RAD001 Plus Best Supportive Care (BSC) Versus BSC Plus Pl... | NCT00410124

NCT00410124

ID	Type	Description	Link
2006-002070-21	EudraCT Number

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
RAD001 +BSC	Experimental	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	Drug: RAD001
Placebo (plus BSC)	Placebo Comparator	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	Drug: Placebo

Name	Type	Description	Arm Group Labels	Other Names
RAD001	Drug	The dose of RAD001 was 10 mg/day. Patients were instructed to take two tablets (5 mg each) by mouth every day.	RAD001 +BSC

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Progressive Free Survival (PFS) in Patients Who Receive RAD001 Plus Best Supportive Care(BSC) Versus Patients Who Receive Matching Placebo Plus BSC	Progression Free survival is defined as the time from randomization to the date of first documented disease progression or death from any cause. The primary statistical analysis of PFS was based on central radiological assessments using a one-sided stratified log-rank test. Radiological assessments: every 8 weeks (+/-1 week) during the first year and every 12 weeks (+/- 1 week) during the second year and thereafter and at the end of the study. Kaplan-Meier methodology was used to estimate the median PFS for each treatment group.	Time from randomization to dates of disease progression, death from any cause or last tumor assessment reported between date of first patient randomized until 28Feb2008 cut of date.

Secondary Outcomes

Measure	Description	Time Frame
Overall Survival (OS) Assessed by the Monthly Overall Survival Assessments	Overall survival (OS) was defined as the time from date of randomization to date of death due to any cause. Kaplan-Meier methodology was used to estimate the median overall survival for each treatment group	Assessed every month up to 2 years after the last patient was randomized into the study from the date of randomization to the time of death. (Data cutoff was 15Nov2009)

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Patients with metastatic carcinoma and with histological or cytological confirmation of clear cell RCC (tissue from the original diagnosis of renal cell cancer is acceptable).
The date of progression on sunitinib and/or sorafenib must be within 6 months.
Patients may have received one or both agents
Prior therapy with cytokines (i.e., IL-2, Interferon) and/or VEGF-ligand inhibitors (i.e., bevacizumab) are permitted.
Prior vaccine therapy in the adjuvant setting is permitted.
Patients with at least one measurable lesion at baseline as per the Response evaluation criteria in solid tumors (RECIST) criteria, either on physical exam or as determined by Computer Tomography (CT) Scan or Magnetic Resonance Imaging (MRI).
Patients with a Karnofsky Performance Status ≥70%.
Adequate bone marrow, liver and renal function.
Patients with a life expectancy ≥ 3 months.
Women of childbearing potential must have had a negative serum or urine pregnancy test 48 hours prior to the administration of the first study treatment.
Patients who give a written informed consent obtained according to local guidelines

Exclusion Criteria:

Patients currently receiving chemotherapy, immunotherapy, or radio-therapy or who have received these within 4 weeks of study entry
Patients who have previously received mTOR inhibitors.
Patients with a known hypersensitivity to RAD001 or other rapamycins (sirolimus, temsirolimus) or to its excipients.
Patients with untreated CNS metastases or who are neurologically unstable despite treatment of the CNS metastases. (Patients with treated CNS metastases, who are neurologically stable off of corticosteroids, are eligible to enter study).
Patients receiving chronic treatment with corticosteroids or another immunosuppressive agent
Patients with a known history of HIV seropositivity.
Patients with an active, bleeding diathesis or on oral anti-vitamin K medication (except low dose coumadin)
Patients who have any severe and/or uncontrolled medical conditions
Patients who have a history of another primary malignancy ≤ 3 years, with the exception of non-melanoma skin cancer, and carcinoma in situ of uterine cervix
Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes.
Patients who are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to randomization
Patients unwilling to or unable to comply with the protocol

Other protocol-defined inclusion/exclusion criteria may apply.

