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Clinical Trial Results:
A Phase III, International, Randomised, Double-Blind, Parallel-Group, Multi-Centre Study to Assess the Efficacy of ZD6474(ZACTIMA™) Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in Patients With Locally Advanced or Metastatic (Stage IIIB – IV) Non-Small Cell Lung Cancer (NSCLC) after Prior Therapy with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI)

Summary
EudraCT number
 2006-002384-12
Trial protocol
 BE   DE   FR   AT   NL   GB   IT   ES  
Global end of trial date
30 Nov 2014

Results information
Results version number
 v1(current)
This version publication date
09 Jun 2016
First version publication date
09 Jun 2016
Other versions

Trial information

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Trial identification
Sponsor protocol code
D4200C00044
Additional study identifiers
ISRCTN number
 -
US NCT number
 NCT00404924
WHO universal trial number (UTN)
 -
Sponsors
Sponsor organisation name
AstraZeneca
Sponsor organisation address
151 85, Södertälje, Sweden,
Public contact
Gabriella Mariani, AstraZeneca, aztrial_results_posting@astrazeneca.com
Scientific contact
Gabriella Mariani, AstraZeneca, aztrial_results_posting@astrazeneca.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)
No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
No
Results analysis stage
Analysis stage
Final
Date of interim/final analysis
30 Mar 2010
Is this the analysis of the primary completion data?
Yes
Primary completion date
19 Oct 2009
Global end of trial reached?
Yes
Global end of trial date
30 Nov 2014
Was the trial ended prematurely?
No
General information about the trial
Main objective of the trial
The primary objective of this study is to demonstrate an improvement in overall survival for ZD6474 plus best supportive care (BSC) compared with placebo plus BSC in patients with locally advanced or metastatic NSCLC after prior therapy with an EGFR TKI.
Protection of trial subjects
The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics.
Background therapy
 -
Evidence for comparator
 -
Actual start date of recruitment
08 Nov 2006
Long term follow-up planned
Yes
Long term follow-up rationale
 Efficacy
Long term follow-up duration
 15 Months
Independent data monitoring committee (IDMC) involvement?
Yes
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled
Argentina: 26
Country: Number of subjects enrolled
Australia: 19
Country: Number of subjects enrolled
Austria: 17
Country: Number of subjects enrolled
Belgium: 44
Country: Number of subjects enrolled
Canada: 73
Country: Number of subjects enrolled
China: 170
Country: Number of subjects enrolled
France: 61
Country: Number of subjects enrolled
Germany: 112
Country: Number of subjects enrolled
Hong Kong: 44
Country: Number of subjects enrolled
Israel: 17
Country: Number of subjects enrolled
Italy: 62
Country: Number of subjects enrolled
Korea, Republic of: 220
Country: Number of subjects enrolled
Mexico: 23
Country: Number of subjects enrolled
Netherlands: 3
Country: Number of subjects enrolled
Peru: 13
Country: Number of subjects enrolled
Philippines: 9
Country: Number of subjects enrolled
Singapore: 16
Country: Number of subjects enrolled
Spain: 18
Country: Number of subjects enrolled
Taiwan: 135
Country: Number of subjects enrolled
Thailand: 33
Country: Number of subjects enrolled
United Kingdom: 24
Country: Number of subjects enrolled
United States: 1
Worldwide total number of subjects
1140
EEA total number of subjects
341
Number of subjects enrolled per age group
In utero
0
Preterm newborn - gestational age
0
Newborns (0-27 days)
0
Infants and toddlers (28 days-23 months)
0
Children (2-11 years)
0
Adolescents (12-17 years)
0
Adults (18-64 years)
700
From 65 to 84 years
434
85 years and over
6

Subject disposition

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Recruitment
Recruitment details
 First patient enrolled 08 November 2006, last patient enrolled 09 October 2008, cut off date 19 October 2009. 1140 patients were screened in the study.

Pre-assignment
Screening details
 1140 patients signed inform consent and 924 randomised

Pre-assignment period milestones
Number of subjects started
 1140
Number of subjects completed
 924

Pre-assignment subject non-completion reasons
Reason: Number of subjects
 Adverse event, serious fatal: 4
Reason: Number of subjects
 Consent withdrawn by subject: 12
Reason: Number of subjects
 Protocol deviation: 200
Period 1
Period 1 title
Overall Study (overall period)
Is this the baseline period?
 Yes
Allocation method
Randomised - controlled
Blinding used
 Double blind
Roles blinded
 Investigator, Monitor, Carer, Data analyst, Subject, Assessor

Arms
Are arms mutually exclusive
Yes

Arm title
 Vandetanib 300 mg
Arm description
 vandetanib (300 mg daily) plus best supportive care
Arm type
 Experimental

Investigational medicinal product name
ZACTIMA
Investigational medicinal product code
ZD6474
Other name
Caprelsa
Pharmaceutical forms
Tablet
Routes of administration
Oral use
Dosage and administration details
Single oral dose 300mg daily

Arm title
 Placebo
Arm description
 Placebo plus best supportive care
Arm type
 Placebo

Investigational medicinal product name
placebo
Investigational medicinal product code
Other name
Pharmaceutical forms
Tablet
Routes of administration
Oral use
Dosage and administration details
Single oral dose 300mg daily

Number of subjects in period 1 [1]
Vandetanib 300 mg Placebo
Started
617
307
Completed
14
1
Not completed
603
306
     Randomised but not received treatment
1
1
     Adverse event, non-fatal
75
16
     Consent withdrawn by subject
26
13
     Condition under investigation worsened
475
264
     Not Specified
25
11
     Lost to follow-up
1
1
Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: I have an error stating that the number for the worldwide enrolled is not equal to the number of patients who started the overall study at baseline - if the number enrolled is the number screened then this won't equal the number at baseline as this is the number randomised

Baseline characteristics

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Baseline characteristics reporting groups
Reporting group title
Vandetanib 300 mg
Reporting group description
 vandetanib (300 mg daily) plus best supportive care

Reporting group title
Placebo
Reporting group description
 Placebo plus best supportive care

Reporting group values
 Vandetanib 300 mg Placebo Total
Number of subjects
 617 307 924
Age categorical
Units: Subjects
    In utero
 0 0 0
    Preterm newborn infants (gestational age < 37 wks)
 0 0 0
    Newborns (0-27 days)
 0 0 0
    Infants and toddlers (28 days-23 months)
 0 0 0
    Children (2-11 years)
 0 0 0
    Adolescents (12-17 years)
 0 0 0
    Adults (18-64 years)
 396 180 576
    From 65-74 years
 157 92 249
    75 years and over
 64 35 99
Age Continuous |
Units: years
    arithmetic mean (full range (min-max))
 59.8 (20 to 85) 60.6 (21 to 84) -
Gender, Male/Female
Units: Participants
    Female
 329 160 489
    Male
 288 147 435

End points

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End points reporting groups
Reporting group title
Vandetanib 300 mg
Reporting group description
 vandetanib (300 mg daily) plus best supportive care

Reporting group title
Placebo
Reporting group description
 Placebo plus best supportive care

Primary: Overall Survival (OS)

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End point title
 Overall Survival (OS)
End point description
Overall Survival (OS) is defined as the time from date of randomization until death. Any blinded/unknown patient which have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive (ie, their status must be known at the censored date and should not be lost to follow up or unknown).
End point type
Primary
End point timeframe
Time to death in months
End point values
 Vandetanib 300 mg Placebo
Number of subjects analysed
617
307
Units: Months
    median (confidence interval)
8.5 (7.81 to 9.76)
7.8 (6.08 to 9.17)
Statistical analysis title
 Summary of Primary Analysis of Overall Survival
Comparison groups
Vandetanib 300 mg v Placebo
Number of subjects included in analysis
924
Analysis specification
Pre-specified
Analysis type
 superiority
P-value
 = 0.5273
Method
 Logrank
Parameter type
 Hazard ratio (HR)
Point estimate
0.95
Confidence interval
     level
 95.2%
     sides
2-sided
     lower limit
 0.81
     upper limit
 1.11

Secondary: Progression-Free Survival (PFS)

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End point title
 Progression-Free Survival (PFS)
End point description
Median time (in months) from randomisation until objective disease progression (determined by RECIST assessments) or death (by any cause in the absence of objective progression) provided death is within 3 months from the last evaluable RECIST assessment
End point type
Secondary
End point timeframe
RECIST tumour assessments carried out every 8 weeks from randomisation until objective disease progression
End point values
 Vandetanib 300 mg Placebo
Number of subjects analysed
617
307
Units: month
    median (confidence interval)
1.9 (1.84 to 2.23)
1.8 (1.74 to 1.84)
No statistical analyses for this end point

Secondary: Objective Response Rate (ORR)

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End point title
 Objective Response Rate (ORR)
End point description
The ORR is the number of patients that are responders ie those patients with a confirmed best objective response of complete response (CR) or partial response (PR) as defined by RECIST criteria. The categories for best objective response are CR, PR, stable disease (SD)>= 8 weeks, progressive disease (PD) or NE.
End point type
Secondary
End point timeframe
Each patient was assessed for objective response from the sequence of RECIST scan data up to data cut off. RECIST tumour assessments carried out every 8 weeks from randomisation until objective disease progression.
End point values
 Vandetanib 300 mg Placebo
Number of subjects analysed
617
307
Units: Participants
16
2
No statistical analyses for this end point

Secondary: Disease Control Rate (DCR)

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End point title
 Disease Control Rate (DCR)
End point description
Disease control rate is defined as the number of patients who achieved disease control at 8 weeks following randomisation. Disease control at 8 weeks is defined as a best objective response of complete response (CR), partial response (PR) or stable disease (SD) >= 8 weeks
End point type
Secondary
End point timeframe
RECIST tumour assessments carried out every 8 weeks from randomisation until objective disease progression
End point values
 Vandetanib 300 mg Placebo
Number of subjects analysed
617
307
Units: Participants
189
48
No statistical analyses for this end point

Secondary: Duration of Response (DoR)

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End point title
 Duration of Response (DoR)
End point description
Response is defined as a confirmed best objective response of CR or PR. Duration of response is defined as time from the date of first documented response until date of documented progression or death in the absence of disease progression (provided death is within 3 months of last RECIST assessment)
End point type
Secondary
End point timeframe
RECIST tumour assessments carried out every 8 weeks from randomisation until objective disease progression
End point values
 Vandetanib 300 mg Placebo
Number of subjects analysed
16
2
Units: Weeks
    median (confidence interval)
23.9 (16.57 to 27)
24.3 (16 to 32.57)
No statistical analyses for this end point

Secondary: Time to deterioration of disease-related symptoms (TDS) by questionnaire - the lung cancer subscale (LCS) a selection of the FACT-L focusing on symptoms of lung cancer plus pain and fatigue (LCS-PF)

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End point title
 Time to deterioration of disease-related symptoms (TDS) by questionnaire - the lung cancer subscale (LCS) a selection of the FACT-L focusing on symptoms of lung cancer plus pain and fatigue (LCS-PF)
End point description
Time to deterioration in symptoms is defined as the interval from the date of randomization to the first assessment of ‘worsened’ with no visit assessment of ‘improved’ within the next 28 days. Where assessment is by a selection of questions from the Functional Assessment of Cancer Therapy for Lung Cancer (FACT-L) questionnaire.
End point type
Secondary
End point timeframe
Disease-related symptom assessments are to be administered at screening (within 7 days before the first dose of study medication) and every 4 weeks thereafter, at discontinuation of study treatment and at the 30-day follow-up visit
End point values
 Vandetanib 300 mg Placebo
Number of subjects analysed
617
307
Units: weeks
    median (inter-quartile range (Q1-Q3))
6.1 (5.14 to 8.14)
7.1 (5.86 to 8.43)
No statistical analyses for this end point

Adverse events

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Adverse events information
Timeframe for reporting adverse events
AEs were collected up to 60days after discontinuation of study treatment.
Adverse event reporting additional description
The Safety Analysis Set included 922 patients (619 vandetanib & 303 placebo), which represents more than 99% of all randomized pts. 2 (1 in each arm) were excluded from the SAS as they were not dosed. Additionally 3 pts randomized to receive placebo received at least one dose of vandetanib, these 3 pts are included in the vandetanib arm in the SAS
Assessment type
 Non-systematic
Dictionary used for adverse event reporting
Dictionary name
 MedDRA
Dictionary version
12.1
Reporting groups
Reporting group title
Vandetanib
Reporting group description
 Vandetanib 300 mg

Reporting group title
Placebo
Reporting group description
 Placebo

Serious adverse events
 Vandetanib Placebo
Total subjects affected by serious adverse events
     subjects affected / exposed
160 / 619 (25.85%)
63 / 303 (20.79%)
     number of deaths (all causes)
474
230
     number of deaths resulting from adverse events
Vascular disorders
Hypertension
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
7 / 619 (1.13%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
5 / 7
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Deep Vein Thrombosis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 3
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Arterial Thrombosis Limb
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Hypotension
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Jugular Vein Thrombosis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Thrombophlebitis Superficial
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Visceral Arterial Ischaemia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer Pain
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Immune system disorders
Drug Hypersensitivity
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
2 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Anaphylactic Reaction
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
General disorders and administration site conditions
Asthenia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
5 / 619 (0.81%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
1 / 5
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Death
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
3 / 619 (0.48%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 3
0 / 0
     deaths causally related to treatment / all
0 / 3
0 / 0
Fatigue
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
3 / 619 (0.48%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
2 / 3
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Pyrexia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
3 / 619 (0.48%)
3 / 303 (0.99%)
     occurrences causally related to treatment / all
0 / 3
0 / 4
     deaths causally related to treatment / all
0 / 0
0 / 0
Chest Pain
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
General Physical Health Deterioration
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Malaise
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Pain
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Psychiatric disorders
Confusional State
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
2 / 303 (0.66%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Anxiety
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Depression
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Injury, poisoning and procedural complications
Femur Fracture
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Femoral Neck Fracture
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Joint Dislocation
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Multiple Injuries
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 1
0 / 0
Pneumothorax Traumatic
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Wound
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Wrist Fracture
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Investigations
Electrocardiogram T Wave Inversion
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Lipase Increased
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Neutrophil Count Decreased
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Cardiac disorders
Atrial Fibrillation
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
2 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Cardiac Failure
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 2
0 / 0
     deaths causally related to treatment / all
1 / 2
0 / 0
Myocardial Infarction
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 2
2 / 2
     deaths causally related to treatment / all
0 / 1
1 / 1
Angina Pectoris
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Arrhythmia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Cardiac Arrest
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 1
0 / 0
Cardiac Valve Disease
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Pericardial Effusion
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
12 / 619 (1.94%)
5 / 303 (1.65%)
     occurrences causally related to treatment / all
1 / 14
2 / 6
     deaths causally related to treatment / all
0 / 0
0 / 0
Pleural Effusion
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
5 / 619 (0.81%)
5 / 303 (1.65%)
     occurrences causally related to treatment / all
0 / 6
0 / 7
     deaths causally related to treatment / all
0 / 0
0 / 0
Pulmonary Embolism
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
3 / 619 (0.48%)
5 / 303 (1.65%)
     occurrences causally related to treatment / all
0 / 3
0 / 5
     deaths causally related to treatment / all
0 / 1
0 / 0
Haemoptysis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
3 / 619 (0.48%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
2 / 3
0 / 0
     deaths causally related to treatment / all
2 / 2
0 / 0
Cough
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 2
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Pneumonia Aspiration
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 2
0 / 0
     deaths causally related to treatment / all
0 / 1
0 / 0
Pneumonitis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 3
0 / 0
     deaths causally related to treatment / all
0 / 1
0 / 0
Acute Respiratory Distress Syndrome
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
1 / 1
0 / 0
Bronchial Haemorrhage
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
1 / 1
0 / 0
Bronchospasm
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 1
0 / 0
Idiopathic Pulmonary Fibrosis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Pneumothorax
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Pulmonary Artery Thrombosis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Pulmonary Haemorrhage
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
1 / 1
1 / 1
     deaths causally related to treatment / all
0 / 0
1 / 1
Respiratory Failure
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 1
0 / 1
Respiratory Tract Haemorrhage
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Blood and lymphatic system disorders
Febrile Neutropenia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
3 / 619 (0.48%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 3
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Anaemia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
2 / 303 (0.66%)
     occurrences causally related to treatment / all
0 / 0
1 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Thrombocytopenia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
2 / 303 (0.66%)
     occurrences causally related to treatment / all
0 / 2
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Leukopenia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Neutropenia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Nervous system disorders
Convulsion
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
5 / 619 (0.81%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
1 / 5
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Cerebral Infarction
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
3 / 303 (0.99%)
     occurrences causally related to treatment / all
0 / 0
2 / 4
     deaths causally related to treatment / all
0 / 0
0 / 0
Cerebral Ischaemia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
3 / 619 (0.48%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 3
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Cerebrovascular Accident
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
3 / 619 (0.48%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
1 / 3
0 / 1
     deaths causally related to treatment / all
0 / 2
0 / 0
Cerebral Haemorrhage
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Cognitive Disorder
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Dizziness
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Encephalitis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Loss Of Consciousness
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
2 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Paraesthesia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Partial Seizures
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Somnolence
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Subarachnoid Haemorrhage
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Syncope
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Transient Ischaemic Attack
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Tremor
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Eye disorders
Diplopia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Vision Blurred
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Visual Acuity Reduced
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Ear and labyrinth disorders
Deafness
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Vertigo
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Gastrointestinal disorders
Diarrhoea
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
8 / 619 (1.29%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
5 / 8
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Vomiting
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
4 / 619 (0.65%)
3 / 303 (0.99%)
     occurrences causally related to treatment / all
2 / 5
1 / 3
     deaths causally related to treatment / all
0 / 0
0 / 0
Nausea
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
2 / 2
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Abdominal Distension
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Abdominal Pain
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Ascites
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Constipation
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Duodenal Ulcer
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Enteritis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Gastrointestinal Perforation
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
1 / 1
     deaths causally related to treatment / all
0 / 0
1 / 1
Gastrooesophageal Reflux Disease
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Gingival Pain
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Ileus Paralytic
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Intestinal Haemorrhage
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 1
Intestinal Perforation
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 1
Neutropenic Colitis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Pancreatitis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Paraesthesia Oral
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Pneumatosis Intestinalis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Proctalgia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Subileus
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Renal and urinary disorders
Urinary Retention
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
2 / 303 (0.66%)
     occurrences causally related to treatment / all
0 / 0
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Calculus Urinary
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Renal Failure
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Renal Failure Acute
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Urinary Incontinence
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Hepatobiliary disorders
Bile Duct Stenosis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Cytolytic Hepatitis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Skin and subcutaneous tissue disorders
Rash
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
4 / 619 (0.65%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
4 / 4
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Stevens-Johnson Syndrome
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
3 / 619 (0.48%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
2 / 3
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Photosensitivity Reaction
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Dermatitis Allergic
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Dry Skin
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Erythema
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Erythema Multiforme
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
2 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Rash Pruritic
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Musculoskeletal and connective tissue disorders
Back Pain
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Musculoskeletal Pain
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
2 / 303 (0.66%)
     occurrences causally related to treatment / all
0 / 3
0 / 2
     deaths causally related to treatment / all
0 / 0
0 / 0
Arthralgia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Bone Pain
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Muscle Twitching
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Musculoskeletal Chest Pain
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Myalgia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Neck Pain
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Osteoarthritis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Pain In Extremity
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Endocrine disorders
Hyperthyroidism
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Metabolism and nutrition disorders
Dehydration
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
4 / 619 (0.65%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
1 / 4
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Decreased Appetite
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
2 / 2
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Hyperglycaemia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Hyponatraemia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
1 / 2
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Hypercalcaemia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Hypoglycaemia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Infections and infestations
Pneumonia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
21 / 619 (3.39%)
6 / 303 (1.98%)
     occurrences causally related to treatment / all
0 / 26
0 / 7
     deaths causally related to treatment / all
0 / 3
0 / 3
Sepsis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
3 / 619 (0.48%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
1 / 3
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 1
Lung Infection
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 2
0 / 1
     deaths causally related to treatment / all
0 / 1
0 / 0
Urinary Tract Infection
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
2 / 619 (0.32%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 2
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Arthritis Bacterial
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Bacterial Sepsis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 1
Bronchitis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Catheter Site Infection
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Cellulitis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Clostridial Infection
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Empyema
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
0 / 619 (0.00%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 0
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Gastroenteritis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Injection Site Abscess
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Lobar Pneumonia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 1
0 / 0
Lower Respiratory Tract Infection
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 1
Pharyngitis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Staphylococcal Sepsis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Subcutaneous Abscess
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Tracheitis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Upper Respiratory Tract Infection
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
1 / 303 (0.33%)
     occurrences causally related to treatment / all
0 / 1
0 / 1
     deaths causally related to treatment / all
0 / 0
0 / 0
Urosepsis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
1 / 619 (0.16%)
0 / 303 (0.00%)
     occurrences causally related to treatment / all
0 / 1
0 / 0
     deaths causally related to treatment / all
0 / 0
0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events
 Vandetanib Placebo
Total subjects affected by non serious adverse events
     subjects affected / exposed
557 / 619 (89.98%)
234 / 303 (77.23%)
Vascular disorders
Hypertension
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
160 / 619 (25.85%)
9 / 303 (2.97%)
     occurrences all number
182
9
Investigations
Weight Decreased
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
47 / 619 (7.59%)
18 / 303 (5.94%)
     occurrences all number
49
18
Electrocardiogram Qt Prolonged
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
37 / 619 (5.98%)
1 / 303 (0.33%)
     occurrences all number
48
1
Respiratory, thoracic and mediastinal disorders
Cough
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
108 / 619 (17.45%)
54 / 303 (17.82%)
     occurrences all number
122
59
Dyspnoea
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
98 / 619 (15.83%)
52 / 303 (17.16%)
     occurrences all number
102
56
Blood and lymphatic system disorders
Anaemia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
19 / 619 (3.07%)
19 / 303 (6.27%)
     occurrences all number
22
22
Nervous system disorders
Dizziness
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
68 / 619 (10.99%)
27 / 303 (8.91%)
     occurrences all number
79
28
Headache
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
61 / 619 (9.85%)
24 / 303 (7.92%)
     occurrences all number
70
25
General disorders and administration site conditions
Fatigue
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
109 / 619 (17.61%)
50 / 303 (16.50%)
     occurrences all number
122
53
Asthenia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
62 / 619 (10.02%)
30 / 303 (9.90%)
     occurrences all number
72
34
Pyrexia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
44 / 619 (7.11%)
29 / 303 (9.57%)
     occurrences all number
52
34
Oedema Peripheral
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
33 / 619 (5.33%)
29 / 303 (9.57%)
     occurrences all number
33
31
Psychiatric disorders
Insomnia
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
63 / 619 (10.18%)
24 / 303 (7.92%)
     occurrences all number
68
24
Gastrointestinal disorders
Diarrhoea
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
284 / 619 (45.88%)
34 / 303 (11.22%)
     occurrences all number
407
38
Nausea
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
138 / 619 (22.29%)
51 / 303 (16.83%)
     occurrences all number
170
63
Constipation
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
88 / 619 (14.22%)
63 / 303 (20.79%)
     occurrences all number
99
69
Vomiting
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
82 / 619 (13.25%)
36 / 303 (11.88%)
     occurrences all number
106
50
Stomatitis
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
34 / 619 (5.49%)
13 / 303 (4.29%)
     occurrences all number
37
14
Abdominal Pain
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
26 / 619 (4.20%)
19 / 303 (6.27%)
     occurrences all number
28
19
Renal and urinary disorders
Proteinuria
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
56 / 619 (9.05%)
10 / 303 (3.30%)
     occurrences all number
66
13
Skin and subcutaneous tissue disorders
Rash
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
258 / 619 (41.68%)
33 / 303 (10.89%)
     occurrences all number
295
35
Pruritus
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
70 / 619 (11.31%)
16 / 303 (5.28%)
     occurrences all number
83
16
Dry Skin
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
49 / 619 (7.92%)
8 / 303 (2.64%)
     occurrences all number
55
8
Musculoskeletal and connective tissue disorders
Back Pain
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
54 / 619 (8.72%)
19 / 303 (6.27%)
     occurrences all number
59
22
Musculoskeletal Pain
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
22 / 619 (3.55%)
20 / 303 (6.60%)
     occurrences all number
22
21
Metabolism and nutrition disorders
Decreased Appetite
alternative dictionary used: MedDRA 12.1
alternative assessment type: Systematic
     subjects affected / exposed
143 / 619 (23.10%)
63 / 303 (20.79%)
     occurrences all number
158
67

More information

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Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date
Amendment
10 May 2007
Procedural clarifications for ECG, archival tumour samples and patients taking contraindicated concomitant medications. Schedule of assessments clarification for RECIST assessments, collection of AE/SAEs. Clarification on statistical analyses, DMC requirements
16 Apr 2009
Procedural clarifications. Clarification of secondary endpoints for PRO analysis. Remove co-primary analysis and adjust significance levels and testing procedures accordingly.
08 Jan 2010
Update to prodecures for patients still receiving treatment after final planned data analysis.

Interruptions (globally)
Were there any global interruptions to the trial? No

Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

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