrhoids  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  3/255 (1.18%)  5/304 (1.64%) 
Melaena  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  1/255 (0.39%)  2/304 (0.66%) 
Mouth Swelling  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Nausea  1  0/2 (0.00%)  1/2 (50.00%)  2/3 (66.67%)  2/3 (66.67%)  10/14 (71.43%)  9/10 (90.00%)  10/10 (100.00%)  5/5 (100.00%)  215/255 (84.31%)  254/304 (83.55%) 
Stomatitis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  17/255 (6.67%)  18/304 (5.92%) 
Toothache  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  3/255 (1.18%)  5/304 (1.64%) 
Vomiting  1  0/2 (0.00%)  1/2 (50.00%)  3/3 (100.00%)  1/3 (33.33%)  8/14 (57.14%)  5/10 (50.00%)  8/10 (80.00%)  4/5 (80.00%)  159/255 (62.35%)  189/304 (62.17%) 
General disorders                     
Asthenia  1  0/2 (0.00%)  1/2 (50.00%)  1/3 (33.33%)  1/3 (33.33%)  2/14 (14.29%)  1/10 (10.00%)  3/10 (30.00%)  3/5 (60.00%)  58/255 (22.75%)  70/304 (23.03%) 
Axillary Pain  1  0/2 (0.00%)  1/2 (50.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Chest Discomfort  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  1/10 (10.00%)  0/10 (0.00%)  1/5 (20.00%)  23/255 (9.02%)  26/304 (8.55%) 
Chest Pain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  18/255 (7.06%)  19/304 (6.25%) 
Chills  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  14/255 (5.49%)  15/304 (4.93%) 
Facial Pain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  3/304 (0.99%) 
Fatigue  1  1/2 (50.00%)  1/2 (50.00%)  1/3 (33.33%)  0/3 (0.00%)  5/14 (35.71%)  4/10 (40.00%)  8/10 (80.00%)  1/5 (20.00%)  111/255 (43.53%)  132/304 (43.42%) 
Gait Disturbance  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  10/255 (3.92%)  11/304 (3.62%) 
Hunger  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  1/5 (20.00%)  0/255 (0.00%)  1/304 (0.33%) 
Inflammation  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Influenza Like Illness  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/14 (14.29%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  6/255 (2.35%)  8/304 (2.63%) 
Local Swelling  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  1/5 (20.00%)  0/255 (0.00%)  1/304 (0.33%) 
Non-Cardiac Chest Pain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  1/5 (20.00%)  28/255 (10.98%)  30/304 (9.87%) 
Oedema  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  1/10 (10.00%)  0/5 (0.00%)  4/255 (1.57%)  6/304 (1.97%) 
Oedema Peripheral  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/14 (7.14%)  1/10 (10.00%)  0/10 (0.00%)  1/5 (20.00%)  32/255 (12.55%)  35/304 (11.51%) 
Pain  1  1/2 (50.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  18/255 (7.06%)  21/304 (6.91%) 
Pyrexia  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  1/10 (10.00%)  1/5 (20.00%)  46/255 (18.04%)  50/304 (16.45%) 
Immune system disorders                     
Seasonal Allergy  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  6/255 (2.35%)  7/304 (2.30%) 
Infections and infestations                     
Bacterial Disease Carrier  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Bronchitis  1  1/2 (50.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  7/255 (2.75%)  9/304 (2.96%) 
Clostridium Difficile Infection  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Cystitis  1  1/2 (50.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  4/255 (1.57%)  5/304 (1.64%) 
Gingivitis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Herpes Dermatitis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  1/255 (0.39%)  2/304 (0.66%) 
Influenza  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  20/255 (7.84%)  22/304 (7.24%) 
Nasopharyngitis  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  1/5 (20.00%)  23/255 (9.02%)  26/304 (8.55%) 
Oral Infection  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Pneumonia  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  1/5 (20.00%)  13/255 (5.10%)  14/304 (4.61%) 
Respiratory Tract Infection  1  0/2 (0.00%)  1/2 (50.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  6/255 (2.35%)  8/304 (2.63%) 
Tonsillitis  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Tooth Abscess  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  2/255 (0.78%)  3/304 (0.99%) 
Upper Respiratory Tract Infection  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  3/14 (21.43%)  2/10 (20.00%)  1/10 (10.00%)  1/5 (20.00%)  32/255 (12.55%)  40/304 (13.16%) 
Urinary Tract Infection  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  2/10 (20.00%)  0/5 (0.00%)  18/255 (7.06%)  21/304 (6.91%) 
Vaginal Infection  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Vulvovaginal Candidiasis  1  1/2 (50.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Injury, poisoning and procedural complications                     
Burns First Degree  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Fall  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  8/255 (3.14%)  10/304 (3.29%) 
Ligament Sprain  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  1/10 (10.00%)  0/5 (0.00%)  2/255 (0.78%)  3/304 (0.99%) 
Spinal Fracture  1  0/2 (0.00%)  0/2 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/14 (0.00%)  0/10 (0.00%)  0/10 (0.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Tendon Rupture  1  0/2 (0.00%)  0/2 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/14 (0.00%)  1/10 (10.00%)  0/10 (0.00%)  0/5 (0.00%)  0/255 (0.00%)  1/304 (0.33%) 
Investigations