Name	Affiliation	Role
Novartis Pharmaceuticals	Novartis Pharmaceuticals	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Novartis Investigative Site		Fayetteville	Arkansas	72703	United States
Novartis Investigative Site

PubMed Identifier	Type	Citation	Retractions
23219086	Derived	Stein A, Bellmunt J, Escudier B, Kim D, Stergiopoulos SG, Mietlowski W, Motzer RJ; RECORD-1 Trial Study Group. Survival prediction in everolimus-treated patients with metastatic renal cell carcinoma incorporating tumor burden response in the RECORD-1 trial. Eur Urol. 2013 Dec;64(6):994-1002. doi: 10.1016/j.eururo.2012.11.032. Epub 2012 Nov 21.
22824201

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	RAD001 +BSC	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	RAD001 +BSC	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
BG001	Placebo + BSC	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
BG002	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Progressive Free Survival (PFS) in Patients Who Receive RAD001 Plus Best Supportive Care(BSC) Versus Patients Who Receive Matching Placebo Plus BSC

Progression Free survival is defined as the time from randomization to the date of first documented disease progression or death from any cause. The primary statistical analysis of PFS was based on central radiological assessments using a one-sided stratified log-rank test. Radiological assessments: every 8 weeks (+/-1 week) during the first year and every 12 weeks (+/- 1 week) during the second year and thereafter and at the end of the study. Kaplan-Meier methodology was used to estimate the median PFS for each treatment group.

Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.

Posted

Median

95% Confidence Interval

Months

Time from randomization to dates of disease progression, death from any cause or last tumor assessment reported between date of first patient randomized until 28Feb2008 cut of date.

ID	Title	Description
OG000	RAD001 +BSC	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
OG001	Placebo + BSC	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression at data cutoff of 28Feb2008, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.

Units	Counts
Participants	OG000277 OG001139

Title

Denominators

Categories

Title	Measurements
	OG0004.90(3.98 to 5.52) OG0011.87(1.84 to 1.94)

Secondary

Overall Survival (OS) Assessed by the Monthly Overall Survival Assessments

Overall survival (OS) was defined as the time from date of randomization to date of death due to any cause. Kaplan-Meier methodology was used to estimate the median overall survival for each treatment group

Full analysis set was performed on the intent-to-treat population which consisted of all randomized patients.

Posted

Median

95% Confidence Interval

Months

Assessed every month up to 2 years after the last patient was randomized into the study from the date of randomization to the time of death. (Data cutoff was 15Nov2009)

ID	Title	Description
OG000	RAD001 +BSC	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
OG001	Placebo + BSC	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care. With the documented disease progression at data cutoff of 28Feb2008, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.

Secondary

Best Overall Response Rate in Patients Who Receive RAD001 Plus BSC Versus Matching Placebo Plus BSC

The Best Overall Response rate (BOR) is defined as the percentage of patients having achieved confirmed Complete Response + Partial Response. Complete Response (CR) = at least two determinations of CR at least 4 weeks apart before progression. • Partial response (PR) = at least two determinations of PR or better at least 4 weeks apart before progression. Radiological assessments: every 8 weeks (+/-1 week) during the first year and every 12 weeks (+/- 1 week) during the second year and thereafter and at the end of the study.

Full analysis set was performed on the intent-to-treat population which consisted of all randomized patients.

Posted

Number

95% Confidence Interval

Percentage of Participants

Time from randomization to dates of disease progression, death from any cause or last tumor assessment reported, between date of first patient randomized until 28Feb2008 cutoff date

ID	Title	Description
OG000	RAD001 +BSC	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.

Secondary

Duration of Response in Patients Who Receive RAD001 Plus BSC Versus Placebo Plus BSC

Duration of overall response (CR or PR) applies only to patients whose Best Overall Response (BOR) was Complete Response (CR) or Partial Response (PR). The start date is the date of first documented response (CR or PR) and the end date is the date of event defined as the first documented progression or death. Radiological assessments: every 8 weeks (+/-1 week) during the first year and every 12 weeks (+/- 1 week) during the second year and thereafter and at the end of the study.

Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.

Posted

Median

95% Confidence Interval

months

Time from randomization to dates of disease progression, death from any cause or last tumor assessment reported, between date of first patient randomized until 28Feb2008 cutoff date

ID	Title	Description
OG000	RAD001 +BSC	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.
OG001

Secondary

Analysis of Time to Definitive Deterioration of the Global Health Status/QoL Scale(QL) Scores of the EORTC QLQ-30 Questionnaire by at Least 10 Percent Using Kaplan Meier Method, by Treatment.

The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) contains 30 items. These include a global health status/QoL scale, five functional scales, three symptom scales, and six single items. Global health status / QoL scale (QL), consisting of 2 questions each scored from 1 (very poor) to 7 (excellent), and with possible scores ranging from 2 to 14. Higher score indicates better functioning. Definitive deterioration by at least 10% is defined as a decrease in score by at least 10% compared to baseline, with no increase above this threshold observed during the course of the study. A single measure reporting a decrease of at least 10% is considered definitive only if it is the last one available for the patient. Time to definitive deterioration is the number of days between the date of randomization and date of assessment at which definitive deterioration is seen.

Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.

Posted

Median

95% Confidence Interval

months

Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date

ID	Title	Description
OG000	RAD001 +BSC	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.

Secondary

Time to Definitive Deterioration of the FKS-DRS Risk Score by at Least 2 Score Units Using Kaplan-Meier Method, by Treatment.

The Functional Assessment of Cancer Therapy - Kidney Symptom Index, Disease Related Symptoms (FKSI-DRS) is a set of items to assess symptoms experienced by patients with advanced kidney cancer. These symptoms include fatigue, pain, weight loss, dyspnea, cough, fever and hematuria. There were 4 response categories (1=Not at all, 2= A little, 3=Quite a bit, 4=Very much), sum of item responses can range from 0 to 36. "0"= severely symptomatic patient and the highest score is an asymptomatic patient. Definitive deterioration of the FKSI-DRS score was defined as a decrease by at least 2 units compared to baseline, with no later increase above this threshold observed during the study. A single measure reporting a decrease of at least 2 units was considered definitive only if it is the last one available for the patient. Time to definitive deterioration is the number of days between the date of randomization and the date of the assessment at which definitive deterioration is seen.

Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.

Posted

Median

95% Confidence Interval

months

Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date

ID	Title	Description
OG000	RAD001 +BSC	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.

Secondary

Time to Definitive Deterioration of the Physical Functioning Scale (PF)Score of the EORTC QLQ-C30 Questionnaire by at Least 10 Percent Using Kaplan_Meier Method, by Treatment.

The EORTC QLQ-C30 contains 30 items. These include five functional scales (physical, role, emotional, social and cognitive functioning), three symptom scales fatigue, pain, nausea, and vomiting), a global health status/QoL scale, and six single items (dyspnea, diarrhea, constipation, anorexia, insomnia and financial impact). Physical Functioning (PF) sub-scale, consisting of 5 questions each scored from 1 (not at all) to 4 (very much), and with possible values ranging from 5 to 20. Definitive deterioration by at least 10% is defined as a decrease in score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study. A single measure reporting a decrease of at least 10% is considered definitive only if it is the last one available for the patient. Time to definitive deterioration is the number of days between the date of randomization and the date of the assessment at which definitive deterioration is seen.

Full Analysis Set was performed on the intent-to-treat population which consisted of all randomized patients.

Posted

Median

95% Confidence Interval

months

Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date

ID	Title	Description
OG000	RAD001 +BSC	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.

Secondary

Pharmacokinetics of RAD001:Peak Concentration in a Dosing Interval (C-max); Pre-dose Concentration at 24-h Time Point in Dosing Interval (C-min) and Average Concentration in a Dosing Interval =(C-avg)

Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol. C-avg= Area under curve (AUC) in a dosing interval from time-zero to time of the last quantifiable concentration (AUC0-tlast)/ time of the last quantifiable concentration in a dosing interval (tlast)

The pharmacokinetics population consists of all patients who have a pharmacokinetic assessment with a sufficient number of evaluable blood samples. The analsyis was limited to RAD001 + BSC arm.

Posted

Mean

Standard Deviation

ng/mL

At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day1, Cycle 1 Day 15 and at pre-dose from Cycle 2(day1) and all subsequent treatment cycles up until data cut-off 28 Feb 2008.

ID	Title	Description
OG000	Day 1	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 1 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed. Troughs were collected for all patients on Day 1 of each treatment Cycle from month 2 until discontinuation from the study drug.
OG001	Day 15	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 15 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed.

Secondary

Pharmacokinetics of RAD001: Time at Which C-Max Occurs (t-Max)

Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.

The pharmacokinetics population consists of all patients who have a pharmacokinetic assessment with a sufficient number of evaluable blood samples. The analsyis was limited to RAD001 + BSC arm.

Posted

Median

Full Range

At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose of From Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008.

ID	Title	Description
OG000	Day 1	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 1 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed. Troughs were collected for all patients on Day 1 of each treatment Cycle from month 2 until discontinuation from the study drug.
OG001	Day 15	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 15 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed.

Units	Counts

Secondary

Pharmacokinetics of RAD001: Area Under Curve (AUC) in a Dosing Interval From Time-zero to Time of the Last Quantifiable Concentration. (AUC 0-tlast)

Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.

The pharmacokinetics population consists of all patients who have a pharmacokinetic assessment with a sufficient number of evaluable blood samples. The analsyis was limited to RAD001 + BSC arm.

Posted

Mean

Standard Deviation

ng.h/mL

At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008.

ID	Title	Description
OG000	Day 1	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 1 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed. Troughs were collected for all patients on Day 1 of each treatment Cycle from month 2 until discontinuation from the study drug.
OG001	Day 15	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 15 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed.

Secondary

Pharmacokinetics of RAD001: Time of the Last Quantifiable Concentration in a Dosing Interval - (Tlast)

Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.

The pharmacokinetics population consists of all patients who have a pharmacokinetic assessment with a sufficient number of evaluable blood samples. The analsyis was limited to RAD001 + BSC arm.

Posted

Median

Full Range

hour

At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008.

ID	Title	Description
OG000	Day 1	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 1 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed. Troughs were collected for all patients on Day 1 of each treatment Cycle from month 2 until discontinuation from the study drug.
OG001	Day 15	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 15 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed.

Units	Counts

Secondary

Pharmacokinetics of RAD001: Apparent Systemic Clearance From Blood Following Extravascular Administration (CL/F)

Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.Apparent oral clearance of RAD001 (CL/F) was calculated using AUC in a dosing interval of 24 hours (AUC0-24hours) value on Day 15 as: CL/F = dose/ AUC0-τ

The pharmacokinetics population consists of all patients who have a pharmacokinetic assessment with a sufficient number of evaluable blood samples. The analsyis was limited to RAD001 + BSC arm.

Posted

Mean

Standard Deviation

L/hour

At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008.

ID	Title	Description
OG000	Day 15	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 15 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed.

Units	Counts
Participants	OG000

Secondary

Pharmacokinetics of RAD001: Normalized to Body Surface Area (CL/F)

Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.

The pharmacokinetics population consists of all patients who have a pharmacokinetic assessment with a sufficient number of evaluable blood samples. The analsyis was limited to RAD001 + BSC arm.

Posted

Mean

Standard Deviation

L/hour/m^2

At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008.

ID	Title	Description
OG000	Day 15	Pharmacokinetic Blood Sampling: Full pharmacokinetic profile assessments on Cycle 1, Day 15 (at pre-dose and at 1h, 2h, 5h, and 24h post-dose) were performed.

Units	Counts
Participants	OG000

Arm/Groups

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Randomized to RAD001+ BSC ( Blinded + Open Label)	The study drugs were self administered by the patients. Patients were instructed to take the study drug as specified in the protocol. Patients were instructed to take two tablets (5 mg each) by mouth every day. Tablets were to be taken one tablet after another with a glass of water, at the same time each day in a fasting state or with a light fat-free meal. If disease progression occurred at data cutoff of 28Feb2008, patients were unblinded and if they were receiving RAD001, they would discontinue the study. Otherwise, they would be given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	135	274	261	274
EG001	Randomized to Placebo + BSC (Open Label)	With the documented disease progression at data cutoff of 28Feb2008, the investigator could unblind the patient. If unblinded patient was receiving placebo treatment, they were given the option to continue in the extension open label phase of 2 tablets of RAD001 5mg by mouth every day.	60	111	106	111
EG002	Randomized to Placebo + BSC (Double Blind Only)	Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care.	17	26	23	26

