Flag of the European Union

EU Clinical Trials Register

Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:

interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC

clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
Clinical Trials Information System (CTIS).

The EU Clinical Trials Register currently displays 43861 clinical trials with a EudraCT protocol, of which 7284 are clinical trials conducted with subjects less than 18 years old. The register also displays information on 18700 older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).

Examples: Cancer AND drug name. Pneumonia AND sponsor name.
How to search [pdf]

Advanced Search:

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

< Back to search results

Clinical Trial Results:
A Phase 3, Randomized, Double-Blinded, Placebo-Controlled Study of ARQ 197 Plus Erlotinib Versus Placebo Plus Erlotinib in Previously Treated Subjects with Locally Advanced or Metastatic, Non-Squamous, Non–Small-Cell Lung Cancer (NSCLC)

Summary
EudraCT number	2010-022365-10
Trial protocol	HU CZ DE ES IT SE GB DK AT BE
Global end of trial date	06 Oct 2016

Results information
Results version number	v1(current)
This version publication date	20 Mar 2018
First version publication date	20 Mar 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

ARQ197-A-U302

ISRCTN number

-

US NCT number

NCT01244191

WHO universal trial number (UTN)

-

Sponsor organisation name

Daiichi Sankyo, Inc.

Sponsor organisation address

211 Mt. Airy Road, Basking Ridge, United States, 07920

Public contact

Clinical Trial Information, Daiichi Sankyo Development Limited, +44 1753482800, info@dsd-eu.com

Scientific contact

Clinical Trial Information, Daiichi Sankyo Development Limited, +44 1753482800, info@dsd-eu.com

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

Analysis stage

Final

Date of interim/final analysis

30 Nov 2017

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

06 Oct 2016

Was the trial ended prematurely?

No

Main objective of the trial

The primary objective of this study is to evaluate overall survival (OS) in the intent-to-treat (ITT) subject population defined by this protocol.

Protection of trial subjects

This study was conducted in compliance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, the International Conference on Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and applicable regulatory requirement(s). Dose delays and/or reductions were permitted.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

11 Jan 2011

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

4 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Russian Federation: 67

Country: Number of subjects enrolled

United States: 229

Country: Number of subjects enrolled

Chile: 17

Country: Number of subjects enrolled

Argentina: 14

Country: Number of subjects enrolled

Australia: 17

Country: Number of subjects enrolled

Brazil: 45

Country: Number of subjects enrolled

Canada: 39

Country: Number of subjects enrolled

Mexico: 10

Country: Number of subjects enrolled

Peru: 11

Country: Number of subjects enrolled

Poland: 78

Country: Number of subjects enrolled

Romania: 13

Country: Number of subjects enrolled

Spain: 79

Country: Number of subjects enrolled

Netherlands: 12

Country: Number of subjects enrolled

Sweden: 2

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

Austria: 1

Country: Number of subjects enrolled

Belgium: 5

Country: Number of subjects enrolled

Czech Republic: 8

Country: Number of subjects enrolled

Denmark: 14

Country: Number of subjects enrolled

France: 101

Country: Number of subjects enrolled

Germany: 93

Country: Number of subjects enrolled

Hungary: 31

Country: Number of subjects enrolled

Italy: 152

Worldwide total number of subjects

1048

EEA total number of subjects

599

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

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)

646

From 65 to 84 years

399

85 years and over

3

Subject disposition

Top of page

Recruitment details

Between Jan 2011 and July 2012, of the 1624 patients screened, 1048 were randomized to treatment and formed the Intent-to-treat (ITT) Population. Results of the interim analysis met the protocol-defined stopping criteria. Protocol amendment 4 allowed only the EGFR mutant subgroup to continue (indicated here as Period 2).

Screening details

A total of 1624 subjects were screened for this study in 23 countries.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Erlotinib plus tivantinib

Arm description

Patients received 1 commercially available erlotinib 150 mg tablet once daily without food, plus 3 tivantinib 120 mg tablets twice daily with meals (for a daily dose of 720 mg).

