RECORD-1: RAD001 Plus Best Supportive Care (BSC) Versus BSC Plus Placebo in Patients With Metastatic Carcinoma of the Kidney Which Has Progressed After Treatment With Sorafenib and/or Sunitinib

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00410124
• Collaborator: (none)
• Enrollment: 416
• Locations: 93
• Arms: 2
• Duration (Months): 59
• Patients Per Site: 4.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To assess whether daily treatment with RAD001 could slow the growth and spread of metastatic carcinoma of the kidney. The safety of RAD001 was also to be studied in this trial.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Renal Cell Carcinoma	Drug: RAD001; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 416 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Multicenter Phase III Study to Compare the Safety and Efficacy of RAD001 Plus Best Supportive Care (BSC) Versus BSC Plus Placebo in Patients With Metastatic Carcinoma of the Kidney Which Has Progressed on VEGF Receptor Tyrosine Kinase Inhibitor
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Oct 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: RAD001; The dose of RAD001 was 10 mg/day. Patients were instructed to take two tablets (5 mg each) by mouth every day.; Other Names: Everolimus
Placebo Comparator: Placebo (plus 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.	Drug: Placebo

Outcome Measures

Primary Outcome Measures

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

   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.

Secondary Outcome Measures

1. Overall Survival (OS) Assessed by the Monthly Overall Survival Assessments [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)]

   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

2. Best Overall Response Rate in Patients Who Receive RAD001 Plus BSC Versus Matching Placebo Plus BSC [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]

   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.

3. Duration of Response in Patients Who Receive RAD001 Plus BSC Versus Placebo Plus BSC [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]

   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.

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

   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.

5. Time to Definitive Deterioration of the FKS-DRS Risk Score by at Least 2 Score Units Using Kaplan-Meier Method, by Treatment. [Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date]

   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.

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

   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.

7. 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) [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.]

   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)

8. Pharmacokinetics of RAD001: Time at Which C-Max Occurs (t-Max) [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.]