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG00013 affected274 at risk EG0015 affected111 at risk EG0020 affected26 at risk
Bone marrow reticulin fibrosis	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Haemolysis	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Aortic valve incompetence	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Cardiac disorder	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Cardiac failure	Cardiac disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Left ventricular dysfunction	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Myocardial infarction	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Myocardial ischaemia	Cardiac disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Pericardial effusion	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Tachycardia	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Adrenal insufficiency	Endocrine disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Hypothyroidism	Endocrine disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Eye pain	Eye disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Abdominal distension	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0007 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Abdominal pain lower	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Ascites	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Constipation	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Dysphagia	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Faecaloma	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Gastrointestinal sounds abnormal	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Haematochezia	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Inguinal hernia	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Intestinal obstruction	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Nausea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0003 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Pancreatitis acute	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Peritoneal effusion	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Peritonitis	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Proctalgia	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Small intestinal obstruction	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Stomatitis	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0003 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Tongue oedema	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Vomiting	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0004 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Asthenia	General disorders	MedDRA	Systematic Assessment	EG0004 affected274 at risk EG0011 affected111 at risk EG0022 affected26 at risk
Chest discomfort	General disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Chest pain	General disorders	MedDRA	Systematic Assessment	EG0004 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Disease progression	General disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Fatigue	General disorders	MedDRA	Systematic Assessment	EG0007 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
General physical health deterioration	General disorders	MedDRA	Systematic Assessment	EG0003 affected274 at risk EG0011 affected111 at risk EG0022 affected26 at risk
Generalised oedema	General disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Malaise	General disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Mucosal inflammation	General disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Non-cardiac chest pain	General disorders	MedDRA	Systematic Assessment	EG0004 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Oedema peripheral	General disorders	MedDRA	Systematic Assessment	EG0003 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Pain	General disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Performance status decreased	General disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0012 affected111 at risk EG0020 affected26 at risk
Pyrexia	General disorders	MedDRA	Systematic Assessment	EG00013 affected274 at risk EG0015 affected111 at risk EG0020 affected26 at risk
Bile duct obstruction	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Biloma	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Cholangitis	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Cholangitis acute	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Cholecystitis	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Cholelithiasis	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0012 affected111 at risk EG0020 affected26 at risk
Cholestasis	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Hepatic failure	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Hepatic steatosis	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Hyperbilirubinaemia	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Jaundice	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Liver disorder	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Hypersensitivity	Immune system disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Appendicitis	Infections and infestations	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Bronchitis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Bronchopulmonary aspergillosis	Infections and infestations	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Cellulitis	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0012 affected111 at risk EG0020 affected26 at risk
Enterococcal infection	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Escherichia infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Fungal infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Gastroenteritis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Incision site infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Klebsiella infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Klebsiella sepsis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Lung abscess	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0012 affected111 at risk EG0020 affected26 at risk
Lung infection	Infections and infestations	MedDRA	Systematic Assessment	EG0004 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Pelvic abscess	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Pleural infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Pneumonia	Infections and infestations	MedDRA	Systematic Assessment	EG00010 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Pneumonia bacterial	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Pneumonia viral	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Pyelonephritis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Rectal abscess	Infections and infestations	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Respiratory tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Salmonellosis	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Sepsis	Infections and infestations	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Septic shock	Infections and infestations	MedDRA	Systematic Assessment	EG0003 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Sinusitis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Staphylococcal sepsis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Viral infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Wound abscess	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Cervical vertebral fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Device dislocation	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Femur fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Humerus fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Ilium fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Lower limb fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Medical device complication	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Post procedural bile leak	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Radiation skin injury	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Rib fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Spinal fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Stent occlusion	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Subdural haematoma	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Subdural haemorrhage	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Tracheal haemorrhage	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Wound dehiscence	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Bile duct pressure increased	Investigations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Blood alkaline phosphatase increased	Investigations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Blood amylase increased	Investigations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Blood bilirubin increased	Investigations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Blood chloride decreased	Investigations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Blood creatine phosphokinase increased	Investigations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Blood creatinine increased	Investigations	MedDRA	Systematic Assessment	EG0004 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Blood urea increased	Investigations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Ejection fraction decreased	Investigations	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Lipase increased	Investigations	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Cachexia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Cell death	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0003 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0009 affected274 at risk EG0012 affected111 at risk EG0021 affected26 at risk
Diabetes mellitus	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Diabetes mellitus inadequate control	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Diabetic ketoacidosis	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Hypercalcaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0003 affected274 at risk EG0010 affected111 at risk EG0022 affected26 at risk
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Hypomagnesaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Hyponatraemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0004 affected274 at risk EG0011 affected111 at risk EG0021 affected26 at risk
Bone pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0004 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Hypercreatinaemia	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Osteonecrosis	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Pathological fracture	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0011 affected111 at risk EG0021 affected26 at risk
Breast cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Cancer pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Infected neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Lung neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Lymphangiosis carcinomatosa	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Metastases to bone	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Metastases to central nervous system	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Metastases to liver	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Metastases to lung	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Metastases to spine	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Pleura carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Renal cancer metastatic	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Transitional cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Tumour haemorrhage	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Tumour pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Aphasia	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Balance disorder	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Cerebral haemorrhage	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Coma	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Convulsion	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0021 affected26 at risk
Depressed level of consciousness	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Dizziness	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Encephalopathy	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Grand mal convulsion	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0021 affected26 at risk
Headache	Nervous system disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Hemiplegia	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Lethargy	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Loss of consciousness	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Paraesthesia	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Spinal cord compression	Nervous system disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Status epilepticus	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Tremor	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Trigeminal neuralgia	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Agitation	Psychiatric disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0021 affected26 at risk
Confusional state	Psychiatric disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Delirium	Psychiatric disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Depression	Psychiatric disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Hallucination	Psychiatric disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Intentional self-injury	Psychiatric disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Mental status changes	Psychiatric disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Psychotic disorder	Psychiatric disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Suicide attempt	Psychiatric disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Haematuria	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0011 affected111 at risk EG0021 affected26 at risk
Hydronephrosis	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0012 affected111 at risk EG0020 affected26 at risk
Renal failure	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0005 affected274 at risk EG0014 affected111 at risk EG0020 affected26 at risk
Renal failure acute	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0003 affected274 at risk EG0013 affected111 at risk EG0021 affected26 at risk
Renal impairment	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Ureteric dilatation	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Ureteric obstruction	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Ureteric stenosis	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Urinary retention	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Pelvic pain	Reproductive system and breast disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0003 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Asphyxia	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Atelectasis	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0004 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG00025 affected274 at risk EG00111 affected111 at risk EG0021 affected26 at risk
Dyspnoea exertional	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0003 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Hydrothorax	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Hypoxia	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Interstitial lung disease	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0006 affected274 at risk EG0013 affected111 at risk EG0020 affected26 at risk
Lung disorder	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0003 affected274 at risk EG0012 affected111 at risk EG0020 affected26 at risk
Lung infiltration	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG00011 affected274 at risk EG0018 affected111 at risk EG0020 affected26 at risk
Pleuritic pain	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0012 affected111 at risk EG0020 affected26 at risk
Pneumonitis	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG00011 affected274 at risk EG0012 affected111 at risk EG0020 affected26 at risk
Pulmonary alveolar haemorrhage	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0012 affected111 at risk EG0020 affected26 at risk
Pulmonary infarction	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Pulmonary toxicity	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Respiratory distress	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0002 affected274 at risk EG0013 affected111 at risk EG0021 affected26 at risk
Night sweats	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Circulatory collapse	Vascular disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Deep vein thrombosis	Vascular disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Haematoma	Vascular disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk
Shock	Vascular disorders	MedDRA	Systematic Assessment	EG0001 affected274 at risk EG0010 affected111 at risk EG0020 affected26 at risk
Thrombosis	Vascular disorders	MedDRA	Systematic Assessment	EG0000 affected274 at risk EG0010 affected111 at risk EG0021 affected26 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG000108 affected274 at risk EG00142 affected111 at risk EG0024 affected26 at risk
Lymphopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG00029 affected274 at risk EG0017 affected111 at risk EG0020 affected26 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG00019 affected274 at risk EG0018 affected111 at risk EG0020 affected26 at risk
Ear pain	Ear and labyrinth disorders	MedDRA	Systematic Assessment	EG0003 affected274 at risk EG0016 affected111 at risk EG0020 affected26 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG00031 affected274 at risk EG00110 affected111 at risk EG0021 affected26 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG00020 affected274 at risk EG0016 affected111 at risk EG0021 affected26 at risk
Aphthous stomatitis	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG00026 affected274 at risk EG00113 affected111 at risk EG0020 affected26 at risk
Constipation	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG00060 affected274 at risk EG00125 affected111 at risk EG0025 affected26 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG00090 affected274 at risk EG00128 affected111 at risk EG0022 affected26 at risk
Dry mouth	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG00022 affected274 at risk EG0015 affected111 at risk EG0024 affected26 at risk
Haemorrhoids	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG00017 affected274 at risk EG0011 affected111 at risk EG0020 affected26 at risk
Nausea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG00078 affected274 at risk EG00127 affected111 at risk EG0025 affected26 at risk
Stomatitis	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG000106 affected274 at risk EG00133 affected111 at risk EG0023 affected26 at risk
Vomiting	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG00063 affected274 at risk EG00119 affected111 at risk EG0023 affected26 at risk
Asthenia	General disorders	MedDRA	Systematic Assessment	EG00096 affected274 at risk EG00131 affected111 at risk EG0029 affected26 at risk
Fatigue	General disorders	MedDRA	Systematic Assessment	EG00086 affected274 at risk EG00140 affected111 at risk EG0028 affected26 at risk
General physical health deterioration	General disorders	MedDRA	Systematic Assessment	EG0006 affected274 at risk EG0013 affected111 at risk EG0022 affected26 at risk
Mucosal inflammation	General disorders	MedDRA	Systematic Assessment	EG00053 affected274 at risk EG00126 affected111 at risk EG0020 affected26 at risk
Non-cardiac chest pain	General disorders	MedDRA	Systematic Assessment	EG00012 affected274 at risk EG0018 affected111 at risk EG0020 affected26 at risk
Oedema peripheral	General disorders	MedDRA	Systematic Assessment	EG00079 affected274 at risk EG00125 affected111 at risk EG0025 affected26 at risk
Pyrexia	General disorders	MedDRA	Systematic Assessment	EG00055 affected274 at risk EG00124 affected111 at risk EG0021 affected26 at risk
Bronchitis	Infections and infestations	MedDRA	Systematic Assessment	EG00017 affected274 at risk EG0016 affected111 at risk EG0021 affected26 at risk
Nasopharyngitis	Infections and infestations	MedDRA	Systematic Assessment	EG00020 affected274 at risk EG0018 affected111 at risk EG0021 affected26 at risk
Urinary tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG00014 affected274 at risk EG0015 affected111 at risk EG0020 affected26 at risk
Blood alkaline phosphatase increased	Investigations	MedDRA	Systematic Assessment	EG00011 affected274 at risk EG0016 affected111 at risk EG0020 affected26 at risk
Blood creatinine increased	Investigations	MedDRA	Systematic Assessment	EG00029 affected274 at risk EG0013 affected111 at risk EG0020 affected26 at risk
Gamma-glutamyltransferase increased	Investigations	MedDRA	Systematic Assessment	EG00020 affected274 at risk EG0017 affected111 at risk EG0020 affected26 at risk
Weight decreased	Investigations	MedDRA	Systematic Assessment	EG00027 affected274 at risk EG00119 affected111 at risk EG0022 affected26 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG00082 affected274 at risk EG00124 affected111 at risk EG0026 affected26 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0009 affected274 at risk EG0015 affected111 at risk EG0022 affected26 at risk
Hypercalcaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG00010 affected274 at risk EG0014 affected111 at risk EG0023 affected26 at risk
Hypercholesterolaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG00060 affected274 at risk EG00121 affected111 at risk EG0020 affected26 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG00036 affected274 at risk EG00115 affected111 at risk EG0022 affected26 at risk
Hypertriglyceridaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG00045 affected274 at risk EG00117 affected111 at risk EG0020 affected26 at risk
Hypophosphataemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG00018 affected274 at risk EG0014 affected111 at risk EG0020 affected26 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00039 affected274 at risk EG00120 affected111 at risk EG0021 affected26 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00039 affected274 at risk EG00113 affected111 at risk EG0022 affected26 at risk
Bone pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00011 affected274 at risk EG0019 affected111 at risk EG0021 affected26 at risk
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00014 affected274 at risk EG0013 affected111 at risk EG0020 affected26 at risk
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00010 affected274 at risk EG0018 affected111 at risk EG0021 affected26 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0007 affected274 at risk EG0018 affected111 at risk EG0020 affected26 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG00034 affected274 at risk EG00117 affected111 at risk EG0023 affected26 at risk
Dizziness	Nervous system disorders	MedDRA	Systematic Assessment	EG00019 affected274 at risk EG0013 affected111 at risk EG0023 affected26 at risk
Dysgeusia	Nervous system disorders	MedDRA	Systematic Assessment	EG00032 affected274 at risk EG00114 affected111 at risk EG0021 affected26 at risk
Headache	Nervous system disorders	MedDRA	Systematic Assessment	EG00053 affected274 at risk EG00114 affected111 at risk EG0022 affected26 at risk
Paraesthesia	Nervous system disorders	MedDRA	Systematic Assessment	EG00012 affected274 at risk EG0011 affected111 at risk EG0022 affected26 at risk
Anxiety	Psychiatric disorders	MedDRA	Systematic Assessment	EG00014 affected274 at risk EG0013 affected111 at risk EG0022 affected26 at risk
Insomnia	Psychiatric disorders	MedDRA	Systematic Assessment	EG00030 affected274 at risk EG00111 affected111 at risk EG0022 affected26 at risk
Dysuria	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0005 affected274 at risk EG0016 affected111 at risk EG0020 affected26 at risk
Haematuria	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0004 affected274 at risk EG0010 affected111 at risk EG0022 affected26 at risk
Nocturia	Renal and urinary disorders	MedDRA	Systematic Assessment	EG00010 affected274 at risk EG0018 affected111 at risk EG0021 affected26 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG00096 affected274 at risk EG00130 affected111 at risk EG0024 affected26 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG00059 affected274 at risk EG00128 affected111 at risk EG0023 affected26 at risk
Dyspnoea exertional	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG00017 affected274 at risk EG0018 affected111 at risk EG0021 affected26 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG00051 affected274 at risk EG00112 affected111 at risk EG0020 affected26 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG00010 affected274 at risk EG0016 affected111 at risk EG0020 affected26 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG00013 affected274 at risk EG0018 affected111 at risk EG0020 affected26 at risk
Pneumonitis	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG00018 affected274 at risk EG0014 affected111 at risk EG0020 affected26 at risk
Dry skin	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG00038 affected274 at risk EG00114 affected111 at risk EG0023 affected26 at risk
Erythema	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG00015 affected274 at risk EG0012 affected111 at risk EG0020 affected26 at risk
Nail disorder	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG00020 affected274 at risk EG0017 affected111 at risk EG0020 affected26 at risk
Onychoclasis	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG00016 affected274 at risk EG0012 affected111 at risk EG0020 affected26 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG00043 affected274 at risk EG00112 affected111 at risk EG0022 affected26 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA	Systematic Assessment	EG00083 affected274 at risk EG00129 affected111 at risk EG0021 affected26 at risk
Hypertension	Vascular disorders	MedDRA	Systematic Assessment	EG00014 affected274 at risk EG0017 affected111 at risk EG0020 affected26 at risk

ID	Term
D002292	Carcinoma, Renal Cell
D007680	Kidney Neoplasms

ID	Term
D000230	Adenocarcinoma
D002277	Carcinoma
D009375	Neoplasms, Glandular and Epithelial
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D014571	Urologic Neoplasms
D014565	Urogenital Neoplasms
D009371	Neoplasms by Site
D052776	Female Urogenital Diseases
D005261	Female Urogenital Diseases and Pregnancy Complications
D000091642	Urogenital Diseases
D007674	Kidney Diseases
D014570	Urologic Diseases
D052801	Male Urogenital Diseases

ID	Term
D020123	Sirolimus
D018942	Macrolides
D007783	Lactones
D009930	Organic Chemicals