Arm type

Experimental

Investigational medicinal product name

Erlotinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Single tablet once daily at least 1 hour before or at least 2 hours after food.

Investigational medicinal product name

Tivantinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Three 120 mg tablets twice daily with meals, for a total daily dose of 720 mg.

Erlotinib plus placebo

Arm description

Patients received 1 commercially available erlotinib 150 mg tablet once daily without food, plus 3 placebo tablets twice daily with meals.

Arm type

Placebo

Investigational medicinal product name

Erlotinib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Single tablet once daily at least 1 hour before or at least 2 hours after food.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Three tablets twice daily with meals.

Number of subjects in period 1	Erlotinib plus tivantinib	Erlotinib plus placebo
Started	526	522
Treated - safety analysis set	520	517
Completed	46	24
Not completed	480	498
Consent withdrawn by subject	31	23
Missing or study terminated by sponsor	12	8
Adverse event, non-fatal	65	48
Death	22	29
Clinical disease progression	54	36
Progressive disease	295	350
Lost to follow-up	-	2
Protocol deviation	1	2

Baseline characteristics

Top of page

Reporting group title

Erlotinib plus tivantinib

Reporting group description

Patients received 1 commercially available erlotinib 150 mg tablet once daily without food, plus 3 tivantinib 120 mg tablets twice daily with meals (for a daily dose of 720 mg).

Reporting group title

Erlotinib plus placebo

Reporting group description

Patients received 1 commercially available erlotinib 150 mg tablet once daily without food, plus 3 placebo tablets twice daily with meals.

Reporting group values	Erlotinib plus tivantinib	Erlotinib plus placebo	Total
Number of subjects	526	522	1048
Age categorical
Units: Subjects
Adults (18-64 years)	320	326	646
From 65-84 years	204	195	399
85 years and over	2	1	3
Age continuous
Units: years
arithmetic mean (standard deviation)	61.2 ( 10.10 )	61.1 ( 9.84 )	-
Gender categorical
Units: Subjects
Female	216	213	429
Male	310	309	619

End points

Top of page

Reporting group title

Erlotinib plus tivantinib

Reporting group description

Patients received 1 commercially available erlotinib 150 mg tablet once daily without food, plus 3 tivantinib 120 mg tablets twice daily with meals (for a daily dose of 720 mg).

Reporting group title

Erlotinib plus placebo

Reporting group description

Patients received 1 commercially available erlotinib 150 mg tablet once daily without food, plus 3 placebo tablets twice daily with meals.

Primary: Overall survival (OS) in Original Intent-to-treat (ITT) Population

Top of page

End point title

Overall survival (OS) in Original Intent-to-treat (ITT) Population

End point description

Median length of time patients survived

End point type

Primary

End point timeframe

by study completion, within 5 years, 9 months

End point values	Erlotinib plus tivantinib	Erlotinib plus placebo
Number of subjects analysed	526	522
Units: months
median (confidence interval 95%)	8.5 (7.1 to 9.3)	7.8 (7.0 to 9.0)

Original ITT - OS Analysis

Comparison groups

Erlotinib plus tivantinib v Erlotinib plus placebo

Number of subjects included in analysis

1048

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.8086 ^[1]

Method

Logrank

Confidence interval

Notes
[1] - p-value from the stratified log-rank test [adjusting for number of prior therapies, gender, and smoking history using the IXRS (Randomization) data set] provides an overall comparison of the OS survival curves.