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

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

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

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

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

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

    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

12. Pharmacokinetics of RAD001: Normalized to Body Surface Area (CL/F) [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.]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Fayetteville	Arkansas	United States	72703
2	Novartis Investigative Site	Duarte	California	United States	91010-3000
3	Novartis Investigative Site	Sacramento	California	United States	95817
4	Novartis Investigative Site	San Francisco	California	United States	94115
5	Novartis Investigative Site	Santa Monica	California	United States	90404
6	Novartis Investigative Site	Ocoee	Florida	United States	*see dep*
7	Novartis Investigative Site	Orlando	Florida	United States	32806
8	Novartis Investigative Site	Indianapolis	Indiana	United States	46202
9	Novartis Investigative Site	Indianapolis	Indiana	United States	46227
10	Novartis Investigative Site	Louisville	Kentucky	United States	40202
11	Novartis Investigative Site	Baltimore	Maryland	United States	21201
12	Novartis Investigative Site	Detroit	Michigan	United States	48201
13	Novartis Investigative Site	Minneapolis	Minnesota	United States	55455
14	Novartis Investigative Site	Columbia	Missouri	United States	65201
15	Novartis Investigative Site	St. Louis	Missouri	United States	63110
16	Novartis Investigative Site	Las Vegas	Nevada	United States	89135
17	Novartis Investigative Site	Buffalo	New York	United States	14263
18	Novartis Investigative Site	New York	New York	United States	10021
19	Novartis Investigative Site	Chapel Hill	North Carolina	United States	27599
20	Novartis Investigative Site	Durham	North Carolina	United States	27710
21	Novartis Investigative Site	Raleigh	North Carolina	United States	27609
22	Novartis Investigative Site	Canton	Ohio	United States	44718
23	Novartis Investigative Site	Portland	Oregon	United States	97210
24	Novartis Investigative Site	Pittsburgh	Pennsylvania	United States	15232
25	Novartis Investigative Site	Bedford	Texas	United States	76022
26	Novartis Investigative Site	Dallas	Texas	United States	75246
27	Novartis Investigative Site	San Antonio	Texas	United States	78229
28	Novartis Investigative Site	Tyler	Texas	United States	75702
29	Novartis Investigative Site	Seattle	Washington	United States	98109-1023
30	Novartis Investigative Site	Spokane	Washington	United States	99202
31	Novartis Investigative Site	Morgantown	West Virginia	United States	26506
32	Novartis Investigative Site	Camperdown	New South Wales	Australia	2050
33	Novartis Investigative Site	Randwick	New South Wales	Australia	2031
34	Novartis Investigative Site	Westmead	New South Wales	Australia	2145
35	Novartis Investigative Site	South Brisbane	Queensland	Australia	4101
36	Novartis Investigative Site	Woodville	South Australia	Australia	5011
37	Novartis Investigative Site	Heidelberg	Victoria	Australia	3084
38	Novartis Investigative Site	Edmonton	Alberta	Canada	T6G 1Z2
39	Novartis Investigative Site	Vancouver	Alberta	Canada	V5Z 4E6
40	Novartis Investigative Site	Hamilton	Ontario	Canada	L8V 5C2
41	Novartis Investigative Site	London	Ontario	Canada	N6A 4G5
42	Novartis Investigative Site	Toronto	Ontario	Canada	M4N 3M5
43	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2M9
44	Novartis Investigative Site	Montreal	Quebec	Canada	H3G 1A4
45	Novartis Investigative Site	Bordeaux Cedex		France	33075
46	Novartis Investigative Site	Lille Cedex		France	59020
47	Novartis Investigative Site	Lyon Cedex		France	69373
48	Novartis Investigative Site	Paris		France	75015
49	Novartis Investigative Site	Saint-Herblain Cédex		France	44805
50	Novartis Investigative Site	Strasbourg		France	67091
51	Novartis Investigative Site	Toulouse Cedex 3		France	31052
52	Novartis Investigative Site	Villejuif Cedex		France	94805
53	Novartis Investigative Site	Dresden		Germany	01307
54	Novartis Investigative Site	Frankfurt/M		Germany	60590
55	Novartis Investigative Site	Hannover		Germany	30625
56	Novartis Investigative Site	Kassel		Germany	34125
57	Novartis Investigative Site	Mainz		Germany	55101
58	Novartis Investigative Site	München		Germany	81675
59	Novartis Investigative Site	Cremona	CR	Italy	26100
60	Novartis Investigative Site	Genova	GE	Italy	16132
61	Novartis Investigative Site	Milano	MI	Italy	20133
62	Novartis Investigative Site	Modena	MO	Italy	41100
63	Novartis Investigative Site	Perugia	PG	Italy	06129
64	Novartis Investigative Site	Pavia	PV	Italy	27100
65	Novartis Investigative Site	Roma	RM	Italy	00152
66	Novartis Investigative Site	Napoli		Italy	80132
67	Novartis Investigative Site	Matsuyama	Ehime	Japan	791-0280
68	Novartis Investigative Site	Sapporo	Hokkaido	Japan	060-8543
69	Novartis Investigative Site	Sapporo	Hokkaido	Japan	060-8648
70	Novartis Investigative Site	Tsukuba	Ibaraki	Japan	305-8576
71	Novartis Investigative Site	Kurashiki	Okayama	Japan	710-8602
72	Novartis Investigative Site	OsakaSayama	Osaka	Japan	589-8511
73	Novartis Investigative Site	Sunto-gun	Shizuoka	Japan	411-8777
74	Novartis Investigative Site	Utsunomiya	Tochigi	Japan	320-0834
75	Novartis Investigative Site	Chuo-ku	Tokyo	Japan	104-0045
76	Novartis Investigative Site	Akita		Japan	010-8543
77	Novartis Investigative Site	Chiba		Japan	260-8717
78	Novartis Investigative Site	Fukuoka		Japan	812-8582
79	Novartis Investigative Site	Osaka		Japan	537-8511
80	Novartis Investigative Site	Tokushima		Japan	770-8503
81	Novartis Investigative Site	Amsterdam		Netherlands
82	Novartis Investigative Site	Leiden		Netherlands	2300 RC
83	Novartis Investigative Site	Nijmegen		Netherlands	6525 GA
84	Novartis Investigative Site	Utrecht		Netherlands	3584CX
85	Novartis Investigative Site	Gdañsk		Poland	80-219
86	Novartis Investigative Site	Lodz		Poland	90-153
87	Novartis Investigative Site	Warszawa		Poland	00-909
88	Novartis Investigative Site	Wroclaw		Poland	50-367
89	Novartis Investigative Site	Hospitalet de LLobregat	Barcelona	Spain	08907
90	Novartis Investigative Site	Barcelona		Spain	08025
91	Novartis Investigative Site	Barcelona		Spain	08035
92	Novartis Investigative Site	Madrid		Spain	28041
93	Novartis Investigative Site	Valencia		Spain	46009

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00410124
• Other Study ID Numbers: CRAD001C2240; 2006-002070-21
• First Posted: Dec 12, 2006
• Last Update Posted: Jan 15, 2013
• Last Verified: Dec 1, 2012

• Keywords provided by Novartis Pharmaceuticals: advanced kidney cancer; everolimus; kidney cancer; oral therapy
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Everolimus

Study Results

Participant Flow

Pre-assignment Detail	Core period was terminated due to early achievements of efficacy targets and patients who were receiving study drug and patients receiving placebo in double blind phase had option to continue into the extension phase to receive open label RAD001.

Arm/Group Title	RAD001 +BSC	Placebo + BSC / RAD001
Arm/Group Description	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.	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.
Period Title: Core Phase Double Blind (15 Months)
STARTED	277	139
Ongoing	13	4
Completed Double Blind Treatment	62	2
COMPLETED	75	6
NOT COMPLETED	202	133
Period Title: Core Phase Double Blind (15 Months)
STARTED	67	111
COMPLETED	0	0
NOT COMPLETED	67	111

Baseline Characteristics

Arm/Group Title	RAD001 +BSC	Placebo + BSC	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	277	139	416
Age, Customized (participants) [Number]
<65 years	165 59.6%	98 70.5%	263 63.2%
>=65 years	112 40.4%	41 29.5%	153 36.8%
Sex: Female, Male (Count of Participants)
Female	61 22%	33 23.7%	94 22.6%
Male	216 78%	106 76.3%	322 77.4%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RAD001 +BSC	Placebo + BSC
Arm/Group Description	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.	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.
Measure Participants	277	139
Median (95% Confidence Interval) [Months]	4.90	1.87

2. Secondary Outcome

Title	Overall Survival (OS) Assessed by the Monthly Overall Survival Assessments
Description	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
Time Frame	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RAD001 +BSC	Placebo + BSC
Arm/Group Description	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.	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.
Measure Participants	277	139
Median (95% Confidence Interval) [Months]	13.57	13.01

3. Secondary Outcome

Title	Best Overall Response Rate in Patients Who Receive RAD001 Plus BSC Versus Matching Placebo Plus BSC
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RAD001 +BSC	Placebo + BSC
Arm/Group Description	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.	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.
Measure Participants	277	139
Number (95% Confidence Interval) [Percentage of Participants]	1.8 0.6%	0.0 0%

4. Secondary Outcome

Title	Duration of Response in Patients Who Receive RAD001 Plus BSC Versus Placebo Plus BSC
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RAD001 +BSC	Placebo + BSC
Arm/Group Description	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.	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.
Measure Participants	5	0
Median (95% Confidence Interval) [months]	NA

5. Secondary Outcome

Title	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.
Description	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.
Time Frame	Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RAD001 +BSC	Placebo + BSC
Arm/Group Description	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.	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.
Measure Participants	277	139
Median (95% Confidence Interval) [months]	4.76 (3.71)	3.91 (23.486)

6. Secondary Outcome

Title	Time to Definitive Deterioration of the FKS-DRS Risk Score by at Least 2 Score Units Using Kaplan-Meier Method, by Treatment.
Description	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.
Time Frame	Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RAD001 +BSC	Placebo + BSC
Arm/Group Description	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.	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.
Measure Participants	277	139
Median (95% Confidence Interval) [months]	4.76	3.84

7. Secondary Outcome

Title	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.
Description	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.
Time Frame	Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	RAD001 +BSC	Placebo + BSC
Arm/Group Description	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.	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.
Measure Participants	277	139
Median (95% Confidence Interval) [months]	5.06	4.57

8. Secondary Outcome

Title	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)
Description	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)
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Day 1	Day 15
Arm/Group Description	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.	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.
Measure Participants	13	12
C-max	68.1 (29.8)	76.7 (39.3)
C-min	7.9 (3.4)	19.8 (12.3)
C-avg	19.0 (7.0)	30.4 (10.9)

9. Secondary Outcome

Title	Pharmacokinetics of RAD001: Time at Which C-Max Occurs (t-Max)
Description	Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Day 1	Day 15
Arm/Group Description	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.	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.
Measure Participants	13	12
Median (Full Range) [h]	1.0	1.0

10. Secondary Outcome

Title	Pharmacokinetics of RAD001: Area Under Curve (AUC) in a Dosing Interval From Time-zero to Time of the Last Quantifiable Concentration. (AUC 0-tlast)
Description	Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Day 1	Day 15
Arm/Group Description	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.	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.
Measure Participants	13	12
Mean (Standard Deviation) [ng.h/mL]	455.0 (168.5)	729.1 (262.7)

11. Secondary Outcome

Title	Pharmacokinetics of RAD001: Time of the Last Quantifiable Concentration in a Dosing Interval - (Tlast)
Description	Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Day 1	Day 15
Arm/Group Description	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.	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.
Measure Participants	13	12
Median (Full Range) [hour]	24.0	24.0

12. Secondary Outcome

Title	Pharmacokinetics of RAD001: Apparent Systemic Clearance From Blood Following Extravascular Administration (CL/F)
Description	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
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Day 15
Arm/Group Description	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.
Measure Participants	12
Mean (Standard Deviation) [L/hour]	15.4 (5.3)

13. Secondary Outcome

Title	Pharmacokinetics of RAD001: Normalized to Body Surface Area (CL/F)
Description	Blood samples will be collected by direct venipuncture during regularly scheduled visits according to the collection plan provided in the study protocol.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Day 15
Arm/Group Description	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.
Measure Participants	12
Mean (Standard Deviation) [L/hour/m^2]	7.5 (2.3)

Adverse Events

Adverse Event Reporting Description	The Safety population consists of all patients who received at least one dose of study drug and who had at least one valid post-baseline safety assessment. Patients were analyzed according to the treatment actually received.
Arm/Group Title	Randomized to RAD001+ BSC ( Blinded + Open Label)		Randomized to Placebo + BSC (Open Label)		Randomized to Placebo + BSC (Double Blind Only)
Arm/Group Description	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.		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.		Patients received matching placebo of RAD001 tablets twice a day along with Best Supportive Care.
All Cause Mortality
	Randomized to RAD001+ BSC ( Blinded + Open Label)		Randomized to Placebo + BSC (Open Label)		Randomized to Placebo + BSC (Double Blind Only)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Randomized to RAD001+ BSC ( Blinded + Open Label)		Randomized to Placebo + BSC (Open Label)		Randomized to Placebo + BSC (Double Blind Only)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	135/274 (49.3%)		60/111 (54.1%)		17/26 (65.4%)
Blood and lymphatic system disorders
Anaemia	13/274 (4.7%)		5/111 (4.5%)		0/26 (0%)
Bone marrow reticulin fibrosis	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Haemolysis	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Thrombocytopenia	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Cardiac disorders
Aortic valve incompetence	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Cardiac disorder	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Cardiac failure	2/274 (0.7%)		0/111 (0%)		0/26 (0%)
Cardiac failure congestive	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Left ventricular dysfunction	1/274 (0.4%)		1/111 (0.9%)		0/26 (0%)
Myocardial infarction	0/274 (0%)		0/111 (0%)		1/26 (3.8%)
Myocardial ischaemia	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Pericardial effusion	1/274 (0.4%)		1/111 (0.9%)		0/26 (0%)
Tachycardia	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Endocrine disorders
Adrenal insufficiency	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Hypothyroidism	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Eye disorders
Eye pain	0/274 (0%)		0/111 (0%)		1/26 (3.8%)
Gastrointestinal disorders
Abdominal distension	1/274 (0.4%)		0/111 (0%)		1/26 (3.8%)
Abdominal pain	7/274 (2.6%)		1/111 (0.9%)		0/26 (0%)
Abdominal pain lower	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Ascites	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Constipation	2/274 (0.7%)		0/111 (0%)		0/26 (0%)
Diarrhoea	2/274 (0.7%)		1/111 (0.9%)		0/26 (0%)
Dysphagia	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Faecaloma	1/274 (0.4%)		0/111 (0%)		1/26 (3.8%)
Gastrointestinal haemorrhage	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Gastrointestinal sounds abnormal	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Haematochezia	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Inguinal hernia	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Intestinal obstruction	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Nausea	3/274 (1.1%)		1/111 (0.9%)		0/26 (0%)
Pancreatitis acute	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Peritoneal effusion	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Peritonitis	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Proctalgia	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Small intestinal obstruction	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Stomatitis	3/274 (1.1%)		0/111 (0%)		0/26 (0%)
Tongue oedema	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Vomiting	4/274 (1.5%)		1/111 (0.9%)		0/26 (0%)
General disorders
Asthenia	4/274 (1.5%)		1/111 (0.9%)		2/26 (7.7%)
Chest discomfort	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Chest pain	4/274 (1.5%)		0/111 (0%)		0/26 (0%)
Disease progression	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Fatigue	7/274 (2.6%)		0/111 (0%)		0/26 (0%)
General physical health deterioration	3/274 (1.1%)		1/111 (0.9%)		2/26 (7.7%)
Generalised oedema	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Malaise	2/274 (0.7%)		0/111 (0%)		0/26 (0%)
Mucosal inflammation	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Non-cardiac chest pain	4/274 (1.5%)		0/111 (0%)		0/26 (0%)
Oedema peripheral	3/274 (1.1%)		1/111 (0.9%)		0/26 (0%)
Pain	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Performance status decreased	1/274 (0.4%)		2/111 (1.8%)		0/26 (0%)
Pyrexia	13/274 (4.7%)		5/111 (4.5%)		0/26 (0%)
Hepatobiliary disorders
Bile duct obstruction	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Biloma	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Cholangitis	2/274 (0.7%)		0/111 (0%)		0/26 (0%)
Cholangitis acute	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Cholecystitis	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Cholelithiasis	1/274 (0.4%)		2/111 (1.8%)		0/26 (0%)
Cholestasis	2/274 (0.7%)		0/111 (0%)		0/26 (0%)
Hepatic failure	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Hepatic steatosis	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Hyperbilirubinaemia	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Jaundice	2/274 (0.7%)		0/111 (0%)		0/26 (0%)
Liver disorder	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Immune system disorders
Hypersensitivity	1/274 (0.4%)		1/111 (0.9%)		0/26 (0%)
Infections and infestations
Appendicitis	2/274 (0.7%)		0/111 (0%)		0/26 (0%)
Bronchitis	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Bronchopulmonary aspergillosis	2/274 (0.7%)		0/111 (0%)		0/26 (0%)
Cellulitis	0/274 (0%)		2/111 (1.8%)		0/26 (0%)
Enterococcal infection	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Escherichia infection	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Fungal infection	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Gastroenteritis	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Incision site infection	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Klebsiella infection	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Klebsiella sepsis	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Lung abscess	1/274 (0.4%)		2/111 (1.8%)		0/26 (0%)
Lung infection	4/274 (1.5%)		0/111 (0%)		0/26 (0%)
Pelvic abscess	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Pleural infection	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Pneumonia	10/274 (3.6%)		1/111 (0.9%)		0/26 (0%)
Pneumonia bacterial	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Pneumonia viral	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Pyelonephritis	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Rectal abscess	2/274 (0.7%)		0/111 (0%)		0/26 (0%)
Respiratory tract infection	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Salmonellosis	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Sepsis	2/274 (0.7%)		0/111 (0%)		0/26 (0%)
Septic shock	3/274 (1.1%)		1/111 (0.9%)		0/26 (0%)
Sinusitis	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Staphylococcal sepsis	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Upper respiratory tract infection	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Viral infection	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Wound abscess	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Injury, poisoning and procedural complications
Cervical vertebral fracture	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Device dislocation	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Femur fracture	1/274 (0.4%)		0/111 (0%)		1/26 (3.8%)
Fracture	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Humerus fracture	0/274 (0%)		0/111 (0%)		1/26 (3.8%)
Ilium fracture	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Lower limb fracture	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Medical device complication	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Post procedural bile leak	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Radiation skin injury	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Rib fracture	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Spinal fracture	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Stent occlusion	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Subdural haematoma	0/274 (0%)		0/111 (0%)		1/26 (3.8%)
Subdural haemorrhage	0/274 (0%)		0/111 (0%)		1/26 (3.8%)
Tracheal haemorrhage	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Wound dehiscence	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Investigations
Bile duct pressure increased	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Blood alkaline phosphatase increased	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Blood amylase increased	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Blood bilirubin increased	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Blood chloride decreased	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Blood creatine phosphokinase increased	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Blood creatinine increased	4/274 (1.5%)		1/111 (0.9%)		0/26 (0%)
Blood urea increased	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Ejection fraction decreased	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Lipase increased	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Metabolism and nutrition disorders
Cachexia	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Cell death	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Decreased appetite	3/274 (1.1%)		1/111 (0.9%)		0/26 (0%)
Dehydration	9/274 (3.3%)		2/111 (1.8%)		1/26 (3.8%)
Diabetes mellitus	2/274 (0.7%)		0/111 (0%)		0/26 (0%)
Diabetes mellitus inadequate control	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Diabetic ketoacidosis	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Hypercalcaemia	3/274 (1.1%)		0/111 (0%)		2/26 (7.7%)
Hyperkalaemia	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Hypomagnesaemia	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Hyponatraemia	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/274 (0.4%)		1/111 (0.9%)		0/26 (0%)
Back pain	4/274 (1.5%)		1/111 (0.9%)		1/26 (3.8%)
Bone pain	4/274 (1.5%)		0/111 (0%)		0/26 (0%)
Hypercreatinaemia	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Muscular weakness	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Musculoskeletal chest pain	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Osteonecrosis	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Pathological fracture	2/274 (0.7%)		1/111 (0.9%)		1/26 (3.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Cancer pain	2/274 (0.7%)		0/111 (0%)		0/26 (0%)
Infected neoplasm	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Lung neoplasm	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Lymphangiosis carcinomatosa	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Metastases to bone	0/274 (0%)		0/111 (0%)		1/26 (3.8%)
Metastases to central nervous system	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Metastases to liver	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Metastases to lung	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Metastases to spine	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Pleura carcinoma	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Renal cancer metastatic	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Transitional cell carcinoma	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Tumour haemorrhage	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Tumour pain	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Nervous system disorders
Aphasia	1/274 (0.4%)		0/111 (0%)		1/26 (3.8%)
Balance disorder	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Cerebral haemorrhage	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Coma	0/274 (0%)		0/111 (0%)		1/26 (3.8%)
Convulsion	0/274 (0%)		1/111 (0.9%)		1/26 (3.8%)
Depressed level of consciousness	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Dizziness	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Encephalopathy	0/274 (0%)		0/111 (0%)		1/26 (3.8%)
Grand mal convulsion	0/274 (0%)		1/111 (0.9%)		1/26 (3.8%)
Headache	2/274 (0.7%)		0/111 (0%)		1/26 (3.8%)
Hemiplegia	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Lethargy	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Loss of consciousness	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Paraesthesia	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Spinal cord compression	2/274 (0.7%)		0/111 (0%)		0/26 (0%)
Status epilepticus	0/274 (0%)		0/111 (0%)		1/26 (3.8%)
Tremor	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Trigeminal neuralgia	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Psychiatric disorders
Agitation	0/274 (0%)		1/111 (0.9%)		1/26 (3.8%)
Confusional state	2/274 (0.7%)		0/111 (0%)		1/26 (3.8%)
Delirium	1/274 (0.4%)		1/111 (0.9%)		0/26 (0%)
Depression	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Hallucination	0/274 (0%)		0/111 (0%)		1/26 (3.8%)
Intentional self-injury	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Mental status changes	2/274 (0.7%)		1/111 (0.9%)		0/26 (0%)
Psychotic disorder	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Suicide attempt	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Renal and urinary disorders
Haematuria	2/274 (0.7%)		1/111 (0.9%)		1/26 (3.8%)
Hydronephrosis	0/274 (0%)		2/111 (1.8%)		0/26 (0%)
Renal failure	5/274 (1.8%)		4/111 (3.6%)		0/26 (0%)
Renal failure acute	3/274 (1.1%)		3/111 (2.7%)		1/26 (3.8%)
Renal impairment	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Ureteric dilatation	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Ureteric obstruction	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Ureteric stenosis	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Urinary retention	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Reproductive system and breast disorders
Pelvic pain	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	3/274 (1.1%)		0/111 (0%)		0/26 (0%)
Asphyxia	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Atelectasis	2/274 (0.7%)		0/111 (0%)		0/26 (0%)
Cough	4/274 (1.5%)		1/111 (0.9%)		0/26 (0%)
Dyspnoea	25/274 (9.1%)		11/111 (9.9%)		1/26 (3.8%)
Dyspnoea exertional	1/274 (0.4%)		1/111 (0.9%)		0/26 (0%)
Haemoptysis	3/274 (1.1%)		1/111 (0.9%)		0/26 (0%)
Hydrothorax	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Hypoxia	2/274 (0.7%)		1/111 (0.9%)		0/26 (0%)
Interstitial lung disease	6/274 (2.2%)		3/111 (2.7%)		0/26 (0%)
Lung disorder	3/274 (1.1%)		2/111 (1.8%)		0/26 (0%)
Lung infiltration	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Pleural effusion	11/274 (4%)		8/111 (7.2%)		0/26 (0%)
Pleuritic pain	0/274 (0%)		2/111 (1.8%)		0/26 (0%)
Pneumonitis	11/274 (4%)		2/111 (1.8%)		0/26 (0%)
Pulmonary alveolar haemorrhage	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Pulmonary embolism	2/274 (0.7%)		2/111 (1.8%)		0/26 (0%)
Pulmonary infarction	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Pulmonary toxicity	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Respiratory distress	0/274 (0%)		1/111 (0.9%)		0/26 (0%)
Respiratory failure	2/274 (0.7%)		3/111 (2.7%)		1/26 (3.8%)
Skin and subcutaneous tissue disorders
Night sweats	0/274 (0%)		0/111 (0%)		1/26 (3.8%)
Pruritus	1/274 (0.4%)		1/111 (0.9%)		0/26 (0%)
Vascular disorders
Circulatory collapse	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Deep vein thrombosis	1/274 (0.4%)		1/111 (0.9%)		0/26 (0%)
Haematoma	0/274 (0%)		0/111 (0%)		1/26 (3.8%)
Shock	1/274 (0.4%)		0/111 (0%)		0/26 (0%)
Thrombosis	0/274 (0%)		0/111 (0%)		1/26 (3.8%)
Other (Not Including Serious) Adverse Events
	Randomized to RAD001+ BSC ( Blinded + Open Label)		Randomized to Placebo + BSC (Open Label)		Randomized to Placebo + BSC (Double Blind Only)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	261/274 (95.3%)		106/111 (95.5%)		23/26 (88.5%)
Blood and lymphatic system disorders
Anaemia	108/274 (39.4%)		42/111 (37.8%)		4/26 (15.4%)
Lymphopenia	29/274 (10.6%)		7/111 (6.3%)		0/26 (0%)
Thrombocytopenia	19/274 (6.9%)		8/111 (7.2%)		0/26 (0%)
Ear and labyrinth disorders
Ear pain	3/274 (1.1%)		6/111 (5.4%)		0/26 (0%)
Gastrointestinal disorders
Abdominal pain	31/274 (11.3%)		10/111 (9%)		1/26 (3.8%)
Abdominal pain upper	20/274 (7.3%)		6/111 (5.4%)		1/26 (3.8%)
Aphthous stomatitis	26/274 (9.5%)		13/111 (11.7%)		0/26 (0%)
Constipation	60/274 (21.9%)		25/111 (22.5%)		5/26 (19.2%)
Diarrhoea	90/274 (32.8%)		28/111 (25.2%)		2/26 (7.7%)
Dry mouth	22/274 (8%)		5/111 (4.5%)		4/26 (15.4%)
Haemorrhoids	17/274 (6.2%)		1/111 (0.9%)		0/26 (0%)
Nausea	78/274 (28.5%)		27/111 (24.3%)		5/26 (19.2%)
Stomatitis	106/274 (38.7%)		33/111 (29.7%)		3/26 (11.5%)
Vomiting	63/274 (23%)		19/111 (17.1%)		3/26 (11.5%)
General disorders
Asthenia	96/274 (35%)		31/111 (27.9%)		9/26 (34.6%)
Fatigue	86/274 (31.4%)		40/111 (36%)		8/26 (30.8%)
General physical health deterioration	6/274 (2.2%)		3/111 (2.7%)		2/26 (7.7%)
Mucosal inflammation	53/274 (19.3%)		26/111 (23.4%)		0/26 (0%)
Non-cardiac chest pain	12/274 (4.4%)		8/111 (7.2%)		0/26 (0%)
Oedema peripheral	79/274 (28.8%)		25/111 (22.5%)		5/26 (19.2%)
Pyrexia	55/274 (20.1%)		24/111 (21.6%)		1/26 (3.8%)
Infections and infestations
Bronchitis	17/274 (6.2%)		6/111 (5.4%)		1/26 (3.8%)
Nasopharyngitis	20/274 (7.3%)		8/111 (7.2%)		1/26 (3.8%)
Urinary tract infection	14/274 (5.1%)		5/111 (4.5%)		0/26 (0%)
Investigations
Blood alkaline phosphatase increased	11/274 (4%)		6/111 (5.4%)		0/26 (0%)
Blood creatinine increased	29/274 (10.6%)		3/111 (2.7%)		0/26 (0%)
Gamma-glutamyltransferase increased	20/274 (7.3%)		7/111 (6.3%)		0/26 (0%)
Weight decreased	27/274 (9.9%)		19/111 (17.1%)		2/26 (7.7%)
Metabolism and nutrition disorders
Decreased appetite	82/274 (29.9%)		24/111 (21.6%)		6/26 (23.1%)
Dehydration	9/274 (3.3%)		5/111 (4.5%)		2/26 (7.7%)
Hypercalcaemia	10/274 (3.6%)		4/111 (3.6%)		3/26 (11.5%)
Hypercholesterolaemia	60/274 (21.9%)		21/111 (18.9%)		0/26 (0%)
Hyperglycaemia	36/274 (13.1%)		15/111 (13.5%)		2/26 (7.7%)
Hypertriglyceridaemia	45/274 (16.4%)		17/111 (15.3%)		0/26 (0%)
Hypophosphataemia	18/274 (6.6%)		4/111 (3.6%)		0/26 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	39/274 (14.2%)		20/111 (18%)		1/26 (3.8%)
Back pain	39/274 (14.2%)		13/111 (11.7%)		2/26 (7.7%)
Bone pain	11/274 (4%)		9/111 (8.1%)		1/26 (3.8%)
Musculoskeletal chest pain	14/274 (5.1%)		3/111 (2.7%)		0/26 (0%)
Musculoskeletal pain	10/274 (3.6%)		8/111 (7.2%)		1/26 (3.8%)
Myalgia	7/274 (2.6%)		8/111 (7.2%)		0/26 (0%)
Pain in extremity	34/274 (12.4%)		17/111 (15.3%)		3/26 (11.5%)
Nervous system disorders
Dizziness	19/274 (6.9%)		3/111 (2.7%)		3/26 (11.5%)
Dysgeusia	32/274 (11.7%)		14/111 (12.6%)		1/26 (3.8%)
Headache	53/274 (19.3%)		14/111 (12.6%)		2/26 (7.7%)
Paraesthesia	12/274 (4.4%)		1/111 (0.9%)		2/26 (7.7%)
Psychiatric disorders
Anxiety	14/274 (5.1%)		3/111 (2.7%)		2/26 (7.7%)
Insomnia	30/274 (10.9%)		11/111 (9.9%)		2/26 (7.7%)
Renal and urinary disorders
Dysuria	5/274 (1.8%)		6/111 (5.4%)		0/26 (0%)
Haematuria	4/274 (1.5%)		0/111 (0%)		2/26 (7.7%)
Nocturia	10/274 (3.6%)		8/111 (7.2%)		1/26 (3.8%)
Respiratory, thoracic and mediastinal disorders
Cough	96/274 (35%)		30/111 (27%)		4/26 (15.4%)
Dyspnoea	59/274 (21.5%)		28/111 (25.2%)		3/26 (11.5%)
Dyspnoea exertional	17/274 (6.2%)		8/111 (7.2%)		1/26 (3.8%)
Epistaxis	51/274 (18.6%)		12/111 (10.8%)		0/26 (0%)
Oropharyngeal pain	10/274 (3.6%)		6/111 (5.4%)		0/26 (0%)
Pleural effusion	13/274 (4.7%)		8/111 (7.2%)		0/26 (0%)
Pneumonitis	18/274 (6.6%)		4/111 (3.6%)		0/26 (0%)
Skin and subcutaneous tissue disorders
Dry skin	38/274 (13.9%)		14/111 (12.6%)		3/26 (11.5%)
Erythema	15/274 (5.5%)		2/111 (1.8%)		0/26 (0%)
Nail disorder	20/274 (7.3%)		7/111 (6.3%)		0/26 (0%)
Onychoclasis	16/274 (5.8%)		2/111 (1.8%)		0/26 (0%)
Pruritus	43/274 (15.7%)		12/111 (10.8%)		2/26 (7.7%)
Rash	83/274 (30.3%)		29/111 (26.1%)		1/26 (3.8%)
Vascular disorders
Hypertension	14/274 (5.1%)		7/111 (6.3%)		0/26 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Principal Investigators are NOT employed by the organization sponsoring the study. Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial.