Clinical Trial Results:
A Phase III Randomised, Double blind, Placebo controlled, Parallel, Multicentre Study to Assess the Efficacy and Safety of continuing IRESSATM 250 mg in addition to Chemotherapy versus Chemotherapy alone in Patients who have Epidermal Growth Factor Receptor (EGFR) Mutation Positive Locally advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) and have progressed on First Line IRESSATM.

Trial information Top of page
Trial identification
Sponsor protocol code	D791LC00001
Additional study identifiers
ISRCTN number	-
US NCT number	-
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	AstraZeneca
Sponsor organisation address	One Medimmune Way, 101 ORD, 2233C, Gaithersburg, MD 20878, United States, 20878
Public contact	Haiyi Jiang/Asia Medical Director, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
Scientific contact	Yuri Rukazenkov, AstraZeneca, +44 01625231825, ClinicalTrialTransparency@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	16 Nov 2015
Is this the analysis of the primary completion data?	No
Global end of trial reached?	Yes
Global end of trial date	20 Nov 2019
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To evaluate Progression Free Survival (PFS) in patients who have acquired resistance to first line gefitinib, comparing continuing gefitinib in addition to cisplatin plus pemetrexed combination chemotherapy versus cisplatin plus pemetrexed combination chemotherapy alone.
Protection of trial subjects	Following documentation of progression, patients were due to enter survival follow-up. The final OS analysis was planned for when 175 deaths had occurred.
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	15 Mar 2012
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	Yes
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	China: 118
Country: Number of subjects enrolled	Germany: 6
Country: Number of subjects enrolled	Spain: 22
Country: Number of subjects enrolled	France: 9
Country: Number of subjects enrolled	Hong Kong: 5
Country: Number of subjects enrolled	Hungary: 4
Country: Number of subjects enrolled	Italy: 16
Country: Number of subjects enrolled	Japan: 23
Country: Number of subjects enrolled	Korea, Democratic People's Republic of: 42
Country: Number of subjects enrolled	Russian Federation: 2
Country: Number of subjects enrolled	Taiwan: 18
Worldwide total number of subjects	265
EEA total number of subjects	57
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)	188
From 65 to 84 years	77
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	A total of 265 (100%) patients randomised were from 61 centres in 11 countries: 133 patients to the gefitinib group and132 patients to the placebo group. Patients received maximum of 6 cycles cisplatin plus pemetrexed chemotherapy in addition to the randomised treatment (gefitinib or placebo).
Pre-assignment
Screening details	A total of 287 patients were enrolled, however only 265 patients were randomised. Randomised patients had epidermal growth factor receptor (EGFR) mutation-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) and who had progressed on first-line gefitinib treatment
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	Subject, Investigator, Monitor, Data analyst, Carer, Assessor
Arms
Are arms mutually exclusive	Yes
Arm title	Gefitinib
Arm description	Gefitinib 250mg and cisplatin plus pemetrexed combination chemotherapy
Arm type	Experimental
Investigational medicinal product name	Gefitinib
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	250mg
Arm title	Placebo
Arm description	Placebo and cisplatin plus pemetrexed combination chemotherapy.
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	0mg
Number of subjects in period 1 Gefitinib Placebo Started 133 132 Received treatment 132 132 Completed 26 38 Not completed 107 94      Consent withdrawn by subject 12 10      Adverse event, non-fatal - 1      Death 94 82      Did not receive treatment 1 -      Lost to follow-up - 1

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Gefitinib
Reporting group description	Gefitinib 250mg and cisplatin plus pemetrexed combination chemotherapy
Reporting group title	Placebo
Reporting group description	Placebo and cisplatin plus pemetrexed combination chemotherapy.
Reporting group values Gefitinib Placebo Total Number of subjects 133 132 265 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) 90 98 188     From 65-84 years 43 34 77     85 years and over 0 0 0 Age continuous Units: years     arithmetic mean (standard deviation) 59.3 ( 10.63 ) 57.0 ( 11.25 ) - Gender, Male/Female Units: Participants     Female 87 84 171     Male 46 48 94 Age, Customized Units: Subjects     <65 years 90 98 188     >=65 years 43 34 77 Race/Ethnicity, Customized Units: Subjects     Asian 104 102 206     Black or African American 0 1 1     White 29 29 58

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Gefitinib
Reporting group description	Gefitinib 250mg and cisplatin plus pemetrexed combination chemotherapy
Reporting group title	Placebo
Reporting group description	Placebo and cisplatin plus pemetrexed combination chemotherapy.

End points Top of page

Primary: Overall survival (OS) at the time of overall survival analysis Top of page
End point title	Overall survival (OS) at the time of overall survival analysis
End point description	OS is the time from the date of randomisation until death due to any cause. Any subject not known to have died at the time of analysis will be censored based on the last recorded date on which the subject was known to be alive.
End point type	Primary
End point timeframe	Following progression survival data was collected every 8 weeks until documentation of death, withdrawal of consent, loss to follow-up or the final data cut-off, whichever occurs first.
End point values Gefitinib Placebo Number of subjects analysed 133 132 Units: Number of patients with an OS event 94 82
Statistical analysis title	Overall survival (OS)
Comparison groups	Gefitinib v Placebo
Number of subjects included in analysis	265
Analysis specification	Pre-specified
Analysis type
P-value	= 0.016
Method	Cox Proportional Hazards
Parameter type	Hazard ratio (HR)
Point estimate	1.44
Confidence interval
level	95%
sides	2-sided
lower limit	1.07
upper limit	1.94

Primary: Overall survival (OS) at the time of overall survival analysis Top of page

Secondary: Median overall survival (OS) at time of overall survival analysis Top of page
End point title	Median overall survival (OS) at time of overall survival analysis
End point description	OS is the time from the date of randomisation until death due to any cause. Any subject not known to have died at the time of analysis will be censored based on the last recorded date on which the subject was known to be alive.
End point type	Secondary
End point timeframe	Following progression survival data was collected every 8 weeks until documentation of death, withdrawal of consent, loss to follow-up or the final data cut-off, whichever occurs first.
End point values Gefitinib Placebo Number of subjects analysed 133 132 Units: Months     median (confidence interval 95%) 13.4 (10.7 to 18.0) 19.5 (15.6 to 21.7)
No statistical analyses for this end point

Secondary: Median overall survival (OS) at time of overall survival analysis Top of page

Secondary: Overall survival (OS) at 9 months Top of page
End point title	Overall survival (OS) at 9 months
End point description	OS is the time from the date of randomisation until death due to any cause. Any subject not known to have died at the time of analysis will be censored based on the last recorded date on which the subject was known to be alive.
End point type	Secondary
End point timeframe	Following progression survival data was collected every 8 weeks until documentation of death, withdrawal of consent, loss to follow-up or the final data cut-off, whichever occurs first.
End point values Gefitinib Placebo Number of subjects analysed 133 132 Units: Percentage     number (confidence interval 95%) 66.7 (57.5 to 74.2) 79.4 (71.3 to 85.5)
No statistical analyses for this end point

Secondary: Overall survival (OS) at 9 months Top of page

Secondary: Overall survival (OS) at 12 months Top of page
End point title	Overall survival (OS) at 12 months
End point description	OS is the time from the date of randomisation until death due to any cause. Any subject not known to have died at the time of analysis will be censored based on the last recorded date on which the subject was known to be alive.
End point type	Secondary
End point timeframe	Following progression survival data was collected every 8 weeks until documentation of death, withdrawal of consent, loss to follow-up or the final data cut-off, whichever occurs first.
End point values Gefitinib Placebo Number of subjects analysed 133 132 Units: Percentage     number (confidence interval 95%) 54.1 (44.8 to 62.5) 68.8 (59.9 to 76.2)
No statistical analyses for this end point

Secondary: Overall survival (OS) at 12 months Top of page

Secondary: Overall survival (OS) at 18 months Top of page
End point title	Overall survival (OS) at 18 months
End point description	OS is the time from the date of randomisation until death due to any cause. Any subject not known to have died at the time of analysis will be censored based on the last recorded date on which the subject was known to be alive.
End point type	Secondary
End point timeframe	Following progression survival data was collected every 8 weeks until documentation of death, withdrawal of consent, loss to follow-up or the final data cut-off, whichever occurs first.
End point values Gefitinib Placebo Number of subjects analysed 133 132 Units: Percentage     number (confidence interval 95%) 41.2 (32.3 to 49.9) 52.9 (43.6 to 61.3)
No statistical analyses for this end point

