Clincosm LogoSign in Get a demo

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

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01283516
Collaborator
(none)
304
Enrollment
21
Locations
3
Arms
63.3
Actual Duration (Months)
14.5
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study assessed the safety and efficacy of LDK378 in adult patients with genetic abnormalities in anaplastic lymphoma kinase (ALK).

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
304 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I, Multi-center, Open Label Dose Escalation Study of LDK378, Administered Orally in Adult Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase (ALK)
Actual Study Start Date :
Jan 24, 2011
Actual Primary Completion Date :
May 3, 2016
Actual Study Completion Date :
May 3, 2016

Arms and Interventions

Arm Intervention/Treatment
Experimental: LDK378 750 mg: Arm 1A and Arm 1B

NSCLC patients previously treated with an ALK inhibitor

Drug: LDK378
LDK378 is a selective and a potent inhibitor of anaplastic lymphoma kinase (ALK) activity, is a capsule and is administered orally.
Experimental: LDK378 750 mg: Arm 2

NSCLC patients not previously treated with an ALK inhibitor

Drug: LDK378
LDK378 is a selective and a potent inhibitor of anaplastic lymphoma kinase (ALK) activity, is a capsule and is administered orally.
Experimental: LDK378 750 mg: Arm 3

Patients with other tumors that are ALK positive other than NSCLC

Drug: LDK378
LDK378 is a selective and a potent inhibitor of anaplastic lymphoma kinase (ALK) activity, is a capsule and is administered orally.

Outcome Measures

Primary Outcome Measures

  1. Number of Participants With Dose Limiting Toxicities (DLTs) [33 months]

    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.

Secondary Outcome Measures

  1. Overall Response Rate (ORR) Based on Investigator Assessment [275 weeks]

    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).

  2. Overall Response Rate Based on Blinded Independent Review Committee (BIRC) Assessment [275 weeks]

    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).

  3. Duration of Response (DOR) Based on Investigator Assessment [275 weeks]

    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.

  4. Duration of Response (DOR) Based on BIRC [275 weeks]

    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.

  5. Progression-free Survival Based on Investigator Assessment [275 weeks]

    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.

  6. Progression-free Survival Based on BIRC Assessment [275 weeks]

    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.

  7. Primary Pharmacokinetics (PK) Parameter: AUC0-last [PK run-in of Dose Escalation phase]

    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.

  8. Primary Pharmacokinetics (PK) Parameter: AUC0-24h [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]

    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.

  9. Primary Pharmacokinetics (PK) Parameter: Tmax [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]

    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.

  10. Primary Pharmacokinetics (PK) Parameter: Cmax [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]

    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.

  11. Secondary Pharmacokinetics (PK) Parameter: T1/2 [PK Run-in dose escalation phase]

    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.

  12. Secondary Pharmacokinetics (PK) Parameter: CL/F [PK Run-in dose escalation phase]

    CL/F is the apparent total body clearance of drug from the plasma

  13. Secondary Pharmacokinetics (PK) Parameter: Vz/F [PK Run-in dose escalation phase]

    Vz/F is the apparent volume of distribution during terminal phase (associated with Lambda_z)

  14. Secondary Pharmacokinetics (PK) Parameter: CLss/F [Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases]

    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.

  15. Secondary Pharmacokinetics (PK) Parameter: Racc [Cycle 1 Day 8 of dose escalation phase, Cycle 2 Day 1 of dose escalation & dose expansion phases]

    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.

Eligibility Criteria

Criteria

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

  • ECOG Performance Status of ≤ 2 and life expectancy of ≥ 12 weeks.

  • Diagnosed with a locally advanced or metastatic malignancy that has progressed despite standard therapy, or for which no effective standard therapy exists. Only patients with tumors characterized by genetic abnormalities in ALK were enrolled.

  • For NSCLC, an ALK translocation must be detected by FISH in ≥ 15% of tumor cells.

  • In patients with diseases other than NSCLC, ALK translocation is not required and overexpression of ALK protein may be considered indicative of a genetic abnormality in ALK.

  • Patients with measurable or non-measurable disease as determined by modified RECIST version 1.0 in dose-escalation phase, and patients with at least one measurable lesion as determined by RECIST 1.0 in expansion phase.

Exclusion Criteria:

  • Patients with symptomatic central nervous system (CNS) metastases who were neurologically unstable or required increasing doses of steroids to control their CNS disease were excluded.

  • Patients with a prior or current history of a second malignancy, impaired GI function, history of pancreatitis or increased amylase or lipase, known diagnosis of HIV, and clinically significant cardiac disease were excluded.

  • Patients treated with chemotherapy or biologic therapy or other investigational agent < 2 weeks prior to starting study drug for compounds with a half-life ≤ 3 days, and < 4 weeks prior to starting study drug for compounds with a prolonged half-life were excluded.