Secondary: Progression-Free Survival (PFS) in the Original ITT Population

Top of page

End point title

Progression-Free Survival (PFS) in the Original ITT Population

End point description

Kaplan-Meier estimates of the median PFS times for each treatment group

End point type

Secondary

End point timeframe

by study completion, within 5 years, 9 months

End point values	Erlotinib plus tivantinib	Erlotinib plus placebo
Number of subjects analysed	526	522
Units: months
median (confidence interval 95%)	3.6 (2.8 to 3.7)	1.9 (1.9 to 2.0)

Period 1 Original ITT

Comparison groups

Erlotinib plus tivantinib v Erlotinib plus placebo

Number of subjects included in analysis

1048

Analysis specification

Pre-specified

Analysis type

other

P-value

< 0.0001 ^[2]

Method

Logrank

Confidence interval

Notes
[2] - p-value from the stratified log-rank test (adjusting for number of prior therapies, gender, and smoking history using the IXRS data set) provides an overall comparison of the PFS survival curves

Other pre-specified: Overall Survival in the EGFR Mutant Subpopulation (ITT)

Top of page

End point title

Overall Survival in the EGFR Mutant Subpopulation (ITT)

End point description

Median length of time patients survived who were in the EGFR-mutant sub-population that continued until November 2014

End point type

Other pre-specified

End point timeframe

by study completion, within 5 years, 9 months

End point values	Erlotinib plus tivantinib	Erlotinib plus placebo
Number of subjects analysed	56	53
Units: months
median (confidence interval 95%)	25.5 (15.6 to 38.9)	20.3 (16.6 to 24.3)

EGFR-Mutant Analysis

Statistical analysis description

Analysis of EGFR-mutant patients who continued during Amended Protocol 4

Comparison groups

Erlotinib plus tivantinib v Erlotinib plus placebo

Number of subjects included in analysis

109

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1013 ^[3]

Method

Logrank

Confidence interval

Notes
[3] - p-value from the stratified log-rank test (adjusting for number of prior therapies, gender, and smoking history) provides an overall comparison of the PFS survival curves

Other pre-specified: Progression-Free Survival in the EGFR Mutant Subpopulation (ITT)

Top of page

End point title

Progression-Free Survival in the EGFR Mutant Subpopulation (ITT)

End point description

Kaplan-Meier estimates of the median PFS times for each treatment group

End point type

Other pre-specified

End point timeframe

by study completion, within 5 years, 9 months

End point values	Erlotinib plus tivantinib	Erlotinib plus placebo
Number of subjects analysed	56	53
Units: months
median (confidence interval 95%)	13.0 (7.3 to 17.7)	7.5 (5.6 to 11.9)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Treatment emergent adverse events (TEAEs) were collected until 30 days after completing treatment, within 5 years, 9 months. TEAEs that occurred more than 30 days after the last dose of study medication are not included unless related to treatment.

Adverse event reporting additional description

At each level of summarizing TEAEs, a patient was counted only once if he/she reported one or more adverse events in this older trial. Therefore, the number of events mirrors the number of patients. Relatedness is based on the experimental products placebo and tivantinib only.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

13.1

Reporting group title

Erlotinib plus placebo

Reporting group description

-

Reporting group title

Erlotinib plus tivantinib

Reporting group description

-

Serious adverse events	Erlotinib plus placebo	Erlotinib plus tivantinib
Total subjects affected by serious adverse events
subjects affected / exposed	198 / 517 (38.30%)	228 / 520 (43.85%)
number of deaths (all causes)	300	314
number of deaths resulting from adverse events	67	82
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	4 / 517 (0.77%)	3 / 520 (0.58%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant ascites
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Malignant pleural effusion
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	3 / 517 (0.58%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Metastases to lung
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to lymph nodes
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to spleen
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastatic pain
subjects affected / exposed	3 / 517 (0.58%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Neoplasm malignant
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neoplasm progression
subjects affected / exposed	1 / 517 (0.19%)	2 / 520 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Paraneoplastic syndrome
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord neoplasm
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour compression
subjects affected / exposed	1 / 517 (0.19%)	2 / 520 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Tumour pain
subjects affected / exposed	1 / 517 (0.19%)	4 / 520 (0.77%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Aortic aneurysm
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	2 / 517 (0.39%)	4 / 520 (0.77%)
occurrences causally related to treatment / all	0 / 2	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism arterial
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 517 (0.00%)	2 / 520 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Jugular vein thrombosis
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Phlebitis
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Shock
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Superior vena caval occlusion
subjects affected / exposed	3 / 517 (0.58%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Venous insufficiency
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	5 / 517 (0.97%)	3 / 520 (0.58%)
occurrences causally related to treatment / all	0 / 5	1 / 3
deaths causally related to treatment / all	0 / 3	0 / 1
Fatigue
subjects affected / exposed	2 / 517 (0.39%)	4 / 520 (0.77%)
occurrences causally related to treatment / all	1 / 2	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	13 / 517 (2.51%)	16 / 520 (3.08%)
occurrences causally related to treatment / all	0 / 13	0 / 16
deaths causally related to treatment / all	0 / 7	0 / 10
Malaise
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Multi-organ disorder
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	2 / 517 (0.39%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0
Non-cardiac chest pain
subjects affected / exposed	3 / 517 (0.58%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 517 (0.00%)	3 / 520 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2
Performance status decreased
subjects affected / exposed	3 / 517 (0.58%)	5 / 520 (0.96%)
occurrences causally related to treatment / all	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 3	0 / 3
Pyrexia
subjects affected / exposed	5 / 517 (0.97%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Sudden death
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute lung injury
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 517 (0.00%)	3 / 520 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchial obstruction
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Bronchospasm
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	4 / 517 (0.77%)	4 / 520 (0.77%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Cough
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diffuse alveolar damage
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Dyspnoea
subjects affected / exposed	24 / 517 (4.64%)	28 / 520 (5.38%)
occurrences causally related to treatment / all	2 / 24	0 / 28
deaths causally related to treatment / all	0 / 8	0 / 11
Dyspnoea exertional
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	4 / 517 (0.77%)	4 / 520 (0.77%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 2	0 / 2
Hypoxia
subjects affected / exposed	0 / 517 (0.00%)	3 / 520 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2
Lung disorder
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mediastinal disorder
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Orthopnoea
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	9 / 517 (1.74%)	13 / 520 (2.50%)
occurrences causally related to treatment / all	0 / 9	0 / 13
deaths causally related to treatment / all	0 / 0	0 / 1
Pleurisy
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumomediastinum
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	2 / 517 (0.39%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 517 (0.00%)	5 / 520 (0.96%)
occurrences causally related to treatment / all	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 1
Productive cough
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	20 / 517 (3.87%)	17 / 520 (3.27%)
occurrences causally related to treatment / all	4 / 20	2 / 17
deaths causally related to treatment / all	0 / 4	0 / 4
Pulmonary haemorrhage
subjects affected / exposed	0 / 517 (0.00%)	2 / 520 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory arrest
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory failure
subjects affected / exposed	9 / 517 (1.74%)	12 / 520 (2.31%)
occurrences causally related to treatment / all	1 / 9	1 / 12
deaths causally related to treatment / all	0 / 8	1 / 8
Tracheal stenosis
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Confusional state
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mental disorder due to a general medical condition
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 517 (0.00%)	3 / 520 (0.58%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Blood lactate dehydrogenase increased