Secondary: Overall survival (OS) at 18 months Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	From first dose of study drug until last study visit
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	18
Reporting groups
Reporting group title	Gefitinib 250 mg
Reporting group description	-
Reporting group title	Placebo
Reporting group description	-
Serious adverse events Gefitinib 250 mg Placebo Total subjects affected by serious adverse events      subjects affected / exposed 38 / 132 (28.79%) 28 / 132 (21.21%)      number of deaths (all causes) 94 82      number of deaths resulting from adverse events 1 0 Vascular disorders Circulatory collapse alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Embolism alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Orthostatic hypotension alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Peripheral artery stenosis alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Vena cava thrombosis alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Venous thrombosis limb alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (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 Multi-organ failure alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 1 Pyrexia alternative dictionary used: MedDRA 18      subjects affected / exposed 2 / 132 (1.52%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 2 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Immune system disorders Anaphylactic shock alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      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 Asthma alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Dyspnoea alternative dictionary used: MedDRA 18      subjects affected / exposed 4 / 132 (3.03%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 4 0 / 1      deaths causally related to treatment / all 0 / 1 0 / 1 Haemoptysis alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 1 Haemothorax alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Pleural effusion alternative dictionary used: MedDRA 18      subjects affected / exposed 2 / 132 (1.52%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Respiratory failure alternative dictionary used: MedDRA 18      subjects affected / exposed 3 / 132 (2.27%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 3 0 / 1      deaths causally related to treatment / all 0 / 3 0 / 0 Psychiatric disorders Delirium alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (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 Craniocerebral injury alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Fall alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Thermal burn alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Cardiac disorders Cardiac failure alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 1 Myocardial infarction alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Pericardial effusion alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Wolff-Parkinson-White syndrome alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Nervous system disorders Aphasia alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Cerebral infarction alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 1 Cerebral ischaemia alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Cerebrovascular accident alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 1 Cognitive disorder alternative dictionary used: MedDRA 18      subjects affected / exposed 2 / 132 (1.52%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Epilepsy alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Haemorrhage intracranial alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Headache alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Loss of consciousness alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Seizure alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      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 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      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 alternative dictionary used: MedDRA 18      subjects affected / exposed 2 / 132 (1.52%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 2 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Bone marrow failure alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Febrile bone marrow aplasia alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Gastrointestinal disorders Abdominal discomfort alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Abdominal pain upper alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Diarrhoea alternative dictionary used: MedDRA 18      subjects affected / exposed 2 / 132 (1.52%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 1 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Dysphagia alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (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 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Gastric perforation alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 1 Gastrointestinal disorder alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Nausea alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 2 / 132 (1.52%)      occurrences causally related to treatment / all 0 / 1 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 Vomiting alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Renal and urinary disorders Acute kidney injury alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Nephrolithiasis alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Renal failure alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Endocrine disorders Inappropriate antidiuretic hormone secretion alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Musculoskeletal and connective tissue disorders Back pain alternative dictionary used: MedDRA 18      subjects affected / exposed 2 / 132 (1.52%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Joint swelling alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Muscular weakness alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Musculoskeletal pain alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Osteonecrosis alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (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 alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (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 Anal abscess alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Bronchitis alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Cellulitis alternative dictionary used: MedDRA 18      subjects affected / exposed 2 / 132 (1.52%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 1 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Lung infection alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Paronychia alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Pneumonia alternative dictionary used: MedDRA 18      subjects affected / exposed 4 / 132 (3.03%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 1 / 5 0 / 1      deaths causally related to treatment / all 1 / 1 0 / 1 Urinary tract infection alternative dictionary used: MedDRA 18      subjects affected / exposed 2 / 132 (1.52%) 0 / 132 (0.00%)      occurrences causally related to treatment / all 0 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Metabolism and nutrition disorders Decreased appetite alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 1 / 132 (0.76%)      occurrences causally related to treatment / all 0 / 1 0 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Hypokalaemia alternative dictionary used: MedDRA 18      subjects affected / exposed 0 / 132 (0.00%) 2 / 132 (1.52%)      occurrences causally related to treatment / all 0 / 0 0 / 2      deaths causally related to treatment / all 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Gefitinib 250 mg Placebo Total subjects affected by non serious adverse events      subjects affected / exposed 125 / 132 (94.70%) 127 / 132 (96.21%) Investigations Alanine aminotransferase increased alternative dictionary used: MedDRA 18      subjects affected / exposed 5 / 132 (3.79%) 11 / 132 (8.33%)      occurrences all number 5 17 Aspartate aminotransferase increased alternative dictionary used: MedDRA 18      subjects affected / exposed 8 / 132 (6.06%) 10 / 132 (7.58%)      occurrences all number 10 16 Blood creatinine increased alternative dictionary used: MedDRA 18      subjects affected / exposed 12 / 132 (9.09%) 12 / 132 (9.09%)      occurrences all number 14 17 Haemoglobin decreased alternative dictionary used: MedDRA 18      subjects affected / exposed 8 / 132 (6.06%) 4 / 132 (3.03%)      occurrences all number 10 5 Neutrophil count decreased alternative dictionary used: MedDRA 18      subjects affected / exposed 16 / 132 (12.12%) 22 / 132 (16.67%)      occurrences all number 31 47 Platelet count decreased alternative dictionary used: MedDRA 18      subjects affected / exposed 9 / 132 (6.82%) 3 / 132 (2.27%)      occurrences all number 15 6 White blood cell count decreased alternative dictionary used: MedDRA 18      subjects affected / exposed 17 / 132 (12.88%) 13 / 132 (9.85%)      occurrences all number 38 24 Nervous system disorders Dizziness alternative dictionary used: MedDRA 18      subjects affected / exposed 9 / 132 (6.82%) 6 / 132 (4.55%)      occurrences all number 9 6 Dysgeusia alternative dictionary used: MedDRA 18      subjects affected / exposed 3 / 132 (2.27%) 7 / 132 (5.30%)      occurrences all number 3 10 Headache alternative dictionary used: MedDRA 18      subjects affected / exposed 11 / 132 (8.33%) 18 / 132 (13.64%)      occurrences all number 14 24 Paraesthesia alternative dictionary used: MedDRA 18      subjects affected / exposed 5 / 132 (3.79%) 7 / 132 (5.30%)      occurrences all number 6 8 Peripheral sensory neuropathy alternative dictionary used: MedDRA 18      subjects affected / exposed 9 / 132 (6.82%) 10 / 132 (7.58%)      occurrences all number 12 12 Blood and lymphatic system disorders Anaemia alternative dictionary used: MedDRA 18      subjects affected / exposed 40 / 132 (30.30%) 32 / 132 (24.24%)      occurrences all number 56 40 Bone marrow failure alternative dictionary used: MedDRA 18      subjects affected / exposed 4 / 132 (3.03%) 8 / 132 (6.06%)      occurrences all number 7 21 Leukopenia alternative dictionary used: MedDRA 18      subjects affected / exposed 27 / 132 (20.45%) 22 / 132 (16.67%)      occurrences all number 61 53 Neutropenia alternative dictionary used: MedDRA 18      subjects affected / exposed 29 / 132 (21.97%) 28 / 132 (21.21%)      occurrences all number 59 69 Thrombocytopenia alternative dictionary used: MedDRA 18      subjects affected / exposed 7 / 132 (5.30%) 9 / 132 (6.82%)      occurrences all number 11 11 General disorders and administration site conditions Asthenia alternative dictionary used: MedDRA 18      subjects affected / exposed 15 / 132 (11.36%) 30 / 132 (22.73%)      occurrences all number 27 43 Fatigue alternative dictionary used: MedDRA 18      subjects affected / exposed 28 / 132 (21.21%) 23 / 132 (17.42%)      occurrences all number 37 31 Malaise alternative dictionary used: MedDRA 18      subjects affected / exposed 10 / 132 (7.58%) 9 / 132 (6.82%)      occurrences all number 10 15 Pyrexia alternative dictionary used: MedDRA 18      subjects affected / exposed 21 / 132 (15.91%) 14 / 132 (10.61%)      occurrences all number 24 15 Gastrointestinal disorders Abdominal pain alternative dictionary used: MedDRA 18      subjects affected / exposed 7 / 132 (5.30%) 4 / 132 (3.03%)      occurrences all number 7 4 Abdominal pain upper alternative dictionary used: MedDRA 18      subjects affected / exposed 12 / 132 (9.09%) 13 / 132 (9.85%)      occurrences all number 16 16 Constipation alternative dictionary used: MedDRA 18      subjects affected / exposed 34 / 132 (25.76%) 35 / 132 (26.52%)      occurrences all number 58 56 Diarrhoea alternative dictionary used: MedDRA 18      subjects affected / exposed 43 / 132 (32.58%) 19 / 132 (14.39%)      occurrences all number 71 22 Nausea alternative dictionary used: MedDRA 18      subjects affected / exposed 84 / 132 (63.64%) 80 / 132 (60.61%)      occurrences all number 180 160 Stomatitis alternative dictionary used: MedDRA 18      subjects affected / exposed 14 / 132 (10.61%) 5 / 132 (3.79%)      occurrences all number 15 8 Vomiting alternative dictionary used: MedDRA 18      subjects affected / exposed 54 / 132 (40.91%) 43 / 132 (32.58%)      occurrences all number 96 75 Respiratory, thoracic and mediastinal disorders Cough alternative dictionary used: MedDRA 18      subjects affected / exposed 20 / 132 (15.15%) 15 / 132 (11.36%)      occurrences all number 23 18 Dyspnoea alternative dictionary used: MedDRA 18      subjects affected / exposed 12 / 132 (9.09%) 9 / 132 (6.82%)      occurrences all number 13 10 Hiccups alternative dictionary used: MedDRA 18      subjects affected / exposed 7 / 132 (5.30%) 7 / 132 (5.30%)      occurrences all number 11 10 Productive cough alternative dictionary used: MedDRA 18      subjects affected / exposed 10 / 132 (7.58%) 10 / 132 (7.58%)      occurrences all number 10 11 Skin and subcutaneous tissue disorders Alopecia alternative dictionary used: MedDRA 18      subjects affected / exposed 9 / 132 (6.82%) 5 / 132 (3.79%)      occurrences all number 9 5 Dermatitis acneiform alternative dictionary used: MedDRA 18      subjects affected / exposed 8 / 132 (6.06%) 4 / 132 (3.03%)      occurrences all number 11 4 Dry skin alternative dictionary used: MedDRA 18      subjects affected / exposed 12 / 132 (9.09%) 8 / 132 (6.06%)      occurrences all number 12 8 Pruritus alternative dictionary used: MedDRA 18      subjects affected / exposed 8 / 132 (6.06%) 7 / 132 (5.30%)      occurrences all number 9 8 Rash alternative dictionary used: MedDRA 18      subjects affected / exposed 15 / 132 (11.36%) 11 / 132 (8.33%)      occurrences all number 20 12 Psychiatric disorders Insomnia alternative dictionary used: MedDRA 18      subjects affected / exposed 10 / 132 (7.58%) 7 / 132 (5.30%)      occurrences all number 12 7 Musculoskeletal and connective tissue disorders Arthralgia alternative dictionary used: MedDRA 18      subjects affected / exposed 8 / 132 (6.06%) 7 / 132 (5.30%)      occurrences all number 9 9 Back pain alternative dictionary used: MedDRA 18      subjects affected / exposed 11 / 132 (8.33%) 14 / 132 (10.61%)      occurrences all number 11 15 Musculoskeletal chest pain alternative dictionary used: MedDRA 18      subjects affected / exposed 8 / 132 (6.06%) 2 / 132 (1.52%)      occurrences all number 10 2 Myalgia alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 9 / 132 (6.82%)      occurrences all number 1 15 Infections and infestations Conjunctivitis alternative dictionary used: MedDRA 18      subjects affected / exposed 1 / 132 (0.76%) 8 / 132 (6.06%)      occurrences all number 1 8 Nasopharyngitis alternative dictionary used: MedDRA 18      subjects affected / exposed 5 / 132 (3.79%) 8 / 132 (6.06%)      occurrences all number 7 9 Metabolism and nutrition disorders Decreased appetite alternative dictionary used: MedDRA 18      subjects affected / exposed 64 / 132 (48.48%) 45 / 132 (34.09%)      occurrences all number 92 74 Hypocalcaemia alternative dictionary used: MedDRA 18      subjects affected / exposed 8 / 132 (6.06%) 2 / 132 (1.52%)      occurrences all number 9 2 Hypokalaemia alternative dictionary used: MedDRA 18      subjects affected / exposed 13 / 132 (9.85%) 5 / 132 (3.79%)      occurrences all number 21 9 Hyponatraemia alternative dictionary used: MedDRA 18      subjects affected / exposed 11 / 132 (8.33%) 3 / 132 (2.27%)      occurrences all number 17 3

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Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
05 Apr 2012	Amendment1: Measures to identify Hy’s law events. Exclusion criteria updated: exclusion of breast feeding, clarity on birth control.
27 Jul 2012	Amendment 2: To provide better clarity on definition of the end of the study
08 Apr 2013	Amendment 3: Update inclusion criteria (prior treatment and concomitant medications) based on the Steering Committee recommendation.
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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