  • Further, patients treated with medications that were known to be strong inhibitors or inducers of CYP3A4/5 that could not be discontinued at least a week prior to start of treatment with LDK378 and for the duration of the study were also excluded.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

Site City State Country Postal Code
1 University of Colorado School of Medicine Colorado Univ Aurora Colorado United States 80045
2 Massachusetts General Hospital Mass General Boston Massachusetts United States 02114
3 Memorial Sloan Kettering MSK New York New York United States 10017
4 Fox Chase Cancer Center Fox Chase Cancer (2) Philadelphia Pennsylvania United States 19111
5 University of Utah / Huntsman Cancer Institute Huntsman Salt Lake City Utah United States 84103
6 Seattle Cancer Care Alliance Seattle Washington United States 98105
7 Novartis Investigative Site Melbourne Victoria Australia 3000
8 Novartis Investigative Site Leuven Belgium 3000
9 Novartis Investigative Site Toronto Ontario Canada M5G 1Z6
10 Novartis Investigative Site Koeln Nordrhein-Westfalen Germany 50937
11 Novartis Investigative Site Essen Germany 45147
12 Novartis Investigative Site Heidelberg Germany 69120
13 Novartis Investigative Site Ulm Germany 89081
14 Novartis Investigative Site Milano MI Italy 20141
15 Novartis Investigative Site Rozzano MI Italy 20089
16 Novartis Investigative Site Seoul Korea Korea, Republic of 03080
17 Novartis Investigative Site Amsterdam Netherlands 1066 CX
18 Novartis Investigative Site Singapore Singapore 169610
19 Novartis Investigative Site Barcelona Catalunya Spain 08035
20 Novartis Investigative Site Glasgow Scotland United Kingdom G12 0YN
21 Novartis Investigative Site Leicester United Kingdom LE1 5WW

Sponsors and Collaborators

  • Novartis Pharmaceuticals

Investigators

  • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01283516
Other Study ID Numbers:
  • CLDK378X2101
  • 2010-019827-70
First Posted:
Jan 26, 2011
Last Update Posted:
Mar 15, 2019
Last Verified:
Nov 1, 2018
Individual Participant Data (IPD) Sharing Statement:
Undecided
Plan to Share IPD:
Undecided
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Novartis Pharmaceuticals
ALK inhibitor,
NSCLC,
LDK378,
ceritinib,
genetic abnormalities
Additional relevant MeSH terms:
Congenital Abnormalities
Ceritinib

Study Results

Participant Flow

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 Detail 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
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 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
COMPLETED 0 0 0 0 0 0 0 0 0
NOT COMPLETED 2 2 3 3 14 10 10 5 255

Baseline Characteristics

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
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 Participants 2 2 3 3 14 10 10 5 255 304
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]
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 (Number) [Number]
<65 years
2
100%
2
100%
2
66.7%
3
100%
12
85.7%
7
70%
7
70%
5
100%
215
84.3%
255
83.9%
>=65 years
0
0%
0
0%
1
33.3%
0
0%
2
14.3%
3
30%
3
30%
0
0%
40
15.7%
49
16.1%
Sex: Female, Male (Count of Participants)
Female
1
50%
1
50%
3
100%
2
66.7%
10
71.4%
6
60%
7
70%
4
80%
136
53.3%
170
55.9%
Male
1
50%
1
50%
0
0%
1
33.3%
4
28.6%
4
40%
3
30%
1
20%
119
46.7%
134
44.1%
Race/Ethnicity, Customized (Number) [Number]
Hispanic or Latino
0
0%
0
0%
1
33.3%
0
0%
0
0%
1
10%
3
30%
1
20%
26
10.2%
32
10.5%
Chinese
0
0%
0
0%
0
0%
0
0%
1
7.1%
1
10%
0
0%
0
0%
17
6.7%
19
6.3%
Indian (Indian subcontinent)
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
6
2.4%
6
2%
Mixed Ethnicity
0
0%
0
0%
0
0%
0
0%
1
7.1%
0
0%
1
10%
0
0%
1
0.4%
3
1%
Other
2
100%
2
100%
2
66.7%
3
100%
12
85.7%
8
80%
6
60%
4
80%
205
80.4%
244
80.3%
Predominant Race (Number) [Number]
Caucasian
2
100%
2
100%
2
66.7%
2
66.7%
12
85.7%
8
80%
8
80%
3
60%
160
62.7%
199
65.5%
Black
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
4
1.6%
4
1.3%
Asian
0
0%
0
0%
0
0%
1
33.3%
2
14.3%
2
20%
2
20%
1
20%
87
34.1%
95
31.3%
Native American
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
0.4%
1
0.3%
Pacific Islander
0
0%
0
0%
1
33.3%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
0.3%
Other
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
20%
3
1.2%
4
1.3%
Weight (Kilograms (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kilograms (kg)]
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 (centimenters (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimenters (cm)]
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)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]
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)
WHO/ECOG Performance status (Number) [Number]
0:Fully active,in line with pre-disease activities
1
50%
1
50%
1
33.3%
0
0%
3
21.4%
2
20%
2
20%
1
20%
65
25.5%
76
25%
1: Able to carry out light work
1
50%
1
50%
2
66.7%
3
100%
8
57.1%
7
70%
7
70%
3
60%
161
63.1%
193
63.5%
2:Capable of self-care up & about >50% of the time
0
0%
0
0%
0
0%
0
0%
3
21.4%
1
10%
1
10%
1
20%
28
11%
34
11.2%
3: Limited self-care, confined to bed/chair >50%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
0.4%
1
0.3%
Smoking History (Number) [Number]
Never Smoked
2
100%
1
50%
1
33.3%
2
66.7%
9
64.3%
7
70%
8
80%
3
60%
159
62.4%
192
63.2%
Ex-Smoker
0
0%
1
50%
2
66.7%
1
33.3%
5
35.7%
3
30%
2
20%
2
40%
88
34.5%
104
34.2%
Current Smoker
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
8
3.1%
8
2.6%

Outcome Measures

1. Primary Outcome
Title Number of Participants With Dose Limiting Toxicities (DLTs)
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

Outcome Measure Data

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
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.
Measure Participants 2 1 3 3 14 8 10 5 8
Diarrhea
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
10%
0
0%
2
0.8%
Vomiting
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
0.4%
Alanine Aminotransferase Increased
0
0%
0
0%
0
0%
0
0%
1
7.1%
0
0%
0
0%
0
0%
0
0%
Transaminases Increased
0
0%
0
0%
0
0%
0
0%
1
7.1%
0
0%
0
0%
0
0%
0
0%
Dehydration
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
10%
0
0%
0
0%
Hypophosphataemia
0
0%
0
0%
0
0%
0
0%
1
7.1%
0
0%
0
0%
0
0%
0
0%
2. Secondary Outcome
Title Overall Response Rate (ORR) Based on Investigator Assessment
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

Outcome Measure Data

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
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.
Measure Participants 163 83 246
Number (95% Confidence Interval) [Percentage of Participants]
56.4
2820%
73.5
3675%
62.2
2073.3%
3. Secondary Outcome
Title Overall Response Rate Based on Blinded Independent Review Committee (BIRC) Assessment
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

Outcome Measure Data

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
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.
Measure Participants 163 83 246
Number (95% Confidence Interval) [Percentage of participants]
49.1
2455%
65.1
3255%
54.5
1816.7%
4. Secondary Outcome
Title Duration of Response (DOR) Based on Investigator Assessment
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

Outcome Measure Data

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
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.
Measure Participants 92 61 153
Median (95% Confidence Interval) [months]
8.25
14.19
10.12
5. Secondary Outcome
Title Duration of Response (DOR) Based on BIRC
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

Outcome Measure Data

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
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.
Measure Participants 80 54 134
Median (95% Confidence Interval) [months]
8.31
21.75
12.45
6. Secondary Outcome
Title Progression-free Survival Based on Investigator Assessment
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

Outcome Measure Data

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
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
Measure Participants 163 83 246
Median (95% Confidence Interval) [months]
6.93
15.21
8.74
7. Secondary Outcome
Title Progression-free Survival Based on BIRC Assessment
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

Outcome Measure Data

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
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.
Measure Participants 163 83 246
Median (95% Confidence Interval) [months]
6.97
19.32
9.53
8. Secondary Outcome
Title Primary Pharmacokinetics (PK) Parameter: AUC0-last
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

Outcome Measure Data

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
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.
Measure Participants 2 2 3 3 14 10 10 5 252
Geometric Mean (Geometric Coefficient of Variation) [ng*h/mL]
366
(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)
9. Secondary Outcome
Title Primary Pharmacokinetics (PK) Parameter: AUC0-24h
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

Outcome Measure Data

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
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.
Measure Participants 2 2 3 3 14 10 10 5 252
PK Run-in dose escalation phase
226
(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
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
3340
(111.9)
C2D1 dose escalation & expansion phases
376
(NA)
894
(NA)
22600
(37.1)
10. Secondary Outcome
Title Primary Pharmacokinetics (PK) Parameter: Tmax
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

Outcome Measure Data

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
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.
Measure Participants 2 2 3 3 14 10 10 5 252
PK run-in dose escalation phase
5.95
15.0
5.08
4.00
4.99
3.98
6.00
6.00
6.02
C1D8 dose escalation phase
2.46
3.49
3.00
4.00
6.08
3.95
4.00
5.97
5.03
C1D1 dose escalation phase for 750mg
6.00
C2D1 dose escalation & dose expansion phases
5.00
2.08
8.00
6.00
11. Secondary Outcome
Title Primary Pharmacokinetics (PK) Parameter: Cmax
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

Outcome Measure Data

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
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.
Measure Participants 2 2 3 3 14 10 10 5 252
PK Run-in dose escalation phase
13.1
(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
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
203
(100.9)
C2D1 dose escalation & dose expansion phases
21.9
(9.4)
53.5
(NA)
229
(120.7)
1010
(44.8)
12. Secondary Outcome
Title Secondary Pharmacokinetics (PK) Parameter: T1/2
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

Outcome Measure Data

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
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.
Measure Participants 1 1 1 3 10 7 6 3 9
Geometric Mean (Geometric Coefficient of Variation) [hour]
19.5
(NA)
19.4
(NA)
33.2
(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)
13. Secondary Outcome
Title Secondary Pharmacokinetics (PK) Parameter: CL/F
Description CL/F is the apparent total body clearance of drug from the plasma
Time Frame PK Run-in dose escalation phase

Outcome Measure Data

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
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.
Measure Participants 1 1 1 2 5 3 2 2 3
Geometric Mean (Geometric Coefficient of Variation) [Litres/hour]
126
(NA)
116
(NA)
77.5
(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)
14. Secondary Outcome
Title Secondary Pharmacokinetics (PK) Parameter: Vz/F
Description Vz/F is the apparent volume of distribution during terminal phase (associated with Lambda_z)
Time Frame PK Run-in dose escalation phase

Outcome Measure Data

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
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.
Measure Participants 1 1 1 2 5 3 2 2 3
Geometric Mean (Geometric Coefficient of Variation) [Litre]
3540
(NA)
3250
(NA)
3720
(NA)
1880
(50.7)
3470
(74.4)
6230
(218.9)
1990
(4.3)
2340
(56.5)
4230
(164.4)
15. Secondary Outcome
Title Secondary Pharmacokinetics (PK) Parameter: CLss/F
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

Outcome Measure Data

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
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.
Measure Participants 2 2 3 3 14 10 10 5 252
C1D8: dose escalation phase
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
133
(NA)
112
(NA)
33.2
(37.1)
16. Secondary Outcome
Title Secondary Pharmacokinetics (PK) Parameter: Racc
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

Outcome Measure Data

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
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.
Measure Participants 2 2 3 3 14 10 10 5 252
C1D8: dose escalation phase
2.56
(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
1.67
(NA)
1.77
(NA)
6.20
(58.5)

Adverse Events

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
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
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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/2 (0%) 1/2 (50%) 1/3 (33.3%) 1/3 (33.3%) 7/14 (50%) 4/10 (40%) 7/10 (70%) 3/5 (60%) 145/255 (56.9%) 169/304 (55.6%)
Blood and lymphatic system disorders
Anaemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Febrile Neutropenia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Cardiac disorders
Acute Myocardial Infarction 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Angina Pectoris 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Atrial Fibrillation 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Cardiac Failure Congestive 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Cardiac Tamponade 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Cardio-Respiratory Arrest 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Pericardial Effusion 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 6/255 (2.4%) 7/304 (2.3%)
Pericarditis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 5/255 (2%) 5/304 (1.6%)
Stress Cardiomyopathy 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Supraventricular Extrasystoles 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Congenital, familial and genetic disorders
Atrial Septal Defect 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Ear and labyrinth disorders
Hearing Impaired 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Eye disorders
Cataract 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Diabetic Retinopathy 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Gastrointestinal disorders
Abdominal Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Abdominal Pain Upper 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Constipation 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Diarrhoea 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 3/255 (1.2%) 3/304 (1%)
Dyspepsia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Dysphagia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Gastric Ulcer 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Gastritis Haemorrhagic 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Ileus 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Intestinal Perforation 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Intra-Abdominal Haemorrhage 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Nausea 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 6/255 (2.4%) 6/304 (2%)
Oesophagitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Pancreatitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Stomatitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Subileus 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Upper Gastrointestinal Haemorrhage 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Vomiting 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 1/10 (10%) 0/5 (0%) 3/255 (1.2%) 6/304 (2%)
General disorders
Asthenia 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Chest Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Drug Withdrawal Syndrome 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Fatigue 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Gait Disturbance 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
General Physical Health Deterioration 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 6/255 (2.4%) 6/304 (2%)
Multi-Organ Failure 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Non-Cardiac Chest Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 4/255 (1.6%) 4/304 (1.3%)
Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Pyrexia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 4/255 (1.6%) 4/304 (1.3%)
Hepatobiliary disorders
Bile Duct Obstruction 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Cholecystitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Drug-Induced Liver Injury 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Gallbladder Fistula 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Gallbladder Oedema 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Gallbladder Perforation 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Hepatitis Cholestatic 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Infections and infestations
Appendicitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Appendicitis Perforated 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Bacterial Sepsis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Bronchitis 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Cellulitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Cranial Nerve Infection 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Diverticulitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Empyema 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Gastroenteritis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Infection 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Ludwig Angina 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Lung Infection 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Neutropenic Sepsis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Oral Candidiasis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Peritonitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Pneumonia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 19/255 (7.5%) 20/304 (6.6%)
Pneumonia Bacterial 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Pulmonary Tuberculosis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Respiratory Tract Infection 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Sepsis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 3/255 (1.2%) 3/304 (1%)
Septic Shock 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Urinary Tract Infection 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Injury, poisoning and procedural complications
Compression Fracture 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Eye Injury 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Facial Bones Fracture 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Pelvic Fracture 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Spinal Fracture 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Toxicity To Various Agents 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Upper Limb Fracture 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Investigations
Alanine Aminotransferase Increased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 5/255 (2%) 6/304 (2%)
Amylase Increased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Aspartate Aminotransferase Increased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 3/255 (1.2%) 4/304 (1.3%)
Blood Creatinine Increased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Blood Urea Increased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Ejection Fraction Decreased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Lipase Increased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Oxygen Saturation Decreased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Platelet Count Decreased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Transaminases Increased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Metabolism and nutrition disorders
Decreased Appetite 0/2 (0%) 1/2 (50%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Dehydration 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 4/255 (1.6%) 5/304 (1.6%)
Diabetic Ketoacidosis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Hypercalcaemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Hyperglycaemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 6/255 (2.4%) 6/304 (2%)
Hyperkalaemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Hyperuricaemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Hypomagnesaemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Hyponatraemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Musculoskeletal and connective tissue disorders
Arthralgia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 1/5 (20%) 2/255 (0.8%) 3/304 (1%)
Back Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Bone Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Fracture Pain 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Muscular Weakness 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Musculoskeletal Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Neck Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Tendon Disorder 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Malignant Neoplasm Of Thorax 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Malignant Pleural Effusion 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Metastases To Central Nervous System 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Metastases To Meninges 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Nervous system disorders
Amnesia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Ataxia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 3/255 (1.2%) 3/304 (1%)
Brain Oedema 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Cauda Equina Syndrome 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Central Nervous System Necrosis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Cognitive Disorder 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Depressed Level Of Consciousness 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Dizziness 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Dysarthria 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Epilepsy 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Generalised Tonic-Clonic Seizure 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Haemorrhage Intracranial 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Headache 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 5/255 (2%) 5/304 (1.6%)
Hemiparesis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Hydrocephalus 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Loss Of Consciousness 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Migraine 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Nervous System Disorder 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Paraplegia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Seizure 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 16/255 (6.3%) 18/304 (5.9%)
Somnolence 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Speech Disorder 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Spinal Cord Compression 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Syncope 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Toxic Encephalopathy 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Psychiatric disorders
Anxiety 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Confusional State 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Mental Disorder 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Mental Status Changes 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Renal and urinary disorders
Acute Kidney Injury 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Azotaemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Calculus Ureteric 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Renal Failure 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Reproductive system and breast disorders
Pelvic Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Atelectasis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Chronic Obstructive Pulmonary Disease 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Dyspnoea 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 15/255 (5.9%) 16/304 (5.3%)
Epistaxis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 1/5 (20%) 0/255 (0%) 1/304 (0.3%)
Haemoptysis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Hiccups 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Hypoxia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Interstitial Lung Disease 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Lung Infiltration 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Obstructive Airways Disorder 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Pleural Effusion 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 3/255 (1.2%) 3/304 (1%)
Pleuritic Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Pneumonia Aspiration 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 2/304 (0.7%)
Pneumonitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 9/255 (3.5%) 9/304 (3%)
Pneumothorax 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 4/255 (1.6%) 5/304 (1.6%)
Pulmonary Embolism 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 3/255 (1.2%) 4/304 (1.3%)
Respiratory Distress 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 1/5 (20%) 0/255 (0%) 2/304 (0.7%)
Respiratory Failure 0/2 (0%) 0/2 (0%) 0/3 (0%) 1/3 (33.3%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 6/255 (2.4%) 8/304 (2.6%)
Skin and subcutaneous tissue disorders
Pruritus 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Vascular disorders
Deep Vein Thrombosis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Embolism 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Thrombophlebitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 1/304 (0.3%)
Other (Not Including 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 (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 2/2 (100%) 2/2 (100%) 3/3 (100%) 3/3 (100%) 14/14 (100%) 10/10 (100%) 10/10 (100%) 5/5 (100%) 254/255 (99.6%) 303/304 (99.7%)
Blood and lymphatic system disorders
Anaemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 1/3 (33.3%) 2/14 (14.3%) 2/10 (20%) 3/10 (30%) 0/5 (0%) 32/255 (12.5%) 40/304 (13.2%)
Leukocytosis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Cardiac disorders
Arrhythmia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 1/5 (20%) 2/255 (0.8%) 3/304 (1%)
Atrial Fibrillation 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Bradycardia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 5/255 (2%) 6/304 (2%)
Sinus Bradycardia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 4/255 (1.6%) 5/304 (1.6%)
Sinus Tachycardia 0/2 (0%) 0/2 (0%) 0/3 (0%) 1/3 (33.3%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 3/304 (1%)
Tachycardia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 6/255 (2.4%) 7/304 (2.3%)
Ear and labyrinth disorders
Tinnitus 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 1/5 (20%) 7/255 (2.7%) 8/304 (2.6%)
Vertigo 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 7/255 (2.7%) 8/304 (2.6%)
Eye disorders
Blepharospasm 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 4/255 (1.6%) 5/304 (1.6%)
Diplopia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Eyelid Ptosis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Photopsia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 2/14 (14.3%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 5/304 (1.6%)
Visual Impairment 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 17/255 (6.7%) 17/304 (5.6%)
Vitreous Floaters 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 1/5 (20%) 1/255 (0.4%) 3/304 (1%)
Gastrointestinal disorders
Abdominal Discomfort 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 18/255 (7.1%) 19/304 (6.3%)
Abdominal Distension 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 2/10 (20%) 0/5 (0%) 9/255 (3.5%) 13/304 (4.3%)
Abdominal Pain 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 1/3 (33.3%) 1/14 (7.1%) 3/10 (30%) 2/10 (20%) 1/5 (20%) 102/255 (40%) 111/304 (36.5%)
Abdominal Pain Lower 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 3/255 (1.2%) 4/304 (1.3%)
Abdominal Pain Upper 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 2/14 (14.3%) 1/10 (10%) 0/10 (0%) 1/5 (20%) 64/255 (25.1%) 68/304 (22.4%)
Ascites 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Constipation 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 3/14 (21.4%) 3/10 (30%) 4/10 (40%) 2/5 (40%) 90/255 (35.3%) 103/304 (33.9%)
Dental Caries 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 4/255 (1.6%) 5/304 (1.6%)
Diarrhoea 0/2 (0%) 0/2 (0%) 2/3 (66.7%) 1/3 (33.3%) 9/14 (64.3%) 7/10 (70%) 8/10 (80%) 4/5 (80%) 221/255 (86.7%) 252/304 (82.9%)
Dyspepsia 1/2 (50%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 2/10 (20%) 4/10 (40%) 1/5 (20%) 35/255 (13.7%) 43/304 (14.1%)
Dysphagia 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 2/10 (20%) 0/10 (0%) 0/5 (0%) 7/255 (2.7%) 10/304 (3.3%)
Flatulence 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 11/255 (4.3%) 12/304 (3.9%)
Gastrointestinal Disorder 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Gastrointestinal Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Gastrooesophageal Reflux Disease 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 1/10 (10%) 0/5 (0%) 20/255 (7.8%) 22/304 (7.2%)
Haemorrhoids 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 3/255 (1.2%) 5/304 (1.6%)
Melaena 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Mouth Swelling 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Nausea 0/2 (0%) 1/2 (50%) 2/3 (66.7%) 2/3 (66.7%) 10/14 (71.4%) 9/10 (90%) 10/10 (100%) 5/5 (100%) 215/255 (84.3%) 254/304 (83.6%)
Stomatitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 17/255 (6.7%) 18/304 (5.9%)
Toothache 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 3/255 (1.2%) 5/304 (1.6%)
Vomiting 0/2 (0%) 1/2 (50%) 3/3 (100%) 1/3 (33.3%) 8/14 (57.1%) 5/10 (50%) 8/10 (80%) 4/5 (80%) 159/255 (62.4%) 189/304 (62.2%)
General disorders
Asthenia 0/2 (0%) 1/2 (50%) 1/3 (33.3%) 1/3 (33.3%) 2/14 (14.3%) 1/10 (10%) 3/10 (30%) 3/5 (60%) 58/255 (22.7%) 70/304 (23%)
Axillary Pain 0/2 (0%) 1/2 (50%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Chest Discomfort 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 1/10 (10%) 0/10 (0%) 1/5 (20%) 23/255 (9%) 26/304 (8.6%)
Chest Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 18/255 (7.1%) 19/304 (6.3%)
Chills 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 14/255 (5.5%) 15/304 (4.9%)
Facial Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Fatigue 1/2 (50%) 1/2 (50%) 1/3 (33.3%) 0/3 (0%) 5/14 (35.7%) 4/10 (40%) 8/10 (80%) 1/5 (20%) 111/255 (43.5%) 132/304 (43.4%)
Gait Disturbance 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 10/255 (3.9%) 11/304 (3.6%)
Hunger 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 1/5 (20%) 0/255 (0%) 1/304 (0.3%)
Inflammation 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Influenza Like Illness 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 2/14 (14.3%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 6/255 (2.4%) 8/304 (2.6%)
Local Swelling 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 1/5 (20%) 0/255 (0%) 1/304 (0.3%)
Non-Cardiac Chest Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 1/5 (20%) 28/255 (11%) 30/304 (9.9%)
Oedema 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 1/10 (10%) 0/5 (0%) 4/255 (1.6%) 6/304 (2%)
Oedema Peripheral 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 1/10 (10%) 0/10 (0%) 1/5 (20%) 32/255 (12.5%) 35/304 (11.5%)
Pain 1/2 (50%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 18/255 (7.1%) 21/304 (6.9%)
Pyrexia 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 1/10 (10%) 1/5 (20%) 46/255 (18%) 50/304 (16.4%)
Immune system disorders
Seasonal Allergy 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 6/255 (2.4%) 7/304 (2.3%)
Infections and infestations
Bacterial Disease Carrier 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Bronchitis 1/2 (50%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 7/255 (2.7%) 9/304 (3%)
Clostridium Difficile Infection 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Cystitis 1/2 (50%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 4/255 (1.6%) 5/304 (1.6%)
Gingivitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Herpes Dermatitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Influenza 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 20/255 (7.8%) 22/304 (7.2%)
Nasopharyngitis 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 1/5 (20%) 23/255 (9%) 26/304 (8.6%)
Oral Infection 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Pneumonia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 1/5 (20%) 13/255 (5.1%) 14/304 (4.6%)
Respiratory Tract Infection 0/2 (0%) 1/2 (50%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 6/255 (2.4%) 8/304 (2.6%)
Tonsillitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Tooth Abscess 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Upper Respiratory Tract Infection 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 3/14 (21.4%) 2/10 (20%) 1/10 (10%) 1/5 (20%) 32/255 (12.5%) 40/304 (13.2%)
Urinary Tract Infection 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 2/10 (20%) 0/5 (0%) 18/255 (7.1%) 21/304 (6.9%)
Vaginal Infection 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Vulvovaginal Candidiasis 1/2 (50%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Injury, poisoning and procedural complications
Burns First Degree 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Fall 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 8/255 (3.1%) 10/304 (3.3%)
Ligament Sprain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Spinal Fracture 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Tendon Rupture 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Investigations
Alanine Aminotransferase Increased 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 2/14 (14.3%) 3/10 (30%) 3/10 (30%) 4/5 (80%) 122/255 (47.8%) 135/304 (44.4%)
Amylase Increased 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 3/10 (30%) 0/5 (0%) 23/255 (9%) 28/304 (9.2%)
Aspartate Aminotransferase Increased 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 3/14 (21.4%) 2/10 (20%) 3/10 (30%) 3/5 (60%) 91/255 (35.7%) 103/304 (33.9%)
Blood Alkaline Phosphatase Increased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 2/10 (20%) 1/5 (20%) 48/255 (18.8%) 52/304 (17.1%)
Blood Creatinine Increased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 47/255 (18.4%) 49/304 (16.1%)
Blood Lactate Dehydrogenase Increased 1/2 (50%) 1/2 (50%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 5/255 (2%) 7/304 (2.3%)
Blood Magnesium Decreased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 2/14 (14.3%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 2/304 (0.7%)
C-Reactive Protein Increased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 10/255 (3.9%) 11/304 (3.6%)
Electrocardiogram Qt Prolonged 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 2/10 (20%) 1/5 (20%) 12/255 (4.7%) 15/304 (4.9%)
Gamma-Glutamyltransferase Increased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 14/255 (5.5%) 14/304 (4.6%)
Haemoglobin Decreased 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Lipase Increased 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 35/255 (13.7%) 38/304 (12.5%)
Transaminases Increased 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 2/14 (14.3%) 0/10 (0%) 2/10 (20%) 0/5 (0%) 10/255 (3.9%) 14/304 (4.6%)
Weight Decreased 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 5/14 (35.7%) 1/10 (10%) 1/10 (10%) 3/5 (60%) 51/255 (20%) 62/304 (20.4%)
Metabolism and nutrition disorders
Decreased Appetite 0/2 (0%) 1/2 (50%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 3/10 (30%) 4/10 (40%) 3/5 (60%) 99/255 (38.8%) 111/304 (36.5%)
Dehydration 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 17/255 (6.7%) 18/304 (5.9%)
Electrolyte Imbalance 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Hypercalcaemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 2/255 (0.8%) 4/304 (1.3%)
Hypercholesterolaemia 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Hyperglycaemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 23/255 (9%) 24/304 (7.9%)
Hyperkalaemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 6/255 (2.4%) 7/304 (2.3%)
Hyperuricaemia 0/2 (0%) 0/2 (0%) 2/3 (66.7%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 8/255 (3.1%) 10/304 (3.3%)
Hypoalbuminaemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 14/255 (5.5%) 15/304 (4.9%)
Hypocalcaemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 11/255 (4.3%) 12/304 (3.9%)
Hypoglycaemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Hypokalaemia 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 2/14 (14.3%) 1/10 (10%) 2/10 (20%) 1/5 (20%) 34/255 (13.3%) 41/304 (13.5%)
Hypomagnesaemia 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 1/14 (7.1%) 1/10 (10%) 2/10 (20%) 0/5 (0%) 25/255 (9.8%) 30/304 (9.9%)
Hyponatraemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 1/10 (10%) 2/10 (20%) 0/5 (0%) 19/255 (7.5%) 23/304 (7.6%)
Hypophosphataemia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 1/10 (10%) 2/10 (20%) 0/5 (0%) 19/255 (7.5%) 23/304 (7.6%)
Musculoskeletal and connective tissue disorders
Arthralgia 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 2/14 (14.3%) 1/10 (10%) 1/10 (10%) 2/5 (40%) 31/255 (12.2%) 38/304 (12.5%)
Back Pain 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 1/3 (33.3%) 3/14 (21.4%) 1/10 (10%) 4/10 (40%) 1/5 (20%) 56/255 (22%) 67/304 (22%)
Bone Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 8/255 (3.1%) 9/304 (3%)
Bursitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Coccydynia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Flank Pain 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 14/255 (5.5%) 15/304 (4.9%)
Fracture Pain 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Muscle Atrophy 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Muscle Spasms 1/2 (50%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 1/5 (20%) 24/255 (9.4%) 27/304 (8.9%)
Muscular Weakness 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 2/14 (14.3%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 17/255 (6.7%) 19/304 (6.3%)
Musculoskeletal Chest Pain 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 32/255 (12.5%) 33/304 (10.9%)
Musculoskeletal Discomfort 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 5/255 (2%) 6/304 (2%)
Musculoskeletal Pain 0/2 (0%) 0/2 (0%) 2/3 (66.7%) 0/3 (0%) 2/14 (14.3%) 2/10 (20%) 1/10 (10%) 1/5 (20%) 40/255 (15.7%) 48/304 (15.8%)
Myalgia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 1/10 (10%) 2/5 (40%) 12/255 (4.7%) 16/304 (5.3%)
Neck Pain 0/2 (0%) 1/2 (50%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 16/255 (6.3%) 17/304 (5.6%)
Osteonecrosis Of Jaw 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Osteoporosis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Pain In Extremity 0/2 (0%) 0/2 (0%) 0/3 (0%) 1/3 (33.3%) 0/14 (0%) 1/10 (10%) 3/10 (30%) 1/5 (20%) 23/255 (9%) 29/304 (9.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic Naevus 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Nervous system disorders
Akathisia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Complex Partial Seizures 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Dizziness 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 2/14 (14.3%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 38/255 (14.9%) 42/304 (13.8%)
Dysgeusia 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 2/5 (40%) 19/255 (7.5%) 23/304 (7.6%)
Headache 1/2 (50%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 2/14 (14.3%) 0/10 (0%) 3/10 (30%) 1/5 (20%) 66/255 (25.9%) 74/304 (24.3%)
Hypoaesthesia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 9/255 (3.5%) 10/304 (3.3%)
Migraine 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 4/255 (1.6%) 5/304 (1.6%)
Neuralgia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Neuropathy Peripheral 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 7/255 (2.7%) 8/304 (2.6%)
Paraesthesia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 2/10 (20%) 0/10 (0%) 1/5 (20%) 23/255 (9%) 26/304 (8.6%)
Peripheral Motor Neuropathy 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Peripheral Sensory Neuropathy 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 3/255 (1.2%) 4/304 (1.3%)
Sensory Loss 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Sinus Headache 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Tremor 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 20/255 (7.8%) 20/304 (6.6%)
Psychiatric disorders
Anxiety 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 24/255 (9.4%) 25/304 (8.2%)
Delirium 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 0/255 (0%) 2/304 (0.7%)
Depression 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 16/255 (6.3%) 17/304 (5.6%)
Insomnia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 3/10 (30%) 2/10 (20%) 1/5 (20%) 45/255 (17.6%) 52/304 (17.1%)
Mood Altered 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Renal and urinary disorders
Dysuria 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 6/255 (2.4%) 7/304 (2.3%)
Haematuria 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 3/255 (1.2%) 4/304 (1.3%)
Renal Failure 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Urinary Incontinence 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 5/255 (2%) 6/304 (2%)
Reproductive system and breast disorders
Breast Oedema 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Retracted Nipple 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Vaginal Odour 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Respiratory, thoracic and mediastinal disorders
Bronchospasm 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Cough 0/2 (0%) 0/2 (0%) 2/3 (66.7%) 0/3 (0%) 3/14 (21.4%) 3/10 (30%) 3/10 (30%) 0/5 (0%) 83/255 (32.5%) 94/304 (30.9%)
Dysphonia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 1/5 (20%) 14/255 (5.5%) 16/304 (5.3%)
Dyspnoea 2/2 (100%) 0/2 (0%) 1/3 (33.3%) 1/3 (33.3%) 2/14 (14.3%) 5/10 (50%) 0/10 (0%) 0/5 (0%) 61/255 (23.9%) 72/304 (23.7%)
Dyspnoea Exertional 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 2/10 (20%) 0/10 (0%) 0/5 (0%) 16/255 (6.3%) 18/304 (5.9%)
Epistaxis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 3/255 (1.2%) 4/304 (1.3%)
Haemoptysis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 1/5 (20%) 11/255 (4.3%) 13/304 (4.3%)
Hiccups 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 3/255 (1.2%) 4/304 (1.3%)
Nasal Congestion 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 5/255 (2%) 6/304 (2%)
Oropharyngeal Pain 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 2/10 (20%) 2/5 (40%) 17/255 (6.7%) 23/304 (7.6%)
Pneumonitis 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 1/5 (20%) 2/255 (0.8%) 3/304 (1%)
Productive Cough 1/2 (50%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 33/255 (12.9%) 36/304 (11.8%)
Pulmonary Embolism 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Rhinorrhoea 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 18/255 (7.1%) 18/304 (5.9%)
Sinus Congestion 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 5/255 (2%) 6/304 (2%)
Tachypnoea 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 1/255 (0.4%) 2/304 (0.7%)
Skin and subcutaneous tissue disorders
Acne 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 4/255 (1.6%) 5/304 (1.6%)
Alopecia 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 1/5 (20%) 13/255 (5.1%) 14/304 (4.6%)
Dermatitis Acneiform 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 10/255 (3.9%) 11/304 (3.6%)
Dry Skin 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 18/255 (7.1%) 20/304 (6.6%)
Erythema 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 0/5 (0%) 5/255 (2%) 6/304 (2%)
Pigmentation Disorder 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 1/10 (10%) 1/5 (20%) 0/255 (0%) 2/304 (0.7%)
Pruritus 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 1/10 (10%) 0/5 (0%) 19/255 (7.5%) 22/304 (7.2%)
Rash 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 1/14 (7.1%) 1/10 (10%) 1/10 (10%) 1/5 (20%) 39/255 (15.3%) 44/304 (14.5%)
Rash Maculo-Papular 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 3/255 (1.2%) 4/304 (1.3%)
Rash Pruritic 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 1/14 (7.1%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 2/255 (0.8%) 3/304 (1%)
Scab 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Vascular disorders
Haemodynamic Instability 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Hot Flush 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 0/10 (0%) 0/5 (0%) 5/255 (2%) 6/304 (2%)
Hypertension 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 1/5 (20%) 12/255 (4.7%) 14/304 (4.6%)
Hypotension 0/2 (0%) 0/2 (0%) 0/3 (0%) 0/3 (0%) 0/14 (0%) 1/10 (10%) 1/10 (10%) 0/5 (0%) 8/255 (3.1%) 10/304 (3.3%)
Jugular Vein Thrombosis 0/2 (0%) 0/2 (0%) 0/3 (0%) 1/3 (33.3%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)
Lymphoedema 0/2 (0%) 0/2 (0%) 1/3 (33.3%) 0/3 (0%) 0/14 (0%) 0/10 (0%) 0/10 (0%) 0/5 (0%) 0/255 (0%) 1/304 (0.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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

Results Point of Contact

Name/Title Study Director
Organization Novartis Pharmaceuticals
Phone 862-778-8300
Email
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01283516
Other Study ID Numbers:
  • CLDK378X2101
  • 2010-019827-70
First Posted:
Jan 26, 2011
Last Update Posted:
Mar 15, 2019
Last Verified:
Nov 1, 2018