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood magnesium decreased
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coagulation test abnormal
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General physical condition abnormal
subjects affected / exposed	2 / 517 (0.39%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	0 / 517 (0.00%)	3 / 520 (0.58%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	0 / 517 (0.00%)	2 / 520 (0.38%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
White blood cell count increased
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Collapse of lung
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug toxicity
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 517 (0.00%)	2 / 520 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sternal fracture
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Arrhythmia supraventricular
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	2 / 517 (0.39%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac failure
subjects affected / exposed	3 / 517 (0.58%)	2 / 520 (0.38%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 1
Cardiac tamponade
subjects affected / exposed	2 / 517 (0.39%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	2 / 517 (0.39%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 2	1 / 1
Cardiopulmonary failure
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pericardial effusion
subjects affected / exposed	1 / 517 (0.19%)	3 / 520 (0.58%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
Pericardial haemorrhage
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericarditis constrictive
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Aphasia
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Balance disorder
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Brain compression
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Brain oedema
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Brain stem infarction
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	4 / 517 (0.77%)	3 / 520 (0.58%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 2	0 / 1
Coma
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Convulsion
subjects affected / exposed	5 / 517 (0.97%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Demyelination
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	2 / 517 (0.39%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 517 (0.00%)	2 / 520 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Epiduritis
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Headache
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	1 / 517 (0.19%)	2 / 520 (0.38%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hemiplegia
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intracranial pressure increased
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	2 / 517 (0.39%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neurological decompensation
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neurological symptom
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Post herpetic neuralgia
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychomotor hyperactivity
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Somnolence
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	7 / 517 (1.35%)	16 / 520 (3.08%)
occurrences causally related to treatment / all	2 / 7	11 / 16
deaths causally related to treatment / all	0 / 1	0 / 0
Febrile bone marrow aplasia
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	2 / 517 (0.39%)	15 / 520 (2.88%)
occurrences causally related to treatment / all	0 / 2	11 / 15
deaths causally related to treatment / all	0 / 0	0 / 0
Idiopathic thrombocytopenic purpura
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Leukocytosis
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	0 / 517 (0.00%)	2 / 520 (0.38%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	1 / 2
Lymphadenopathy
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 517 (0.19%)	12 / 520 (2.31%)
occurrences causally related to treatment / all	0 / 1	12 / 12
deaths causally related to treatment / all	0 / 0	1 / 1
Pancytopenia
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 517 (0.00%)	3 / 520 (0.58%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (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
subjects affected / exposed	2 / 517 (0.39%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Abdominal pain lower
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colonic obstruction
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 517 (0.00%)	4 / 520 (0.77%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	7 / 517 (1.35%)	4 / 520 (0.77%)
occurrences causally related to treatment / all	2 / 7	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal perforation
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	2 / 517 (0.39%)	3 / 520 (0.58%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Gastric ulcer
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Intestinal infarction
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Intestinal obstruction
subjects affected / exposed	2 / 517 (0.39%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	6 / 517 (1.16%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	2 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal disorder
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal stenosis
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pancreatitis
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Periodontal disease
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Vomiting
subjects affected / exposed	5 / 517 (0.97%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	3 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hepatic function abnormal
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Skin and subcutaneous tissue disorders
Nail toxicity
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	2 / 517 (0.39%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous nodule
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute prerenal failure
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oliguria
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	2 / 517 (0.39%)	3 / 520 (0.58%)
occurrences causally related to treatment / all	1 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	3 / 517 (0.58%)	5 / 520 (0.96%)
occurrences causally related to treatment / all	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 1
Bone pain
subjects affected / exposed	2 / 517 (0.39%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	3 / 517 (0.58%)	2 / 520 (0.38%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Neck pain
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteolysis
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	0 / 517 (0.00%)	2 / 520 (0.38%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Bacteraemia
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	5 / 517 (0.97%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 5	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Bronchopneumonia
subjects affected / exposed	2 / 517 (0.39%)	3 / 520 (0.58%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 2	0 / 1
Cystitis
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Empyema
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Escherichia infection
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Genital infection
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes virus infection
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	4 / 517 (0.77%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Perirectal abscess
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	13 / 517 (2.51%)	22 / 520 (4.23%)
occurrences causally related to treatment / all	1 / 13	2 / 22
deaths causally related to treatment / all	1 / 3	1 / 3
Pyelonephritis acute
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyothorax
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	3 / 517 (0.58%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 517 (0.39%)	6 / 520 (1.15%)
occurrences causally related to treatment / all	1 / 2	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 4
Septic shock
subjects affected / exposed	1 / 517 (0.19%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Skin infection
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	3 / 517 (0.58%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 517 (0.19%)	0 / 520 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	7 / 517 (1.35%)	2 / 520 (0.38%)
occurrences causally related to treatment / all	2 / 7	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Dehydration
subjects affected / exposed	4 / 517 (0.77%)	5 / 520 (0.96%)
occurrences causally related to treatment / all	1 / 4	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hypercalcaemia
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 517 (0.00%)	1 / 520 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 517 (0.00%)	2 / 520 (0.38%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Erlotinib plus placebo	Erlotinib plus tivantinib
Total subjects affected by non serious adverse events
subjects affected / exposed	496 / 517 (95.94%)	505 / 520 (97.12%)
Investigations
Weight decreased
subjects affected / exposed	59 / 517 (11.41%)	59 / 520 (11.35%)
occurrences all number	59	59
Nervous system disorders
Headache
subjects affected / exposed	29 / 517 (5.61%)	43 / 520 (8.27%)
occurrences all number	29	43
General disorders and administration site conditions
Fatigue
subjects affected / exposed	113 / 517 (21.86%)	139 / 520 (26.73%)
occurrences all number	113	139
Asthenia
subjects affected / exposed	91 / 517 (17.60%)	101 / 520 (19.42%)
occurrences all number	91	101
Pyrexia
subjects affected / exposed	41 / 517 (7.93%)	62 / 520 (11.92%)
occurrences all number	41	62
Oedema peripheral
subjects affected / exposed	30 / 517 (5.80%)	40 / 520 (7.69%)
occurrences all number	30	40
Non-cardiac chest pain
subjects affected / exposed	23 / 517 (4.45%)	35 / 520 (6.73%)
occurrences all number	23	35
Mucosal inflammation
subjects affected / exposed	24 / 517 (4.64%)	29 / 520 (5.58%)
occurrences all number	24	29
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	48 / 517 (9.28%)	78 / 520 (15.00%)
occurrences all number	48	78
Neutropenia
subjects affected / exposed	11 / 517 (2.13%)	57 / 520 (10.96%)
occurrences all number	11	57
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	215 / 517 (41.59%)	181 / 520 (34.81%)
occurrences all number	215	181
Nausea
subjects affected / exposed	123 / 517 (23.79%)	123 / 520 (23.65%)
occurrences all number	123	123
Vomiting
subjects affected / exposed	81 / 517 (15.67%)	77 / 520 (14.81%)
occurrences all number	81	77
Constipation
subjects affected / exposed	54 / 517 (10.44%)	58 / 520 (11.15%)
occurrences all number	54	58
Abdominal pain
subjects affected / exposed	26 / 517 (5.03%)	35 / 520 (6.73%)
occurrences all number	26	35
Dyspepsia
subjects affected / exposed	24 / 517 (4.64%)	31 / 520 (5.96%)
occurrences all number	24	31
Abdominal pain upper
subjects affected / exposed	19 / 517 (3.68%)	33 / 520 (6.35%)
occurrences all number	19	33
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	102 / 517 (19.73%)	128 / 520 (24.62%)
occurrences all number	102	128
Cough
subjects affected / exposed	95 / 517 (18.38%)	115 / 520 (22.12%)
occurrences all number	95	115
Haemoptysis
subjects affected / exposed	15 / 517 (2.90%)	30 / 520 (5.77%)
occurrences all number	15	30
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	193 / 517 (37.33%)	173 / 520 (33.27%)
occurrences all number	193	173
Dermatitis acneiform
subjects affected / exposed	98 / 517 (18.96%)	91 / 520 (17.50%)
occurrences all number	98	91
Dry skin
subjects affected / exposed	57 / 517 (11.03%)	42 / 520 (8.08%)
occurrences all number	57	42
Pruritus
subjects affected / exposed	45 / 517 (8.70%)	32 / 520 (6.15%)
occurrences all number	45	32
Alopecia
subjects affected / exposed	14 / 517 (2.71%)	27 / 520 (5.19%)
occurrences all number	14	27
Psychiatric disorders
Insomnia
subjects affected / exposed	29 / 517 (5.61%)	34 / 520 (6.54%)
occurrences all number	29	34
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	47 / 517 (9.09%)	55 / 520 (10.58%)
occurrences all number	47	55
Pain in extremity
subjects affected / exposed	19 / 517 (3.68%)	31 / 520 (5.96%)
occurrences all number	19	31
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	149 / 517 (28.82%)	152 / 520 (29.23%)
occurrences all number	149	152

