Everolimus Plus Best Supportive Care vs Placebo Plus Best Supportive Care in the Treatment of Patients With Advanced Neuroendocrine Tumors (GI or Lung Origin) (RADIANT-4)

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ClinicalTrials.gov Identifier: NCT01524783

Recruitment Status : Completed

First Posted : February 2, 2012

Results First Posted : December 28, 2016

Last Update Posted : August 5, 2021

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Sponsor:

Information provided by (Responsible Party):

Novartis ( Novartis Pharmaceuticals )

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Conditions	Advanced NET of GI Origin Advanced NET of Lung Origin Neuroendocrine Tumors
Interventions	Drug: Everolimus Drug: Placebo Other: Best suportive care (BSC)
Enrollment	302

Participant Flow

Recruitment Details

Pre-assignment Details

At baseline, participants were randomized to either everolimus+BSC or placebo+BSC arm. Two patients randomized to the everolimus arm were not treated due to withdrawal of consent and protocol deviation.

As per Data Monitoring Committee recommendation (03-Jun-2015), implemented through protocol amendment 3 (issued on 06-May-2016), remaining participants entered the open-label part of the study, where participants in the placebo arm were allowed to crossover to open-label treatment with everolimus


Arm/Group Title	Everolimus + BSC (Throughout Study)	Placebo+BSC (Blinded Period)	Everolimus+BSC (Crossover)
Arm/Group Description	Participants received everolimus 10...	Participants received matching plac...	Participants who crossed over from ...
Arm/Group Description	Participants received everolimus 10 mg once daily BSC throughout the study	Participants received matching placebo once daily plus BSC during the blinded period	Participants who crossed over from placebo arm (blinded period) to open-label treatment with everolimus 10mg once daily plus BSC
Period Title: Blinded Period
Started	205	97	0
Completed ^[1]	26	6	0
Not Completed	179	91	0
Reason Not Completed
Adverse Event	64	7	0
Disease Progression	89	75	0
Withdrawal by Subject	19	6	0
Protocol deviation	2	1	0
Death	5	2	0
[1] Participants who entered the open-label part of the study
Period Title: Open-label Period
Started	26	0	6
Completed	0	0	0
Not Completed	26	0	6
Reason Not Completed
Disease progression	13	0	2
Administrative problems	5	0	2
Adverse Event	5	0	1
Withdrawal by Subject	2	0	1
Protocol deviation	1	0	0

Baseline Characteristics

Arm/Group Title		Everolimus + BSC	Placebo+BSC	Total
Arm/Group Description		Participants received everolimus 10...	Participants received matching plac...	Total of all reporting groups
Arm/Group Description		Participants received everolimus 10 mg once daily BSC throughout the study	Participants received matching placebo once daily plus BSC during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period	Total of all reporting groups
Overall Number of Baseline Participants		205	97	302
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous ^[1] Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	205 participants	97 participants	302 participants
		62.9 (11.70)	59.4 (12.89)	61.7 (12.18)
		[1] Measure Description: Age continuous at Baseline: Blinded Period
Sex: Female, Male ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	205 participants	97 participants	302 participants
	Female	116 56.6%	44 45.4%	160 53.0%
	Male	89 43.4%	53 54.6%	142 47.0%
		[1] Measure Description: Gender at Baseline: Blinded period
Race/Ethnicity, Customized ^[1] Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	205 participants	97 participants	302 participants
	Caucasian	162 79.0%	68 70.1%	230 76.2%
	Asian	32 15.6%	18 18.6%	50 16.6%
	Black	6 2.9%	9 9.3%	15 5.0%
	Other	5 2.4%	2 2.1%	7 2.3%
		[1] Measure Description: Race at Baseline: Blinded-period

Outcome Measures

1.Primary Outcome


Title	Probability of Participants Remaining Event-Free in Progression-Free Survival (PFS) Based on Central Radiology Assessment
Description	PFS is defined as the time from randomization to the date of the first...
Description	PFS is defined as the time from randomization to the date of the first documented tumor progression or death from any cause, whichever comes first. Progression was defined using modified RECIST 1.0 and as per central radiology assessment as at least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. Progression was assessed by cat scan (CT) and/or magnetic resonance imaging (MRI). For participants who had not progressed or died at the analysis cut-off date, PFS was censored at the date of the last adequate tumor evaluation date. An adequate tumour assessment is a tumour assessment with an overall response other than unknown. The percentage event-free probability estimate is the estimated probability that a patient will remain event-free in PFS up to the specified time point.
Time Frame	From date of randomization to progression or death, whichever comes first, assessed up to 27 months

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Everolimus + BSC	Placebo + BSC
Arm/Group Description:	Participants received everolimus 10...	Participants received matching plac...
Arm/Group Description:	Participants received everolimus 10 mg once daily BSC throughout the study	Participants received matching placebo once daily plus BSC during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period
Overall Number of Participants Analyzed	205	97
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percent event-free probability in PFS
2 months	90.1 (84.8 to 93.5)	74.6 (64.3 to 82.4)
4 months	81.2 (74.9 to 86.2)	49.1 (38.1 to 59.2)
6 months	72.1 (65.0 to 78.0)	40.1 (29.5 to 50.5)
8 months	62.4 (54.8 to 69.1)	35.8 (25.4 to 46.2)
10 months	51.7 (44.0 to 59.0)	31.3 (21.3 to 41.7)
12 months	44.4 (36.7 to 51.8)	28.1 (18.5 to 38.6)
15 months	40.1 (32.5 to 47.6)	26.4 (16.9 to 36.8)
18 months	31.8 (24.1 to 39.8)	24.4 (15.0 to 34.9)
21 months	27.6 (19.0 to 36.8)	17.4 (9.0 to 28.2)
24 months	22.0 (13.0 to 32.5)	17.4 (9.0 to 28.2)
27 months	NA ^[1] (NA to NA)	17.4 (9.0 to 28.2)

[1]

Not estimable due to the low number of events

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Everolimus + BSC, Placebo + BSC
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.48
	Confidence Interval	(2-Sided) 95% 0.35 to 0.67
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Overall Survival (OS)
Description	OS is defined as the time from the date of randomization to date of de...
Description	OS is defined as the time from the date of randomization to date of death due to any cause. If a death had not been observed by the date of analysis cut-off, then OS was censored at the date of last contact. All participants randomized to placebo arm who crossed over to everolimus were censored.
Time Frame	From date of randomization to date of death, assessed up to approximately 8 years

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Everolimus + BSC	Placebo + BSC
Arm/Group Description:	Participants received everolimus 10...	Participants received matching plac...
Arm/Group Description:	Participants received everolimus 10 mg once daily BSC throughout the study	Participants received matching placebo once daily plus BSC during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period
Overall Number of Participants Analyzed	205	97
Median (95% Confidence Interval) Unit of Measure: Months
	43.1 (36.27 to 54.24)	41.76 (23.46 to 53.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Everolimus + BSC, Placebo + BSC
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.259
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95% 0.66 to 1.24
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Overall Response Rate (ORR) as Per Modified RECIST 1.0 According to Central Evaluation
Description	ORR is defined as the proportion of patients with best overall respons...
Description	ORR is defined as the proportion of patients with best overall response (BOR) of complete response (CR) or partial response (PR), according to central evaluation and as per modified RECIST 1.0. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.
Time Frame	From randomization until end of treatment, assessed up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Everolimus + BSC	Placebo + BSC
Arm/Group Description:	Participants received everolimus 10...	Participants received matching plac...
Arm/Group Description:	Participants received everolimus 10 mg once daily BSC throughout the study	Participants received matching placebo once daily plus BSC during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period
Overall Number of Participants Analyzed	205	97
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of participants
	2.0 (0.5 to 4.9)	1.0 (0.0 to 5.6)

4.Secondary Outcome


Title	Disease Control Rate (DCR) Based on Modified RECIST 1.0 and as Per Central Radiology Assessment
Description	DCR is defined as the proportion of subjects with best overall respons...
Description	DCR is defined as the proportion of subjects with best overall response of CR or PR or stable disease based on modified RECIST 1.0 and as per central radiology assessment. CR: disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters. Stable disease: Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression.
Time Frame	From randomization until end of treatment, assessed up to approximately 2.5 years

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Everolimus + BSC	Placebo + BSC
Arm/Group Description:	Participants received everolimus 10...	Participants received matching plac...
Arm/Group Description:	Participants received everolimus 10 mg once daily BSC throughout the study	Participants received matching placebo once daily plus BSC during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period
Overall Number of Participants Analyzed	205	97
Measure Type: Number Number (95% Confidence Interval) Unit of Measure: Percentage of participants
	82.4 (76.5 to 87.4)	64.9 (54.6 to 74.4)

5.Secondary Outcome


Title	Time to Definitive Deterioration in Functional Assessment of Cancer Therapy - General (FACT-G) Questionnaire Total Score
Description	FACT-G is a self-assessed health-related quality of life questionnaire...
Description	FACT-G is a self-assessed health-related quality of life questionnaire. The questionnaire is comprised of 27 questions examining physical, social/family, emotional, and functional well-being. Participants responded to the items on a five-point scale, ranging from 0: "Not at all" to 4: "Very much." The total score ranges from 0 to 108, with higher scores indicating a better patient-reported outcome/quality of life. Definitive deterioration is defined as a decrease in the total score by at least 7 points compared to baseline with no further improvement. Death was considered as worsening of the FACT-G total score if it occurred close to the last available assessment, where "close" was defined as twice the planned period between two assessments. Patients without definitive worsening prior to analysis cut-off or prior to start of another anticancer therapy were censored at the date of their last assessment.
Time Frame	From randomization to definitive deterioration of FACT-G total score, assessed up to approximately 3 years

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Everolimus + BSC	Placebo + BSC
Arm/Group Description:	Participants received everolimus 10...	Participants received matching plac...
Arm/Group Description:	Participants received everolimus 10 mg once daily BSC throughout the study	Participants received matching placebo once daily plus BSC during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period
Overall Number of Participants Analyzed	205	97
Median (95% Confidence Interval) Unit of Measure: Months
	13.01 (9.33 to 24.80)	9.23 (5.52 to 28.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Everolimus + BSC, Placebo + BSC
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.073
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95% 0.50 to 1.10
	Estimation Comments	[Not Specified]

6.Secondary Outcome


Title	Change From Baseline in Chromogranin A (CgA) Levels
Description	CgA is a potential biomarker for tumor response. Blood samples were co...
Description	CgA is a potential biomarker for tumor response. Blood samples were collected for assessment of CgA levels. Change from Baseline at a particular visit was calculated as the CgA level at that visit minus Baseline.
Time Frame	From baseline (every 4 weeks) up to 116 weeks

Outcome Measure Data

Analysis Population Description

The full analysis set (FAS) consists of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment arm and stratification factors they were assigned to at randomization. Number analyzed signified number of participants with available data for this outcome measure at specified timepoints.


Arm/Group Title		Everolimus + BSC	Placebo + BSC
Arm/Group Description:		Participants received everolimus 10...	Participants received matching plac...
Arm/Group Description:		Participants received everolimus 10 mg once daily BSC throughout the study	Participants received matching placebo once daily plus BSC during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period
Overall Number of Participants Analyzed		205	97
Mean (Standard Deviation) Unit of Measure: microgram/liter (ug/L)
Week 4	Number Analyzed	164 participants	90 participants
Week 4		434.8 (2306.70)	1154.3 (9083.39)
Week 8	Number Analyzed	156 participants	88 participants
Week 8		162.3 (2550.65)	2697.6 (19956.90)
Week 12	Number Analyzed	143 participants	75 participants
Week 12		396.7 (2401.78)	1176.0 (3322.13)
Week 16	Number Analyzed	141 participants	62 participants
Week 16		263.5 (2946.76)	1450.4 (4825.78)
Week 20	Number Analyzed	131 participants	51 participants
Week 20		162.1 (2464.47)	3640.1 (12653.42)
Week 24	Number Analyzed	119 participants	39 participants
Week 24		253.2 (3487.27)	1783.9 (5399.98)
Week 28	Number Analyzed	112 participants	35 participants
Week 28		587.2 (4861.35)	1350.3 (5701.70)
Week 32	Number Analyzed	109 participants	31 participants
Week 32		508.5 (6102.61)	2000.7 (6362.83)
Week 36	Number Analyzed	97 participants	26 participants
Week 36		94.7 (4905.17)	180.9 (383.93)
Week 40	Number Analyzed	87 participants	24 participants
Week 40		511.4 (6180.67)	207.6 (403.30)
Week 44	Number Analyzed	86 participants	23 participants
Week 44		552.8 (4173.44)	140.6 (328.02)
Week 48	Number Analyzed	77 participants	23 participants
Week 48		1326.2 (8718.92)	129.0 (326.69)
Week 52	Number Analyzed	70 participants	24 participants
Week 52		1196.2 (7737.76)	124.2 (452.38)
Week 56	Number Analyzed	60 participants	21 participants
Week 56		1920.6 (11250.07)	134.9 (346.33)
Week 60	Number Analyzed	60 participants	19 participants
Week 60		1722.0 (13155.03)	120.9 (415.73)
Week 64	Number Analyzed	59 participants	19 participants
Week 64		3811.0 (26656.45)	141.6 (281.38)
Week 68	Number Analyzed	56 participants	17 participants
Week 68		1413.3 (9588.68)	222.6 (333.93)
Week 72	Number Analyzed	53 participants	17 participants
Week 72		239.5 (2318.79)	233.7 (400.43)
Week 76	Number Analyzed	51 participants	16 participants
Week 76		3256.5 (19395.40)	210.9 (522.62)
Week 80	Number Analyzed	49 participants	15 participants
Week 80		5421.0 (32471.22)	286.3 (425.45)
Week 84	Number Analyzed	45 participants	14 participants
Week 84		4379.9 (28302.84)	175.4 (575.98)
Week 88	Number Analyzed	36 participants	11 participants
Week 88		571.2 (2694.44)	-9.4 (473.66)
Week 92	Number Analyzed	30 participants	10 participants
Week 92		765.5 (2913.15)	63.7 (477.53)
Week 96	Number Analyzed	24 participants	10 participants
Week 96		984.6 (3379.28)	146.5 (468.24)
Week 100	Number Analyzed	22 participants	6 participants
Week 100		935.3 (2961.60)	-12.7 (399.25)
Week 104	Number Analyzed	15 participants	6 participants
Week 104		1466.4 (4257.03)	-21.7 (285.99)
Week 108	Number Analyzed	12 participants	6 participants
Week 108		2245.8 (6077.99)	215.9 (293.87)
Week 112	Number Analyzed	12 participants	4 participants
Week 112		2817.0 (7786.28)	514.5 (661.80)
Week 116	Number Analyzed	6 participants	4 participants
Week 116		2951.8 (6745.06)	99.6 (92.91)

7.Secondary Outcome


Title	Change From Baseline in Neuron Specific Enolase (NSE) Levels
Description	NSE is a potential biomarker for tumor response. Blood samples were co...
Description	NSE is a potential biomarker for tumor response. Blood samples were collected for assessment of NSE levels. Change from Baseline at a particular visit was calculated as the NSE level at that visit minus Baseline.
Time Frame	From baseline (every 4 weeks) up to Week 116

Outcome Measure Data

Analysis Population Description


Arm/Group Title		Everolimus + BSC	Placebo + BSC
Arm/Group Description:		Participants received everolimus 10...	Participants received matching plac...
Arm/Group Description:		Participants received everolimus 10 mg once daily BSC throughout the study	Participants received matching placebo once daily plus BSC during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period
Overall Number of Participants Analyzed		205	97
Mean (Standard Deviation) Unit of Measure: microgram/liter (ug/L)
Week 4	Number Analyzed	158 participants	89 participants
Week 4		0.1 (5.21)	-2.2 (39.87)
Week 8	Number Analyzed	151 participants	85 participants
Week 8		0.3 (8.71)	-4.2 (36.71)
Week 12	Number Analyzed	139 participants	74 participants
Week 12		-0.3 (8.37)	15.5 (163.75)
Week 16	Number Analyzed	135 participants	62 participants
Week 16		2.0 (8.34)	4.1 (19.44)
Week 20	Number Analyzed	128 participants	50 participants
Week 20		0.8 (6.21)	5.3 (18.26)
Week 24	Number Analyzed	117 participants	39 participants
Week 24		1.7 (8.99)	6.7 (23.47)
Week 28	Number Analyzed	110 participants	35 participants
Week 28		1.1 (6.37)	0.4 (9.16)
Week 32	Number Analyzed	106 participants	31 participants
Week 32		1.5 (14.24)	3.1 (8.96)
Week 36	Number Analyzed	96 participants	27 participants
Week 36		2.0 (15.11)	2.0 (5.90)
Week 40	Number Analyzed	86 participants	24 participants
Week 40		1.2 (6.48)	1.2 (4.49)
Week 44	Number Analyzed	87 participants	23 participants
Week 44		0.8 (5.10)	1.2 (4.46)
Week 48	Number Analyzed	74 participants	23 participants
Week 48		2.0 (9.20)	0.6 (4.06)
Week 52	Number Analyzed	71 participants	23 participants
Week 52		1.5 (5.82)	0.7 (4.19)
Week 56	Number Analyzed	60 participants	21 participants
Week 56		3.6 (18.56)	0.9 (5.89)
Week 60	Number Analyzed	63 participants	20 participants
Week 60		2.4 (8.19)	0.1 (3.35)
Week 64	Number Analyzed	58 participants	18 participants
Week 64		4.4 (23.22)	0.9 (3.80)
Week 68	Number Analyzed	58 participants	18 participants
Week 68		1.1 (4.68)	1.9 (4.48)
Week 72	Number Analyzed	53 participants	18 participants
Week 72		1.6 (4.46)	0.7 (3.91)
Week 76	Number Analyzed	52 participants	16 participants
Week 76		1.7 (5.11)	0.6 (3.89)
Week 80	Number Analyzed	51 participants	13 participants
Week 80		2.9 (10.15)	0.7 (2.83)
Week 84	Number Analyzed	41 participants	14 participants
Week 84		8.0 (33.13)	0.1 (3.47)
Week 88	Number Analyzed	37 participants	11 participants
Week 88		2.2 (3.89)	0.6 (2.47)
Week 92	Number Analyzed	29 participants	10 participants
Week 92		4.0 (7.24)	0.1 (3.79)
Week 96	Number Analyzed	23 participants	10 participants
Week 96		4.3 (5.96)	0.0 (2.99)
Week 100	Number Analyzed	22 participants	5 participants
Week 100		1.8 (3.79)	-0.2 (5.10)
Week 104	Number Analyzed	15 participants	6 participants
Week 104		2.9 (4.11)	-1.7 (4.76)
Week 108	Number Analyzed	12 participants	6 participants
Week 108		5.5 (13.48)	-0.5 (4.33)
Week 112	Number Analyzed	11 participants	3 participants
Week 112		2.8 (5.72)	-3.2 (3.30)
Week 116	Number Analyzed	6 participants	4 participants
Week 116		10.6 (14.92)	0.2 (4.17)

8.Secondary Outcome


Title	Time to Definitive Deterioration in World Health Organization (WHO) Performance Status (PS) Change
Description	WHO PS is a scale rated from 0 (fully active) to 5 (death) by a health...
Description	WHO PS is a scale rated from 0 (fully active) to 5 (death) by a healthcare professional to assess the overall status of a patient: a lower score represents a higher ability to perform daily tasks. Deterioration is defined as an increase of at least one point compared to baseline. Deterioration is considered definitive if no improvements in the WHO PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed. Death was considered as worsening of the WHO PS if it occurred close to the last available assessment, where "close" was defined as twice the planned period between two assessments. Patients without definitive worsening prior to analysis cut-off or prior to start of another anticancer therapy were censored at the date of their last assessment.
Time Frame	From randomization to definitive deterioration of WHO performance status, assessed up to approximately 3 years

Outcome Measure Data

Analysis Population Description


Arm/Group Title	Everolimus + BSC	Placebo + BSC
Arm/Group Description:	Participants received everolimus 10...	Participants received matching plac...
Arm/Group Description:	Participants received everolimus 10 mg once daily BSC throughout the study	Participants received matching placebo once daily plus BSC during the blinded period. Participants were allowed to crossover to treatment with everolimus 10mg once daily plus BSC during the open-label period
Overall Number of Participants Analyzed	205	97
Median (95% Confidence Interval) Unit of Measure: Months
	24.08 ^[1] (17.05 to NA)	24.15 ^[1] (8.31 to NA)

[1]

NA. Not evaluable due to the low number of participants with an event of interest.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Everolimus + BSC, Placebo + BSC
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.539
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95% 0.65 to 1.61
	Estimation Comments	[Not Specified]

9.Secondary Outcome


Title	Pharmacokinetics (PK): Predose Concentration (Cmin) of Everolimus at Day 29
Description	A pre-dose blood sample at day 29 was collected to determine the expos...
Description	A pre-dose blood sample at day 29 was collected to determine the exposure of everolimus at the steady-state pre-dose concentration (Cmin). Cmin is provided for participants randomized to everolimus+BSC who received 10mg of everolimus daily and also for participants randomized to everolimus+BSC who received 5mg of everolimus daily which was required for a number of participants in the study experiencing adverse events requiring dose modifications
Time Frame	Pre-dose at Day 29.

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of the study drug with evaluable blood samples for this endpoint.


Arm/Group Title		Everolimus + BSC
Arm/Group Description:		Participants received everolimus 10...
Arm/Group Description:		Participants received everolimus 10 mg once daily BSC throughout the study
Overall Number of Participants Analyzed		48
Mean (Standard Deviation) Unit of Measure: nanogram/milliliter (ng/mL)
10mg daily dose	Number Analyzed	48 participants
10mg daily dose		16.382 (13.2767)
5mg daily dose	Number Analyzed	3 participants
5mg daily dose		4.700 (3.8396)

10.Post-Hoc Outcome


Title	All Collected Deaths
Description	Deaths on-treatment were collected from first dose of study treatment ...
Description	Deaths on-treatment were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approximately 8 years. Total Deaths were collected from first dose of study treatment until end of post-treatment survival follow, up to maximum duration of approximately 8 years.
Time Frame	On-treatment deaths: up to approximately 8 years. All deaths: up to approximately 8 years

Outcome Measure Data

Analysis Population Description

The safety set consists of all participants who received at least one dose of the study drug and had at least one post-baseline safety evaluation. Participants were analyzed according to treatment actually received: One participant randomized to everolimus arm received only placebo and therefore, appears in the placebo arm in the safety set


Arm/Group Title	Everolimus + BSC (Throughout the Study)	Everolimus +BSC (Crossover)	Everolimus+BSC (All)	Placebo + BSC (Blinded Period)
Arm/Group Description:	Participants received everolimus 10...	Participants who crossed over from ...	All participants who received evero...	Participants received matching plac...
Arm/Group Description:	Participants received everolimus 10 mg once daily BSC throughout the study	Participants who crossed over from placebo arm (blinded period) to open-label treatment with everolimus 10mg once daily plus BSC	All participants who received everolimus 10 mg once daily plus BSC (including those who received everolimus+BSC from start to end of the study and those who received everolimus+BSC after crossover)	Participants received matching placebo once daily plus BSC during the blinded period
Overall Number of Participants Analyzed	202	6	208	98
Measure Type: Number Unit of Measure: Participants
On-treatment deaths	10	0	10	5
Total deaths	126	1	127	57

Adverse Events

Time Frame	Adverse events and all-cause mortality were collected from date of first dose of study treatment until end of study treatment plus 30 days post treatment, assessed up to a maximum duration of approximately 8 years
Adverse Event Reporting Description	Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. The safety set consists of all participants who received at least one dose of the study drug and had at least one post-baseline safety evaluation. Participants were analyzed according to treatment actually received: One participant randomized to everolimus arm received only placebo and therefore, appears in the placebo arm in the safety set

Arm/Group Title	Everolimus+BSC (Throughout Study)	Everolimus +BSC (Crossover)	Everolimus+BSC (All)	Placebo+BSC (Blinded Period)
Arm/Group Description	Participants received everolimus 10...	Participants who crossed over from ...	All participants who received evero...	Participants received matching plac...
Arm/Group Description	Participants received everolimus 10 mg once daily plus BSC throughout the study	Participants who crossed over from placebo arm (blinded period) to open-label treatment with everolimus 10mg once daily plus BSC	All participants who received everolimus 10 mg once daily plus BSC (including those who received everolimus+BSC from start to end of the study and those who received everolimus+BSC after crossover)	Participants received matching placebo once daily plus best supportive care (BSC) during the blinded period.
All-Cause Mortality
	Everolimus+BSC (Throughout Study)	Everolimus +BSC (Crossover)	Everolimus+BSC (All)	Placebo+BSC (Blinded Period)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	10/202 (4.95%)	0/6 (0.00%)	10/208 (4.81%)	5/98 (5.10%)
Serious Adverse Events Serious Adverse Events
	Everolimus+BSC (Throughout Study)	Everolimus +BSC (Crossover)	Everolimus+BSC (All)	Placebo+BSC (Blinded Period)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	93/202 (46.04%)	1/6 (16.67%)	94/208 (45.19%)	21/98 (21.43%)
Blood and lymphatic system disorders
Anaemia ^† 1	7/202 (3.47%)	0/6 (0.00%)	7/208 (3.37%)	0/98 (0.00%)
Thrombocytopenia ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Cardiac disorders
Acute coronary syndrome ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Atrial fibrillation ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Atrial flutter ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Cardiac failure ^† 1	3/202 (1.49%)	0/6 (0.00%)	3/208 (1.44%)	0/98 (0.00%)
Cardiac failure acute ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	1/98 (1.02%)
Cardiac failure chronic ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Cardiac failure congestive ^† 1	3/202 (1.49%)	0/6 (0.00%)	3/208 (1.44%)	0/98 (0.00%)
Cardiovascular disorder ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Myocardial infarction ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Myocardial ischaemia ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Pericardial effusion ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Supraventricular tachycardia ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Tachycardia ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Endocrine disorders
Adrenal insufficiency ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Eye disorders
Blindness unilateral ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	1/98 (1.02%)
Gastrointestinal disorders
Abdominal pain ^† 1	13/202 (6.44%)	1/6 (16.67%)	14/208 (6.73%)	4/98 (4.08%)
Ascites ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	1/98 (1.02%)
Colitis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Constipation ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Diarrhoea ^† 1	10/202 (4.95%)	0/6 (0.00%)	10/208 (4.81%)	0/98 (0.00%)
Enterocolitis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Gastric ulcer ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Gastrointestinal haemorrhage ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Gastrointestinal oedema ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Ileus ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	1/98 (1.02%)
Intestinal obstruction ^† 1	3/202 (1.49%)	0/6 (0.00%)	3/208 (1.44%)	1/98 (1.02%)
Intestinal perforation ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Jejunal perforation ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Nausea ^† 1	3/202 (1.49%)	0/6 (0.00%)	3/208 (1.44%)	1/98 (1.02%)
Obstructive pancreatitis ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	1/98 (1.02%)
Pancreatic necrosis ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	1/98 (1.02%)
Rectal haemorrhage ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Small intestinal obstruction ^† 1	6/202 (2.97%)	1/6 (16.67%)	7/208 (3.37%)	0/98 (0.00%)
Small intestinal perforation ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	1/98 (1.02%)
Subileus ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Upper gastrointestinal haemorrhage ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Vomiting ^† 1	5/202 (2.48%)	0/6 (0.00%)	5/208 (2.40%)	2/98 (2.04%)
General disorders
Asthenia ^† 1	6/202 (2.97%)	0/6 (0.00%)	6/208 (2.88%)	0/98 (0.00%)
Chest discomfort ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Chills ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Fatigue ^† 1	7/202 (3.47%)	0/6 (0.00%)	7/208 (3.37%)	0/98 (0.00%)
General physical health deterioration ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Mucosal inflammation ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Non-cardiac chest pain ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	2/98 (2.04%)
Oedema peripheral ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	1/98 (1.02%)
Organ failure ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Performance status decreased ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Pyrexia ^† 1	11/202 (5.45%)	0/6 (0.00%)	11/208 (5.29%)	1/98 (1.02%)
Hepatobiliary disorders
Bile duct stone ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	1/98 (1.02%)
Cholangitis ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Cholecystitis ^† 1	3/202 (1.49%)	0/6 (0.00%)	3/208 (1.44%)	0/98 (0.00%)
Cholelithiasis ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	1/98 (1.02%)
Hepatic failure ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Hepatic pain ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Immune system disorders
Contrast media allergy ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Infections and infestations
Bronchopulmonary aspergillosis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Campylobacter gastroenteritis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Cellulitis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Clostridium difficile infection ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Device related infection ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Incision site cellulitis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Infection ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Lower respiratory tract infection ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Peritonitis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Pneumocystis jirovecii pneumonia ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Pneumonia ^† 1	7/202 (3.47%)	0/6 (0.00%)	7/208 (3.37%)	1/98 (1.02%)
Pneumonia bacterial ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Respiratory tract infection ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Salmonellosis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Sepsis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Septic shock ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Skin infection ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Upper respiratory tract infection ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Urinary tract infection ^† 1	4/202 (1.98%)	0/6 (0.00%)	4/208 (1.92%)	0/98 (0.00%)
Urosepsis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Viral myocarditis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Injury, poisoning and procedural complications
Facial bones fracture ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	1/98 (1.02%)
Fall ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Incisional hernia ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Investigations
Ejection fraction decreased ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Gamma-glutamyltransferase increased ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Gastrointestinal stoma output decreased ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Troponin increased ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Weight decreased ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	1/98 (1.02%)
Dehydration ^† 1	3/202 (1.49%)	0/6 (0.00%)	3/208 (1.44%)	1/98 (1.02%)
Diabetes mellitus ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Hyperglycaemia ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Hypoalbuminaemia ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Hypocalcaemia ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Hypoglycaemia ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Hypokalaemia ^† 1	3/202 (1.49%)	1/6 (16.67%)	4/208 (1.92%)	0/98 (0.00%)
Hyponatraemia ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Hypovolaemia ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Type 2 diabetes mellitus ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Musculoskeletal and connective tissue disorders
Back pain ^† 1	3/202 (1.49%)	0/6 (0.00%)	3/208 (1.44%)	0/98 (0.00%)
Flank pain ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Musculoskeletal pain ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer recurrent ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Cancer pain ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	1/98 (1.02%)
Pituitary tumour benign ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Prostate cancer ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Tumour associated fever ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Nervous system disorders
Amnesia ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	1/98 (1.02%)
Cerebral haemorrhage ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	1/98 (1.02%)
Cerebral infarction ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Disturbance in attention ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Dysarthria ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Epilepsy ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Headache ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Intracranial pressure increased ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	1/98 (1.02%)
Seizure ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Somnolence ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Syncope ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Psychiatric disorders
Anxiety ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	1/98 (1.02%)
Confusional state ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	1/98 (1.02%)
Delirium ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Panic attack ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	1/98 (1.02%)
Stress ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Renal and urinary disorders
Acute kidney injury ^† 1	4/202 (1.98%)	0/6 (0.00%)	4/208 (1.92%)	3/98 (3.06%)
Hydronephrosis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Nephrolithiasis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Renal failure ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Renal impairment ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Urinary tract obstruction ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Reproductive system and breast disorders
Ovarian cyst ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Cough ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Dyspnoea ^† 1	3/202 (1.49%)	0/6 (0.00%)	3/208 (1.44%)	1/98 (1.02%)
Interstitial lung disease ^† 1	3/202 (1.49%)	0/6 (0.00%)	3/208 (1.44%)	0/98 (0.00%)
Obliterative bronchiolitis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Pleural effusion ^† 1	5/202 (2.48%)	0/6 (0.00%)	5/208 (2.40%)	0/98 (0.00%)
Pneumonitis ^† 1	4/202 (1.98%)	0/6 (0.00%)	4/208 (1.92%)	0/98 (0.00%)
Pneumothorax ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Pulmonary alveolar haemorrhage ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Pulmonary embolism ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
Pulmonary mass ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Respiratory failure ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	1/98 (1.02%)
Skin and subcutaneous tissue disorders
Angioedema ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Drug eruption ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Hyperhidrosis ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Toxic skin eruption ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Vascular disorders
Aortic stenosis ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	1/98 (1.02%)
Hypertension ^† 1	1/202 (0.50%)	0/6 (0.00%)	1/208 (0.48%)	0/98 (0.00%)
Hypotension ^† 1	2/202 (0.99%)	0/6 (0.00%)	2/208 (0.96%)	0/98 (0.00%)
1 Term from vocabulary, MedDRA (23.0.) † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Everolimus+BSC (Throughout Study)	Everolimus +BSC (Crossover)	Everolimus+BSC (All)	Placebo+BSC (Blinded Period)
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	197/202 (97.52%)	6/6 (100.00%)	203/208 (97.60%)	81/98 (82.65%)
Blood and lymphatic system disorders
Anaemia ^† 1	47/202 (23.27%)	0/6 (0.00%)	47/208 (22.60%)	9/98 (9.18%)
Ear and labyrinth disorders
Deafness ^† 1	1/202 (0.50%)	1/6 (16.67%)	2/208 (0.96%)	0/98 (0.00%)
Vertigo ^† 1	3/202 (1.49%)	2/6 (33.33%)	5/208 (2.40%)	2/98 (2.04%)
Endocrine disorders
Carcinoid syndrome ^† 1	1/202 (0.50%)	1/6 (16.67%)	2/208 (0.96%)	0/98 (0.00%)
Eye disorders
Blindness ^† 1	0/202 (0.00%)	1/6 (16.67%)	1/208 (0.48%)	0/98 (0.00%)
Dry eye ^† 1	4/202 (1.98%)	1/6 (16.67%)	5/208 (2.40%)	0/98 (0.00%)
Eye pain ^† 1	1/202 (0.50%)	1/6 (16.67%)	2/208 (0.96%)	0/98 (0.00%)
Visual impairment ^† 1	0/202 (0.00%)	1/6 (16.67%)	1/208 (0.48%)	0/98 (0.00%)
Gastrointestinal disorders
Abdominal discomfort ^† 1	0/202 (0.00%)	0/6 (0.00%)	0/208 (0.00%)	8/98 (8.16%)
Abdominal pain ^† 1	38/202 (18.81%)	1/6 (16.67%)	39/208 (18.75%)	17/98 (17.35%)
Abdominal pain upper ^† 1	21/202 (10.40%)	0/6 (0.00%)	21/208 (10.10%)	11/98 (11.22%)
Aphthous ulcer ^† 1	8/202 (3.96%)	3/6 (50.00%)	11/208 (5.29%)	2/98 (2.04%)
Constipation ^† 1	25/202 (12.38%)	2/6 (33.33%)	27/208 (12.98%)	19/98 (19.39%)
Diarrhoea ^† 1	88/202 (43.56%)	3/6 (50.00%)	91/208 (43.75%)	30/98 (30.61%)
Dry mouth ^† 1	18/202 (8.91%)	0/6 (0.00%)	18/208 (8.65%)	5/98 (5.10%)
Dyspepsia ^† 1	11/202 (5.45%)	1/6 (16.67%)	12/208 (5.77%)	5/98 (5.10%)
Flatulence ^† 1	7/202 (3.47%)	1/6 (16.67%)	8/208 (3.85%)	6/98 (6.12%)
Mouth ulceration ^† 1	18/202 (8.91%)	0/6 (0.00%)	18/208 (8.65%)	1/98 (1.02%)
Nausea ^† 1	58/202 (28.71%)	0/6 (0.00%)	58/208 (27.88%)	16/98 (16.33%)
Proctalgia ^† 1	0/202 (0.00%)	1/6 (16.67%)	1/208 (0.48%)	2/98 (2.04%)
Stomatitis ^† 1	113/202 (55.94%)	2/6 (33.33%)	115/208 (55.29%)	19/98 (19.39%)
Tongue ulceration ^† 1	2/202 (0.99%)	1/6 (16.67%)	3/208 (1.44%)	0/98 (0.00%)
Toothache ^† 1	11/202 (5.45%)	2/6 (33.33%)	13/208 (6.25%)	3/98 (3.06%)
Vomiting ^† 1	33/202 (16.34%)	0/6 (0.00%)	33/208 (15.87%)	10/98 (10.20%)
General disorders
Asthenia ^† 1	46/202 (22.77%)	0/6 (0.00%)	46/208 (22.12%)	9/98 (9.18%)
Chills ^† 1	6/202 (2.97%)	1/6 (16.67%)	7/208 (3.37%)	1/98 (1.02%)
Fatigue ^† 1	76/202 (37.62%)	2/6 (33.33%)	78/208 (37.50%)	36/98 (36.73%)
Oedema peripheral ^† 1	81/202 (40.10%)	1/6 (16.67%)	82/208 (39.42%)	5/98 (5.10%)
Peripheral swelling ^† 1	11/202 (5.45%)	0/6 (0.00%)	11/208 (5.29%)	2/98 (2.04%)
Pyrexia ^† 1	49/202 (24.26%)	2/6 (33.33%)	51/208 (24.52%)	9/98 (9.18%)
Immune system disorders
Hypersensitivity ^† 1	1/202 (0.50%)	1/6 (16.67%)	2/208 (0.96%)	0/98 (0.00%)
Infections and infestations
Bronchitis ^† 1	8/202 (3.96%)	2/6 (33.33%)	10/208 (4.81%)	2/98 (2.04%)
Cystitis ^† 1	7/202 (3.47%)	1/6 (16.67%)	8/208 (3.85%)	1/98 (1.02%)
Gastrointestinal viral infection ^† 1	1/202 (0.50%)	1/6 (16.67%)	2/208 (0.96%)	0/98 (0.00%)
Influenza ^† 1	9/202 (4.46%)	2/6 (33.33%)	11/208 (5.29%)	1/98 (1.02%)
Nasopharyngitis ^† 1	22/202 (10.89%)	2/6 (33.33%)	24/208 (11.54%)	4/98 (4.08%)
Pneumonia ^† 1	18/202 (8.91%)	0/6 (0.00%)	18/208 (8.65%)	0/98 (0.00%)
Pulpitis dental ^† 1	0/202 (0.00%)	1/6 (16.67%)	1/208 (0.48%)	0/98 (0.00%)
Rhinitis ^† 1	4/202 (1.98%)	1/6 (16.67%)	5/208 (2.40%)	1/98 (1.02%)
Upper respiratory tract infection ^† 1	18/202 (8.91%)	1/6 (16.67%)	19/208 (9.13%)	6/98 (6.12%)
Urinary tract infection ^† 1	23/202 (11.39%)	1/6 (16.67%)	24/208 (11.54%)	6/98 (6.12%)
Injury, poisoning and procedural complications
Fall ^† 1	3/202 (1.49%)	1/6 (16.67%)	4/208 (1.92%)	0/98 (0.00%)
Limb injury ^† 1	1/202 (0.50%)	1/6 (16.67%)	2/208 (0.96%)	0/98 (0.00%)
Investigations
Alanine aminotransferase increased ^† 1	12/202 (5.94%)	0/6 (0.00%)	12/208 (5.77%)	2/98 (2.04%)
Blood alkaline phosphatase increased ^† 1	3/202 (1.49%)	0/6 (0.00%)	3/208 (1.44%)	5/98 (5.10%)
Blood creatinine increased ^† 1	11/202 (5.45%)	1/6 (16.67%)	12/208 (5.77%)	1/98 (1.02%)
Blood urea ^† 1	0/202 (0.00%)	1/6 (16.67%)	1/208 (0.48%)	0/98 (0.00%)
Blood uric acid ^† 1	0/202 (0.00%)	1/6 (16.67%)	1/208 (0.48%)	0/98 (0.00%)
Gamma-glutamyltransferase increased ^† 1	9/202 (4.46%)	1/6 (16.67%)	10/208 (4.81%)	2/98 (2.04%)
Weight decreased ^† 1	51/202 (25.25%)	2/6 (33.33%)	53/208 (25.48%)	11/98 (11.22%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	53/202 (26.24%)	1/6 (16.67%)	54/208 (25.96%)	17/98 (17.35%)
Hypercholesterolaemia ^† 1	16/202 (7.92%)	1/6 (16.67%)	17/208 (8.17%)	2/98 (2.04%)
Hypercreatininaemia ^† 1	1/202 (0.50%)	1/6 (16.67%)	2/208 (0.96%)	0/98 (0.00%)
Hyperglycaemia ^† 1	24/202 (11.88%)	1/6 (16.67%)	25/208 (12.02%)	6/98 (6.12%)
Hypertriglyceridaemia ^† 1	12/202 (5.94%)	1/6 (16.67%)	13/208 (6.25%)	0/98 (0.00%)
Hypokalaemia ^† 1	21/202 (10.40%)	3/6 (50.00%)	24/208 (11.54%)	4/98 (4.08%)
Hypomagnesaemia ^† 1	5/202 (2.48%)	1/6 (16.67%)	6/208 (2.88%)	0/98 (0.00%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	31/202 (15.35%)	0/6 (0.00%)	31/208 (14.90%)	8/98 (8.16%)
Back pain ^† 1	34/202 (16.83%)	0/6 (0.00%)	34/208 (16.35%)	14/98 (14.29%)
Bursitis ^† 1	0/202 (0.00%)	1/6 (16.67%)	1/208 (0.48%)	0/98 (0.00%)
Musculoskeletal pain ^† 1	5/202 (2.48%)	1/6 (16.67%)	6/208 (2.88%)	3/98 (3.06%)
Myalgia ^† 1	15/202 (7.43%)	0/6 (0.00%)	15/208 (7.21%)	4/98 (4.08%)
Osteoarthritis ^† 1	2/202 (0.99%)	2/6 (33.33%)	4/208 (1.92%)	0/98 (0.00%)
Osteoporosis ^† 1	1/202 (0.50%)	1/6 (16.67%)	2/208 (0.96%)	0/98 (0.00%)
Pain in extremity ^† 1	19/202 (9.41%)	0/6 (0.00%)	19/208 (9.13%)	5/98 (5.10%)
Nervous system disorders
Carpal tunnel syndrome ^† 1	0/202 (0.00%)	1/6 (16.67%)	1/208 (0.48%)	0/98 (0.00%)
Dizziness ^† 1	11/202 (5.45%)	0/6 (0.00%)	11/208 (5.29%)	5/98 (5.10%)
Dysgeusia ^† 1	26/202 (12.87%)	1/6 (16.67%)	27/208 (12.98%)	3/98 (3.06%)
Headache ^† 1	27/202 (13.37%)	1/6 (16.67%)	28/208 (13.46%)	15/98 (15.31%)
Paraesthesia ^† 1	5/202 (2.48%)	2/6 (33.33%)	7/208 (3.37%)	1/98 (1.02%)
Polyneuropathy ^† 1	0/202 (0.00%)	1/6 (16.67%)	1/208 (0.48%)	0/98 (0.00%)
Syncope ^† 1	1/202 (0.50%)	1/6 (16.67%)	2/208 (0.96%)	1/98 (1.02%)
Taste disorder ^† 1	13/202 (6.44%)	1/6 (16.67%)	14/208 (6.73%)	1/98 (1.02%)
Psychiatric disorders
Anxiety ^† 1	9/202 (4.46%)	1/6 (16.67%)	10/208 (4.81%)	1/98 (1.02%)
Insomnia ^† 1	20/202 (9.90%)	0/6 (0.00%)	20/208 (9.62%)	8/98 (8.16%)
Renal and urinary disorders
Dysuria ^† 1	8/202 (3.96%)	0/6 (0.00%)	8/208 (3.85%)	5/98 (5.10%)
Haematuria ^† 1	11/202 (5.45%)	1/6 (16.67%)	12/208 (5.77%)	4/98 (4.08%)
Proteinuria ^† 1	18/202 (8.91%)	0/6 (0.00%)	18/208 (8.65%)	2/98 (2.04%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	63/202 (31.19%)	1/6 (16.67%)	64/208 (30.77%)	20/98 (20.41%)
Dysphonia ^† 1	6/202 (2.97%)	1/6 (16.67%)	7/208 (3.37%)	1/98 (1.02%)
Dyspnoea ^† 1	42/202 (20.79%)	0/6 (0.00%)	42/208 (20.19%)	11/98 (11.22%)
Epistaxis ^† 1	28/202 (13.86%)	2/6 (33.33%)	30/208 (14.42%)	3/98 (3.06%)
Laryngeal pain ^† 1	0/202 (0.00%)	1/6 (16.67%)	1/208 (0.48%)	0/98 (0.00%)
Oropharyngeal pain ^† 1	13/202 (6.44%)	1/6 (16.67%)	14/208 (6.73%)	3/98 (3.06%)
Pleural effusion ^† 1	12/202 (5.94%)	0/6 (0.00%)	12/208 (5.77%)	2/98 (2.04%)
Pneumonitis ^† 1	30/202 (14.85%)	0/6 (0.00%)	30/208 (14.42%)	2/98 (2.04%)
Rhinitis allergic ^† 1	2/202 (0.99%)	1/6 (16.67%)	3/208 (1.44%)	0/98 (0.00%)
Skin and subcutaneous tissue disorders
Dermatitis acneiform ^† 1	20/202 (9.90%)	0/6 (0.00%)	20/208 (9.62%)	3/98 (3.06%)
Dry skin ^† 1	18/202 (8.91%)	0/6 (0.00%)	18/208 (8.65%)	2/98 (2.04%)
Eczema ^† 1	6/202 (2.97%)	1/6 (16.67%)	7/208 (3.37%)	0/98 (0.00%)
Erythema ^† 1	11/202 (5.45%)	0/6 (0.00%)	11/208 (5.29%)	2/98 (2.04%)
Nail ridging ^† 1	1/202 (0.50%)	1/6 (16.67%)	2/208 (0.96%)	0/98 (0.00%)
Pruritus ^† 1	37/202 (18.32%)	2/6 (33.33%)	39/208 (18.75%)	9/98 (9.18%)
Rash ^† 1	62/202 (30.69%)	3/6 (50.00%)	65/208 (31.25%)	9/98 (9.18%)
Vascular disorders
Hypertension ^† 1	28/202 (13.86%)	1/6 (16.67%)	29/208 (13.94%)	10/98 (10.20%)
1 Term from vocabulary, MedDRA (23.0.) † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights 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 the clinical trial

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Study Director
Organization:	Novartis Pharmaceuticals
Phone:	862-778-8300
EMail:	novartis.email@novartis.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Chan DL, Yao JC, Carnaghi C, Buzzoni R, Herbst F, Ridolfi A, Strosberg J, Kulke MH, Pavel M, Singh S. Markers of Systemic Inflammation in Neuroendocrine Tumors: A Pooled Analysis of the RADIANT-3 and RADIANT-4 Studies. Pancreas. 2021 Feb 1;50(2):130-137. doi: 10.1097/MPA.0000000000001745.

Buzzoni R, Carnaghi C, Strosberg J, Fazio N, Singh S, Herbst F, Ridolfi A, Pavel ME, Wolin EM, Valle JW, Oh DY, Yao JC, Pommier R. Impact of prior therapies on everolimus activity: an exploratory analysis of RADIANT-4. Onco Targets Ther. 2017 Oct 16;10:5013-5030. doi: 10.2147/OTT.S142087. eCollection 2017.

Fazio N, Buzzoni R, Delle Fave G, Tesselaar ME, Wolin E, Van Cutsem E, Tomassetti P, Strosberg J, Voi M, Bubuteishvili-Pacaud L, Ridolfi A, Herbst F, Tomasek J, Singh S, Pavel M, Kulke MH, Valle JW, Yao JC. Everolimus in advanced, progressive, well-differentiated, non-functional neuroendocrine tumors: RADIANT-4 lung subgroup analysis. Cancer Sci. 2018 Jan;109(1):174-181. doi: 10.1111/cas.13427. Epub 2017 Nov 9.

Pavel ME, Singh S, Strosberg JR, Bubuteishvili-Pacaud L, Degtyarev E, Neary MP, Carnaghi C, Tomasek J, Wolin E, Raderer M, Lahner H, Valle JW, Pommier R, Van Cutsem E, Tesselaar MET, Fave GD, Buzzoni R, Hunger M, Eriksson J, Cella D, Ricci JF, Fazio N, Kulke MH, Yao JC. Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1411-1422. doi: 10.1016/S1470-2045(17)30471-0. Epub 2017 Aug 30.

Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H, Voi M, Pacaud LB, Rouyrre N, Sachs C, Valle JW, Fave GD, Van Cutsem E, Tesselaar M, Shimada Y, Oh DY, Strosberg J, Kulke MH, Pavel ME; RAD001 in Advanced Neuroendocrine Tumours, Fourth Trial (RADIANT-4) Study Group. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet. 2016 Mar 5;387(10022):968-977. doi: 10.1016/S0140-6736(15)00817-X. Epub 2015 Dec 17.

Layout table for additonal information

Responsible Party:	Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:	NCT01524783
Other Study ID Numbers:	CRAD001T2302 2011-002887-26 ( Registry Identifier: EudraCT )
First Submitted:	December 22, 2011
First Posted:	February 2, 2012
Results First Submitted:	March 26, 2016
Results First Posted:	December 28, 2016
Last Update Posted:	August 5, 2021

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