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Clinical Trial Results:
A randomized, double-blind, multi-center phase III study comparing everolimus (RAD001) plus best supportive care versus placebo plus best supportive care in patients with advanced gastric cancer after progression on prior systemic chemotherapy.

Summary
EudraCT number	2008-006544-20
Trial protocol	NL BE DE GB FR IT ES
Global end of trial date	30 Jan 2014

Results information
Results version number	v1(current)
This version publication date	13 Jul 2016
First version publication date	07 Aug 2015
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

CRAD001R2301

ISRCTN number

-

US NCT number

NCT00879333

WHO universal trial number (UTN)

-

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

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 Jan 2014

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

30 Jan 2014

Was the trial ended prematurely?

No

Main objective of the trial

To compare overall survival between everolimus (RAD001)+best supportive care (BSC) and placebo+BSC in patients with advanced gastric cancer after progression on prior systemic chemotherapy.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

-

Evidence for comparator

Best supportive care (BSC) plus placebo was used as the comparator. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.

Actual start date of recruitment

07 Jul 2009

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

Netherlands: 3

Country: Number of subjects enrolled

United Kingdom: 31

Country: Number of subjects enrolled

Belgium: 25

Country: Number of subjects enrolled

France: 43

Country: Number of subjects enrolled

Germany: 25

Country: Number of subjects enrolled

Italy: 24

Country: Number of subjects enrolled

China: 128

Country: Number of subjects enrolled

Hong Kong: 4

Country: Number of subjects enrolled

Japan: 116

Country: Number of subjects enrolled

Korea, Republic of: 77

Country: Number of subjects enrolled

Taiwan: 26

Country: Number of subjects enrolled

Thailand: 11

Country: Number of subjects enrolled

Australia: 54

Country: Number of subjects enrolled

Canada: 19

Country: Number of subjects enrolled

Peru: 11

Country: Number of subjects enrolled

Argentina: 11

Country: Number of subjects enrolled

New Zealand: 3

Country: Number of subjects enrolled

Russian Federation: 9

Country: Number of subjects enrolled

Israel: 9

Country: Number of subjects enrolled

Mexico: 9

Country: Number of subjects enrolled

Colombia: 1

Country: Number of subjects enrolled

United States: 11

Worldwide total number of subjects

656

EEA total number of subjects

157

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)

389

From 65 to 84 years

261

85 years and over

6

Subject disposition

Top of page

Recruitment details

Six hundred and fifty-six patients with advanced gastric cancer (AGC) who had progressed after one or two prior lines of systemic chemotherapy were randomized to receive either everolimus or placebo.

Screening details

Adult patients with histologically or cytologically confirmed AGC which progressed after 1 or 2 prior systemic chemotherapy lines were enrolled in the study, stratified by both number of prior chemotherapy lines for advanced disease (1 line vs 2 lines) and region (Asia vs ROW). Intended samples size was 633, with 656 randomized.

Period 1 title

Overall Trial (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

Are arms mutually exclusive

Yes

Everolimus + BSC

Arm description

All patients were randomized to receive everolimus (RAD001) + best supportive care (BSC). All patients took two 5 mg tablets orally of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

RAD001

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

All patients took two 5 mg tablets of everolimus orally once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg.

Placebo + BSC

Arm description

All patients were randomized to receive placebo + BSC. All patients took two 5 mg tablets orally of matching placebo once daily. Therefore, all patients in the placebo receive matching tablets of total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anticancer treatments.

Arm type

Placebo

Investigational medicinal product name

Matching Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

All patients took two 5 mg tablets of matching placebo orally once daily. Therefore, all patients in the placebo arm received matching tablets of a total daily dose of 10 mg.

Number of subjects in period 1	Everolimus + BSC	Placebo + BSC
Started	439	217
Completed	11	0
Not completed	428	217
Adverse event, serious fatal	16	5
Abnormal Laboratory	1	-
Adverse event, non-fatal	94	34
Withdrawal by Subject	20	7
Administrative Problems	2	-
Protocol Violation	1	1
Lost to follow-up	2	1
Disease Progression	292	169

Baseline characteristics

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Reporting group title

Everolimus + BSC

Reporting group description

All patients were randomized to receive everolimus (RAD001) + best supportive care (BSC). All patients took two 5 mg tablets orally of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.

Reporting group title

Placebo + BSC

Reporting group description

All patients were randomized to receive placebo + BSC. All patients took two 5 mg tablets orally of matching placebo once daily. Therefore, all patients in the placebo receive matching tablets of total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anticancer treatments.

Reporting group values	Everolimus + BSC	Placebo + BSC	Total
Number of subjects	439	217	656
Age categorical
Units: Subjects
< 65 years	260	129	389
>=65 years	179	88	267
Age continuous
The EMA result system autopopulates the “-“ and will not allow the entry of the mean age for the trial, which is 60.4 (standard deviation: 11.59).
Units: years
arithmetic mean (standard deviation)	60.3 ( 11.59 )	60.8 ( 11.61 )	-
Gender categorical
Units: Subjects
Female	117	56	173
Male	322	161	483
Race/Ethnicity
Units: Subjects
Caucasian	166	75	241
Black	3	1	4
Asian	251	126	377
Native American	0	1	1
Other	19	14	33

End points

Top of page

Reporting group title

Everolimus + BSC

Reporting group description

All patients were randomized to receive everolimus (RAD001) + best supportive care (BSC). All patients took two 5 mg tablets orally of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.

Reporting group title

Placebo + BSC

Reporting group description

All patients were randomized to receive placebo + BSC. All patients took two 5 mg tablets orally of matching placebo once daily. Therefore, all patients in the placebo receive matching tablets of total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anticancer treatments.

Primary: Overall Survival

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End point title

Overall Survival

End point description

The primary objective of this study was to compare OS between everolimus + best supportive care (BSC) and placebo + BSC. OS, was defined as the time from date of randomization to the date of death due to any cause. If at the analysis cut-off date a patient was not known to have died, survival was censored at the date of the last contact. OS was analyzed using the Kaplan Meier estimates method. The Full Analysis Set (FAS) was used.

End point type

Primary

End point timeframe

2.5 years

End point values	Everolimus + BSC	Placebo + BSC
Number of subjects analysed	439	217
Units: Months
median (confidence interval 95%)
Median Overall Survival (Months)	5.39 (4.8 to 6.01)	4.34 (3.81 to 5.49)

Analysis of overall survival using K-M and Cox PH

Statistical analysis description

The primary analysis was a comparison of OS between the treatment groups in the FAS. The statistical hypotheses were: H0: SEverolimus(t) = SPlacebo(t) vs H1: SEverolimus(t) > SPlacebo(t), where SEverolimus(t) and SPlacebo(t) are the survival functions in everolimus + BSC and placebo + BSC groups, respectively. The null hypothesis was tested with the one-sided log-rank test using an overall type I error rate of 2.5%. Two-sided 95% CI was estimated from a Cox proportional hazard model.

Comparison groups

Everolimus + BSC v Placebo + BSC

Number of subjects included in analysis

656

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.1244 ^[1]

Method

Kaplan-Meier method and Cox PH model

Confidence interval

Notes
[1] - one-sided stratified log-rank test p-value

Secondary: Progression Free Survival

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End point title

Progression Free Survival

End point description

Progression free survival is defined as time from the date of randomization to the date of the first documented disease progression or death due to any cause where progression was based on Investigator assessment of baseline and post-baseline scans according to RECIST. Progression free survival was censored if no PFS event was observed before the first to occur out of (i) the cut-off date, or (ii) the date when a further anticancer therapy was started. The censoring date was the date of the last adequate tumor assessment before either of these two events occurred. If a PFS event was observed after two or more missing or non-evaluable tumor assessments, then the date of progression was censored at the date of the last adequate tumor assessment; for a PFS event observed after a single missing or non-evaluable tumor assessment, the actual date of disease progression was used. Anslsis was done using Kaplan-Meier estimates method.

End point type

Secondary

End point timeframe

2.5 years

End point values	Everolimus + BSC	Placebo + BSC
Number of subjects analysed	439	217
Units: Months
median (confidence interval 95%)
Progression Free Survival (months)	1.68 (1.51 to 1.94)	1.41 (1.38 to 1.45)

No statistical analyses for this end point

Secondary: Patient Reported Outcome: Time to definitive deterioration of EORTC QLQ-C30 scores

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End point title

Patient Reported Outcome: Time to definitive deterioration of EORTC QLQ-C30 scores

End point description

The EORTC QLQ-C30 global health status/quality of life sub-scale (QL) was pre-specified as the primary domain of interest, followed by physical functioning (PF), social functioning (SF) and emotional functioning (EF). The EORTC QLQ-C30 questionnaire, along with a module specific for gastric cancer patients (EORTC QLQ-STO22), was used to evaluate patient-reported outcome (PRO). The QLQ-C30 has five function scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, pain and nausea/vomiting) and a global health status/quality of life scale. In addition, there are questions that assess specific symptoms. The QLQ-STO22 consists of 22 questions that make up five multi-item scales (dysphagia, pain, reflux, eating and anxiety) and four single-item scales (dry mouth, tasting, body image and hair loss).

End point type

Secondary

End point timeframe

2.5 years

End point values	Everolimus + BSC	Placebo + BSC
Number of subjects analysed	439	217
Units: Months
median (confidence interval 95%)
In QL score by at least 5 %	1.51 (1.28 to 1.84)	1.45 (1.05 to 1.68)
In PF score by at least 5 %	1.35 (1.12 to 1.54)	1.15 (1.02 to 1.64)
In SF score by at least 5 %	1.87 (1.84 to 2.3)	1.87 (1.64 to 2.46)
In EF score by at least 5 %	1.84 (1.61 to 2.1)	1.71 (1.41 to 1.87)

No statistical analyses for this end point

Secondary: Time to definitive deterioration of Eastern Cooperative Oncology Group Performance Status

Top of page

End point title

Time to definitive deterioration of Eastern Cooperative Oncology Group Performance Status

End point description

The ECOG PS scale was used to classify patients according to their functional impairment, with scores ranging from 0 (fully active) to 5 (dead). An analysis of the time to definitive deterioration of the ECOG PS by one category of the score from baseline was performed. Definitive deterioration was defined as a definitive increase by one category from baseline in ECOG PS, with no later improvements observed during the course of the study. A single measure reporting an increase in ECOG PS is sufficient to consider it as a definitive worsening only if it was the last one available for the patient. Kaplan-Meier method was used to estimate the distribution function of time to definitive worsening.

End point type

Secondary

End point timeframe

2.5 years

End point values	Everolimus + BSC	Placebo + BSC
Number of subjects analysed	439	217
Units: Months
median (confidence interval 95%)
Time to definitive deterioration of ECOG PS Score	2.3 (1.97 to 2.79)	2.23 (1.87 to 2.92)

No statistical analyses for this end point

Secondary: Overall Response Rate (ORR)

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End point title

Overall Response Rate (ORR)

End point description

Overall response rate (ORR) was defined as the proportion of patients with measurable disease in whom best overall response (OR) was either complete response (CR) or partial response (PR) according to RECIST criteria.

End point type

Secondary

End point timeframe

2.5 years

End point values	Everolimus + BSC	Placebo + BSC
Number of subjects analysed	439	217
Units: Participants
number (not applicable)
Measurable Disease	379	191
Complete Response (CR)	1	0
Partial Response (PR)	16	4
Overall Response Rate (ORR)	17	4

No statistical analyses for this end point

Secondary: Everolimus steady state concentrations at predose (Cmin) and Cmax at Week 5

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End point title

Everolimus steady state concentrations at predose (Cmin) and Cmax at Week 5

End point description

Cmin is the minimum (trough) steady-state drug concentration in the blood during multiple dosing and Cmax is the maximum (peak) blood drug concentration after dose administration. Cmax is estimated as the maximum of C1h and C2H. C1h is 1 hour post-dose blood concentration and C2h is 2 hour post-dose blood concentration. Only valid pre-dose (Cmin), C1h, and C2h everolimus samples were included in the analysis. Valid pre-dose samples were confirmed blood samples collected at steady-state, collected immediately prior to dosing on the same study day, and collected at approximately 24 ± 4 hours after the previous dose and with no vomiting within the first 4 hours following the last dose. Valid C1h and C2h samples were confirmed blood samples collected at steady-state and within ± 1 hour window and with no vomiting within the first 4 hours following the current and previous dose.

End point type

Secondary

End point timeframe

Week 5

End point values	Everolimus + BSC	Placebo + BSC
Number of subjects analysed	218 ^[2]	18 ^[3]
Units: ng/mL
arithmetic mean (standard deviation)
Pre-dose (Cmin) (n: 201,18)	16.143 ( 10.7723 )	10.498 ( 6.1432 )
Cmax (n: 218,16)	72.775 ( 36.5435 )	37.269 ( 27.2086 )

Notes
[2] - All PK analyses were based on the safety population in patients with evaluable samples.
[3] - All PK analyses were based on the safety population in patients with evaluable samples.

No statistical analyses for this end point

Secondary: Everolimus steady state concentrations at predose (Cmin) and Cmax by region Asia vs. rest of world

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End point title

Everolimus steady state concentrations at predose (Cmin) and Cmax by region Asia vs. rest of world

End point description

Cmin is the minimum (trough) steady-state drug concentration in the blood during multiple dosing and Cmax is the maximum (peak) blood drug concentration after dose administration. Cmax is estimated as the maximum of C1h and C2H. C1h is 1 hour post-dose blood concentration and C2h is 2 hour post-dose blood concentration. Only valid pre-dose (Cmin), C1h, and C2h everolimus samples were included in the analysis. Valid pre-dose samples were confirmed blood samples collected at steady-state, collected immediately prior to dosing on the same study day, and collected at approximately 24 ± 4 hours after the previous dose and with no vomiting within the first 4 hours following the last dose. Valid C1h and C2h samples were confirmed blood samples collected at steady-state and within ± 1 hour window and with no vomiting within the first 4 hours following the current and previous dose.

End point type

Secondary

End point timeframe

Week 5

End point values	Everolimus + BSC	Placebo + BSC
Number of subjects analysed	218 ^[4]	18 ^[5]
Units: ng/mL
arithmetic mean (standard deviation)
Asia: Pre-dose (n:127, 11)	16.804 ( 9.6163 )	9.921 ( 5.1565 )
Asia: Cmax (n:132, 10)	73.568 ( 34.1898 )	34.58 ( 26.811 )
Rest of World: Pre-dose (n=74, 7)	15.009 ( 12.5 )	11.406 ( 7.8128 )
Rest of World: Cmax (n=86, 6)	71.558 ( 40.0655 )	41.75 ( 29.8074 )

Notes
[4] - All PK analyses were based on the safety population in patients with evaluable samples.
[5] - All PK analyses were based on the safety population in patients with evaluable samples.

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

RAD001 plus best supportive care

Reporting group description

RAD001 plus best supportive care

Reporting group title

Placebo plus best supportive care

Reporting group description

Placebo plus best supportive care

Serious adverse events	RAD001 plus best supportive care	Placebo plus best supportive care
Total subjects affected by serious adverse events
subjects affected / exposed	210 / 437 (48.05%)	89 / 215 (41.40%)
number of deaths (all causes)	88	49
number of deaths resulting from adverse events	1	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphangiosis carcinomatosa
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	3 / 437 (0.69%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour perforation
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Circulatory collapse
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Extremity necrosis
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (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	3 / 437 (0.69%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphoedema
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pallor
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic venous thrombosis
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
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	12 / 437 (2.75%)	6 / 215 (2.79%)
occurrences causally related to treatment / all	4 / 12	3 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Chest discomfort
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device dislocation
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device malfunction
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device occlusion
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug intolerance
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Facial pain
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fatigue
subjects affected / exposed	8 / 437 (1.83%)	4 / 215 (1.86%)
occurrences causally related to treatment / all	3 / 8	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	14 / 437 (3.20%)	4 / 215 (1.86%)
occurrences causally related to treatment / all	4 / 16	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Local swelling
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multi-organ failure
subjects affected / exposed	1 / 437 (0.23%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Non-cardiac chest pain
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 437 (0.00%)	2 / 215 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Performance status decreased
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	10 / 437 (2.29%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	6 / 11	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Stent malfunction
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Scrotal oedema
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	9 / 437 (2.06%)	3 / 215 (1.40%)
occurrences causally related to treatment / all	2 / 10	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	2 / 437 (0.46%)	2 / 215 (0.93%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	9 / 437 (2.06%)	3 / 215 (1.40%)
occurrences causally related to treatment / all	0 / 9	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	3 / 437 (0.69%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Productive cough
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	2 / 437 (0.46%)	2 / 215 (0.93%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary fibrosis
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory arrest
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	4 / 437 (0.92%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract congestion
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Confusional state
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Expressive language disorder
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	1 / 437 (0.23%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
C-reactive protein increased
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General physical condition abnormal
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
International normalised ratio increased
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Colon injury
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Compression fracture
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic rupture
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ligament sprain
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle injury
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal injury
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haematuria
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Pyloric stenosis
subjects affected / exposed	1 / 437 (0.23%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac disorder
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Palpitations
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Brain stem infarction
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Depressed level of consciousness
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 437 (0.23%)	2 / 215 (0.93%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hemiplegia
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Paraparesis
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	15 / 437 (3.43%)	2 / 215 (0.93%)
occurrences causally related to treatment / all	5 / 15	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Coagulopathy
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	3 / 437 (0.69%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	4 / 437 (0.92%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	4 / 4	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Retinal detachment
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal adhesions
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal compartment syndrome
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal distension
subjects affected / exposed	2 / 437 (0.46%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	21 / 437 (4.81%)	12 / 215 (5.58%)
occurrences causally related to treatment / all	6 / 22	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	2 / 437 (0.46%)	2 / 215 (0.93%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal rigidity
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	9 / 437 (2.06%)	4 / 215 (1.86%)
occurrences causally related to treatment / all	0 / 10	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic gastrointestinal bleeding
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 437 (0.00%)	2 / 215 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	6 / 437 (1.37%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	2 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal perforation
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	3 / 437 (0.69%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	1 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	5 / 437 (1.14%)	2 / 215 (0.93%)
occurrences causally related to treatment / all	1 / 7	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Flatulence
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric perforation
subjects affected / exposed	2 / 437 (0.46%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric stenosis
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	13 / 437 (2.97%)	3 / 215 (1.40%)
occurrences causally related to treatment / all	5 / 14	1 / 3
deaths causally related to treatment / all	1 / 1	0 / 0
Gastrointestinal obstruction
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal pain
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal toxicity
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	2 / 437 (0.46%)	3 / 215 (1.40%)
occurrences causally related to treatment / all	1 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	5 / 437 (1.14%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Internal hernia
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	5 / 437 (1.14%)	5 / 215 (2.33%)
occurrences causally related to treatment / all	0 / 6	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	3 / 437 (0.69%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mallory-Weiss syndrome
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (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	1 / 437 (0.23%)	3 / 215 (1.40%)
occurrences causally related to treatment / all	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	9 / 437 (2.06%)	9 / 215 (4.19%)
occurrences causally related to treatment / all	3 / 10	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Obstruction gastric
subjects affected / exposed	2 / 437 (0.46%)	2 / 215 (0.93%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal perforation
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal stenosis
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritoneal adhesions
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritoneal disorder
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritoneal haemorrhage
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
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 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal obstruction
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 437 (0.00%)	3 / 215 (1.40%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	3 / 437 (0.69%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	3 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subileus
subjects affected / exposed	2 / 437 (0.46%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	3 / 437 (0.69%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	14 / 437 (3.20%)	10 / 215 (4.65%)
occurrences causally related to treatment / all	6 / 16	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	2 / 437 (0.46%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	3 / 437 (0.69%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis acute
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholestasis
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
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 / 437 (0.23%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	1 / 437 (0.23%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	4 / 437 (0.92%)	5 / 215 (2.33%)
occurrences causally related to treatment / all	0 / 4	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (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 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	1 / 437 (0.23%)	4 / 215 (1.86%)
occurrences causally related to treatment / all	1 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Ureteric obstruction
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary incontinence
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (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	5 / 437 (1.14%)	2 / 215 (0.93%)
occurrences causally related to treatment / all	2 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bone pain
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Flank pain
subjects affected / exposed	1 / 437 (0.23%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (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 / 437 (0.23%)	0 / 215 (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
Acinetobacter infection
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric infection
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 437 (0.23%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	3 / 437 (0.69%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oral herpes
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	2 / 437 (0.46%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	12 / 437 (2.75%)	4 / 215 (1.86%)
occurrences causally related to treatment / all	4 / 12	0 / 4
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 437 (0.46%)	2 / 215 (0.93%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Septic shock
subjects affected / exposed	4 / 437 (0.92%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Skin infection
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Streptococcal sepsis
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	4 / 437 (0.92%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 437 (0.00%)	2 / 215 (0.93%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	1 / 437 (0.23%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	21 / 437 (4.81%)	8 / 215 (3.72%)
occurrences causally related to treatment / all	6 / 21	2 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	3 / 437 (0.69%)	2 / 215 (0.93%)
occurrences causally related to treatment / all	1 / 3	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Feeding disorder
subjects affected / exposed	0 / 437 (0.00%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid intake reduced
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Food intolerance
subjects affected / exposed	1 / 437 (0.23%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophagia
subjects affected / exposed	1 / 437 (0.23%)	1 / 215 (0.47%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	1 / 437 (0.23%)	0 / 215 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	RAD001 plus best supportive care	Placebo plus best supportive care
Total subjects affected by non serious adverse events
subjects affected / exposed	416 / 437 (95.19%)	193 / 215 (89.77%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	28 / 437 (6.41%)	9 / 215 (4.19%)
occurrences all number	29	9
Aspartate aminotransferase increased
subjects affected / exposed	34 / 437 (7.78%)	8 / 215 (3.72%)
occurrences all number	35	8
Blood alkaline phosphatase increased
subjects affected / exposed	34 / 437 (7.78%)	6 / 215 (2.79%)
occurrences all number	36	7
Weight decreased
subjects affected / exposed	87 / 437 (19.91%)	19 / 215 (8.84%)
occurrences all number	92	19
Nervous system disorders
Dizziness
subjects affected / exposed	22 / 437 (5.03%)	12 / 215 (5.58%)
occurrences all number	27	12
Dysgeusia
subjects affected / exposed	26 / 437 (5.95%)	7 / 215 (3.26%)
occurrences all number	29	8
Headache
subjects affected / exposed	32 / 437 (7.32%)	8 / 215 (3.72%)
occurrences all number	37	8
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	108 / 437 (24.71%)	42 / 215 (19.53%)
occurrences all number	135	47
Leukopenia
subjects affected / exposed	30 / 437 (6.86%)	3 / 215 (1.40%)
occurrences all number	38	3
Neutropenia
subjects affected / exposed	47 / 437 (10.76%)	6 / 215 (2.79%)
occurrences all number	65	6
Thrombocytopenia
subjects affected / exposed	77 / 437 (17.62%)	4 / 215 (1.86%)
occurrences all number	93	4
General disorders and administration site conditions
Asthenia
subjects affected / exposed	67 / 437 (15.33%)	18 / 215 (8.37%)
occurrences all number	72	19
Fatigue
subjects affected / exposed	146 / 437 (33.41%)	63 / 215 (29.30%)
occurrences all number	169	68
Oedema peripheral
subjects affected / exposed	49 / 437 (11.21%)	21 / 215 (9.77%)
occurrences all number	53	23
Pyrexia
subjects affected / exposed	77 / 437 (17.62%)	24 / 215 (11.16%)
occurrences all number	108	35
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	39 / 437 (8.92%)	20 / 215 (9.30%)
occurrences all number	39	21
Abdominal pain
subjects affected / exposed	90 / 437 (20.59%)	49 / 215 (22.79%)
occurrences all number	105	51
Abdominal pain upper
subjects affected / exposed	51 / 437 (11.67%)	26 / 215 (12.09%)
occurrences all number	59	30
Constipation
subjects affected / exposed	92 / 437 (21.05%)	41 / 215 (19.07%)
occurrences all number	101	45
Diarrhoea
subjects affected / exposed	112 / 437 (25.63%)	33 / 215 (15.35%)
occurrences all number	159	37
Dyspepsia
subjects affected / exposed	22 / 437 (5.03%)	8 / 215 (3.72%)
occurrences all number	24	8
Nausea
subjects affected / exposed	129 / 437 (29.52%)	63 / 215 (29.30%)
occurrences all number	147	76
Stomatitis
subjects affected / exposed	173 / 437 (39.59%)	22 / 215 (10.23%)
occurrences all number	241	26
Vomiting
subjects affected / exposed	98 / 437 (22.43%)	54 / 215 (25.12%)
occurrences all number	125	70
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	50 / 437 (11.44%)	17 / 215 (7.91%)
occurrences all number	57	18
Dyspnoea
subjects affected / exposed	54 / 437 (12.36%)	21 / 215 (9.77%)
occurrences all number	59	21
Epistaxis
subjects affected / exposed	29 / 437 (6.64%)	1 / 215 (0.47%)
occurrences all number	32	1
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	23 / 437 (5.26%)	7 / 215 (3.26%)
occurrences all number	27	7
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	22 / 437 (5.03%)	2 / 215 (0.93%)
occurrences all number	23	2
Pruritus
subjects affected / exposed	47 / 437 (10.76%)	9 / 215 (4.19%)
occurrences all number	54	9
Rash
subjects affected / exposed	86 / 437 (19.68%)	19 / 215 (8.84%)
occurrences all number	110	21
Psychiatric disorders
Insomnia
subjects affected / exposed	51 / 437 (11.67%)	22 / 215 (10.23%)
occurrences all number	57	23
Renal and urinary disorders
Proteinuria
subjects affected / exposed	24 / 437 (5.49%)	5 / 215 (2.33%)
occurrences all number	28	5
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	46 / 437 (10.53%)	16 / 215 (7.44%)
occurrences all number	52	16
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	202 / 437 (46.22%)	76 / 215 (35.35%)
occurrences all number	235	82
Hyperglycaemia
subjects affected / exposed	31 / 437 (7.09%)	6 / 215 (2.79%)
occurrences all number	40	6
Hypoalbuminaemia
subjects affected / exposed	25 / 437 (5.72%)	12 / 215 (5.58%)
occurrences all number	26	13
Hypokalaemia
subjects affected / exposed	52 / 437 (11.90%)	9 / 215 (4.19%)
occurrences all number	61	13

More information

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Were there any global substantial amendments to the protocol? Yes

29 Jan 2010

Clarifications to GEJ tumor language added, removal of amylase and lipase levels as an inclusion criterion, permitting enrollment of patients with grade 2 neuropathy, adding exclusion for patients with prior malignancies, removal of pulmonary function testing at screening, amending the pulmonary exclusion criterion, patients who were enterally fed were not eligible, and patients qualified for the study based on local laboratory results. Guidance provided for identification of patients at risk for hepatitis B, that include providing prophylactic treatment to them prior to and throughout everolimus therapy, monitoring them for reactivation of HBV, and management of patients at risk of hepatitis C viral reactivation. Guidance provided for management of hyperglycemia and duration of use of adequate contraception after end of trial therapy. Guidance provided regarding use of CYP3A4 and/or PgP inducers and inhibitors as modified with the Internal Clinical Pharmacology Drug-drug interaction memo; language modified regarding the administration of everolimus after meals; planned IDMC outputs excluded PK data; instead to receive unblinded safety data by prior gastrectomy (y/n); added separate exploratory Cox model on the sub-set of distal gastric tumor patients.

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.

Four randomized patients, 2 patients each from the everolimus and placebo arms were excluded from the safety analyses as they did not receive any dose of study treatment. This study did not meet its primary objective.

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