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

20 Oct 2010

- Revised to require prior platinum-doublet therapy, and clarify eligibility requirements for subjects with prior adjuvant or maintenance therapy - Specified that subjects who experienced ≥ Grade 3 neutropenia were to be monitored closely throughout study and offered hematopoietic growth factor therapy as per ASCO guidelines. Also, increased frequency of ANC monitoring for Cycles 3+ from every 4 weeks to every 2 weeks for all subjects, not only those receiving CYP 2C19 or CYP 3A4 inhibitors. - Added precaution for potential of concomitant medications altering gastric pH to affect erlotinib absorption - Added fluconazole, ticlopidine, rabeprazole, and fluoxetine to list of example CYP 2C19 inhibitors to be used with caution concomitantly - Clarified that AEs recorded at Screening visit were to include only those AEs occurring after consent was signed - Removed qualification “if not restricted by local regulation” to require collection of pharmacogenomic data at all sites - Modified language to specify that hematology testing would be performed for all subjects every 2 weeks rather than every 4 weeks in Cycle 3 and beyond - Removed limit of precaution to only “strong” CYP 2C19 inhibitors, but clarified limit to precaution for only strong inhibitors of CYP 3A4 - Specified requirement for biomarker testing for tumor MET, EGFR, and KRAS for all subjects, as well as testing for pre- and posttreatment circulating HGF - Added language specifying data sets and analyses for pharmacogenomic data and PK–pharmacodynamic analyses

01 Jun 2011

- Added exception for enrollment of subjects with ≤ Grade 2 neuropathy - Reduced window for prior surgical procedure, prior systemic anti-tumor therapy, and prior radiotherapy from 4 weeks to 3 weeks - Clarified description of exploratory objectives, endpoints, and analyses with regard to MET status as determined by IHC and FISH. Specifically, the exploratory analysis for evaluating OS and PFS by MET/MET was to be performed using both IHC and FISH analytical methods instead of FISH method only. - Clarified that either archival or fresh tissue biopsy samples would qualify for study eligibility; documented EGFR and KRAS status must have been from an accredited lab; specified that tissue must be provided to central laboratories for MET analysis even if EGFR, KRAS results were obtained locally - Noted that EGFR status was required for study eligibility; in the absence of confirmation of a subject’s KRAS status, the subject was to be categorized as “indeterminate” for KRAS - Added exception to the prohibition of highdose corticosteroids for short-term treatment of COPD or other inflammation exacerbation

28 Nov 2012

- Revised text to indicate that only subjects with EGFR-mutant disease would be included in survival followup evaluations - Revised text to indicate that study closure was to be defined as the final subject visit/contact rather than when the pre-specified 735 deaths have occurred The interim results for this study met the protocol-defined stopping boundary for futility based on overall survival (OS). After reviewing the interim analysis, the data management committee (DMC) concluded that the study would not meet its primary endpoint of improved OS in the intent to treat (ITT) population, and therefore recommended that the study be stopped early. However, the DMC noted that there was no unexpected safety concern requiring immediate treatment discontinuation, and there was a trend toward improvement in progression free survival (PFS) in the ITT population at the interim analysis. Based upon this result, the data were cut on 15 Dec 2012 for the main study analyses included in the original CSR. Patients receiving clinical benefit were allowed to continue. At the time of the data-cut for the main study analyses, the results for EGFR mutant subgroup, which responds well to erlotinib therapy, were not mature. The clinical trial protocol was amended to allow these subjects to continue with follow-up assessments in order to provide mature results for this subgroup. The results posted herein incorporate the tables, figures, and listings for the pre-specified data-cut (Nov 2014) for the EGFR mutant subgroup. This clinical study has now been completed and the full database is locked. This record also includes the isolated EGFR mutant data that were collected during the study.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

For support, Contact us.

The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

European Medicines Agency © 1995-Thu Apr 25 17:39:53 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands