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Global Study Looking at the Combination of RAD001 Plus Best Supportive Care (BSC) and Placebo Plus BSC to Treat Patients With Advanced Hepatocellular Carcinoma. (EVOLVE-1)

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ClinicalTrials.gov Identifier: NCT01035229
Recruitment Status : Completed
First Posted : December 18, 2009
Results First Posted : October 27, 2014
Last Update Posted : September 22, 2016
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Carcinoma
Interventions Drug: Everolimus
Drug: Everolimus Placebo
Other: Best Supportive Care (BSC)
Enrollment 546
Recruitment Details 763 patients screened, 546 randomized. At 14Jun2013 data cut-off (final analysis), 3 pts in everolimus arm, 6 in placebo arm were still on treatment. Of 9 pts, 3 receiving placebo discontinued due to disease progression. Remaining 6 completed study due to sponsor’s decision to end study after final results. The LPLV was 15Oct2013.
Pre-assignment Details  
Arm/Group Title Everolimus + Best Supportive Care (BSC) Placebo + Best Supportive Care
Hide Arm/Group Description Patients were assigned to the Everolimus + BSC arm in a ratio of 2:1 over the Placebo arm. Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed. In addition to taking Everolimus, all patients also received BSC as per normal local practice. Placebo-Everolimus was taken as a daily oral dose of 7.5 mg and was defined as the control drug. In addition to taking Placebo Everolimus, all patients also received BSC as per normal local practice.
Period Title: Overall Study
Started 362 184
Completed 0 0
Not Completed 362 184
Reason Not Completed
Adverse Event             61             14
Withdrawal by Subject             20             7
Lost to Follow-up             1             0
Administrative problems             1             1
Death             13             5
New cancer therapy             2             0
Protocol Violation             0             2
Sponsor's decision to end study             3             3
Disease Progression             261             152
Arm/Group Title Everolimus + Best Supportive Care (BSC) Placebo + Best Supportive Care Total
Hide Arm/Group Description Patients were assigned to the Everolimus + BSC arm in a ratio of 2:1 over the Placebo arm. Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed. In addition to taking Everolimus, all patients also received BSC as per normal local practice. Placebo-Everolimus was taken as a daily oral dose of 7.5 mg and was defined as the control drug. In addition to taking Placebo Everolimus, all patients also received BSC as per normal local practice. Total of all reporting groups
Overall Number of Baseline Participants 362 184 546
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 362 participants 184 participants 546 participants
65.1  (11.70) 64.2  (10.41) 64.8  (11.28)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 362 participants 184 participants 546 participants
< 35 years 7 1 8
>=35 - <55 years 48 31 79
>=55 - <65 years 100 61 161
>= 65 years 207 91 298
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 362 participants 184 participants 546 participants
Female
59
  16.3%
24
  13.0%
83
  15.2%
Male
303
  83.7%
160
  87.0%
463
  84.8%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 362 participants 184 participants 546 participants
Caucasian 192 110 302
Black 6 3 9
Asian 137 58 195
Pacific Islander 0 1 1
Other 27 12 39
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 362 participants 184 participants 546 participants
69.6  (15.62) 71.3  (17.71) 70.2  (16.35)
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 362 participants 184 participants 546 participants
167.9  (8.66) 169.2  (8.84) 168.3  (8.73)
BMI  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 362 participants 184 participants 546 participants
24.5  (4.64) 24.8  (4.99) 24.6  (4.76)
1.Primary Outcome
Title Overall Survival (OS)
Hide Description OS was defined as the time from the date of randomization to the date of death from any cause. The comparison of OS between the 2 arms was done using a stratified log-rank test at one-sided 2.5% level of significance.
Time Frame When 454 OS events were observed
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all randomized patients.
Arm/Group Title Everolimus + Best Supportive Care (BSC) Placebo + Best Supportive Care
Hide Arm/Group Description:
Patients were assigned to the Everolimus + BSC arm in a ratio of 2:1 over the Placebo arm. Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed. In addition to taking Everolimus, all patients also received BSC as per normal local practice.
Placebo-Everolimus was taken as a daily oral dose of 7.5 mg and was defined as the control drug. In addition to taking Placebo Everolimus, all patients also received BSC as per normal local practice.
Overall Number of Participants Analyzed 362 184
Median (95% Confidence Interval)
Unit of Measure: Months
7.56
(6.70 to 8.74)
7.33
(6.28 to 8.74)
2.Secondary Outcome
Title Time to Tumor Progression (TTP)
Hide Description TTP was defined as the time from the date of randomization to the date of the first documented radiologic confirmation of disease progression. Since the study did not meet the primary objective, TTP was not formally tested.
Time Frame Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all randomized patients.
Arm/Group Title Everolimus + Best Supportive Care (BSC) Placebo + Best Supportive Care
Hide Arm/Group Description:
Patients were assigned to the Everolimus + BSC arm in a ratio of 2:1 over the Placebo arm. Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed. In addition to taking Everolimus, all patients also received BSC as per normal local practice.
Placebo-Everolimus was taken as a daily oral dose of 7.5 mg and was defined as the control drug. In addition to taking Placebo Everolimus, all patients also received BSC as per normal local practice.
Overall Number of Participants Analyzed 362 184
Median (95% Confidence Interval)
Unit of Measure: Months
2.96
(2.79 to 4.01)
2.60
(1.48 to 2.83)
3.Secondary Outcome
Title Percentage of Participants With Disease Control Rate (DCR)
Hide Description DCR is defined as the proportion of participants with a best objective response (BOR) of complete response (CR) or partial response (PR) or stable disease (SD) according to RECIST. The BOR was the best response recorded from the start of the treatment until disease progression. CR is disappearance of all target lesions; PR is 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; SD is neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. PD is at least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.
Time Frame Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all randomized patients.
Arm/Group Title Everolimus + Best Supportive Care (BSC) Placebo + Best Supportive Care
Hide Arm/Group Description:
Patients were assigned to the Everolimus + BSC arm in a ratio of 2:1 over the Placebo arm. Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed. In addition to taking Everolimus, all patients also received BSC as per normal local practice.
Placebo-Everolimus was taken as a daily oral dose of 7.5 mg and was defined as the control drug. In addition to taking Placebo Everolimus, all patients also received BSC as per normal local practice.
Overall Number of Participants Analyzed 362 184
Measure Type: Number
Unit of Measure: Percentage of Participants
56.1 45.1
4.Secondary Outcome
Title Time to Definitive Deterioration of ECOG Performance Score (PS) Score
Hide Description Change in Eastern Cooperative Oncology Group (ECOG) were assessed by time to definitive performance status deterioration by at least one category on the ECOG scale. Deterioration was considered definitive if no improvement in the ECOG PS was observed at a subsequent measurement. ECOG PS: 0=Fully active, able to carry on all pre-disease performance without restriction, 1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2=Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3=Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4=Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair; 5=Dead
Time Frame Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient.
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all randomized patients.
Arm/Group Title Everolimus + Best Supportive Care (BSC) Placebo + Best Supportive Care
Hide Arm/Group Description:
Patients were assigned to the Everolimus + BSC arm in a ratio of 2:1 over the Placebo arm. Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed. In addition to taking Everolimus, all patients also received BSC as per normal local practice.
Placebo-Everolimus was taken as a daily oral dose of 7.5 mg and was defined as the control drug. In addition to taking Placebo Everolimus, all patients also received BSC as per normal local practice.
Overall Number of Participants Analyzed 362 184
Median (95% Confidence Interval)
Unit of Measure: Months
4.27
(3.32 to 4.86)
4.47
(3.02 to 6.08)
5.Secondary Outcome
Title Time to Definitive Deterioration of EORTC QLQ-C30 Scores
Hide Description The primary quality of life endpoint was the time to definitive 5% deterioration from baseline in the global health status/quality of life scale of the EORTC QLQ-C30 questionnaire. Definitive deterioration by at least 5% is defined as a decrease in score by at least 5% compared to baseline, with no later observed increase above this threshold. The EORTC quality of life questionnaire (QLQ) is an integrated system for assessing the healthrelated quality of life (QoL) of cancer patients participating in international clinical trials. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems.
Time Frame Until all patients have disease progression or leave study due to intolerable adverse events - Estimate of 1 year for each patient.
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) comprised all randomized patients.
Arm/Group Title Everolimus + Best Supportive Care (BSC) Placebo + Best Supportive Care
Hide Arm/Group Description:
Patients were assigned to the Everolimus + BSC arm in a ratio of 2:1 over the Placebo arm. Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed. In addition to taking Everolimus, all patients also received BSC as per normal local practice.
Placebo-Everolimus was taken as a daily oral dose of 7.5 mg and was defined as the control drug. In addition to taking Placebo Everolimus, all patients also received BSC as per normal local practice.
Overall Number of Participants Analyzed 362 184
Median (95% Confidence Interval)
Unit of Measure: Months
2.86
(2.66 to 4.11)
3.45
(2.79 to 4.17)
6.Secondary Outcome
Title Pharmacokinetics Assessments - Cmin
Hide Description Cmin is the pre-dose blood concentration at steady-state (ng/mL). Pre-dose (Cmin) blood samples were collected from all patients in both arms at Visit 3. Steady-state for the Cmin sample was defined as continuous administration of the same dose in the last 4 days prior to the collection of the Cmin sample. Steady-state for the 5 mg every other day regimen was defined as the state when the 5 mg dose was taken 2 days and 4 days before sampling. PK samples were only drawn at visit 3, and only analyzed for patients receiving everolimus at steady state (if patients had received the dose the previous 4 days). In addition summary statistics were only done for each everolimus dose when 3 samples were available. Only valid pre-dose (Cmin) everolimus samples were included in the analysis.
Time Frame Until all patients have disease progression or leave study due to intolerable adverse events - Estimate of 1 year for each patient.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Set consisted of all patients who received at least one dose of study treatment with a valid postbaseline assessment. All PK analyses were based on the Safety Set.
Arm/Group Title Everolimus 7.5mg + Best Supportive Care (BSC) Everolimus 5mg + Best Supportive Care (BSC)
Hide Arm/Group Description:
Patients were assigned to the Everolimus + BSC arm in a ratio of 2:1 over the Placebo arm. Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed. In addition to taking Everolimus, all patients also received BSC as per normal local practice.
Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed.
Overall Number of Participants Analyzed 206 10
Mean (Standard Deviation)
Unit of Measure: ng/mL
16.141  (9.2297) 9.318  (4.9705)
7.Secondary Outcome
Title Pharmacokinetics Assessments - Cmax
Hide Description Cmax is the maximum (peak) blood drug concentration after dose administration (ng/mL) calculated as the maximum of C1h and C2h. C1h was 1 hour post-dose blood concentration (ng/mL) and C2h was 2 hour post-dose blood concentration (ng/mL). C1h and C2h post-dose samples were collected from all patients in both arms at Visit 3. Steady-state for the C1h and C2h samples was defined as continuous administration of the same dose in the previous 4 days and the day on which the C1h and C2h samples were collected. Steady-state for the 5 mg every other day regimen was defined as the state when the 5 mg dose was taken 2 days and 4 days before sampling. PK samples were only drawn at visit 3, and only analyzed for patients receiving everolimus at steady state (if patients had received the dose the previous 4 days). In addition summary statistics were only done for each everolimus dose when 3 samples were available. Only valid C1h and C2h everolimus samples were included in the analysis.
Time Frame Until all patients have disease progression or leave study due to intolerable adverse events- Estimate of 1 year for each patient.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Set consists of all patients who received at least one dose of study treatment with a valid postbaseline assessment. All PK analyses were based on the Safety Set.
Arm/Group Title Everolimus 7.5mg + Best Supportive Care (BSC) Everolimus 5mg + Best Supportive Care (BSC)
Hide Arm/Group Description:
Patients were assigned to the Everolimus + BSC arm in a ratio of 2:1 over the Placebo arm. Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed. In addition to taking Everolimus, all patients also received BSC as per normal local practice.
Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed.
Overall Number of Participants Analyzed 229 13
Mean (Standard Deviation)
Unit of Measure: ng/mL
47.881  (21.0999) 31.592  (21.1622)
Time Frame [Not Specified]
Adverse Event Reporting Description Three patients (1 in the everolimus arm and 2 in the placebo arm) were excluded from the Safety Set as these patients were randomized but never received any study treatment.
 
Arm/Group Title Everolimus + Best Supportive Care (BSC) Placebo + Best Supportive Care
Hide Arm/Group Description Patients were assigned to the Everolimus + BSC arm in a ratio of 2:1 over the Placebo arm. Everolimus was taken as a daily oral dose of 7.5 mg but dose adjustments of study drug (reduction, interruption or possible dose re-escalation to starting dose) according to safety findings were allowed. In addition to taking Everolimus, all patients also received BSC as per normal local practice. Placebo-Everolimus was taken as a daily oral dose of 7.5 mg and was defined as the control drug. In addition to taking Placebo Everolimus, all patients also received BSC as per normal local practice.
All-Cause Mortality
Everolimus + Best Supportive Care (BSC) Placebo + Best Supportive Care
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Everolimus + Best Supportive Care (BSC) Placebo + Best Supportive Care
Affected / at Risk (%) Affected / at Risk (%)
Total   171/361 (47.37%)   64/182 (35.16%) 
Blood and lymphatic system disorders     
Anaemia  1  14/361 (3.88%)  3/182 (1.65%) 
Leukocytosis  1  0/361 (0.00%)  1/182 (0.55%) 
Leukopenia  1  2/361 (0.55%)  0/182 (0.00%) 
Neutropenia  1  3/361 (0.83%)  0/182 (0.00%) 
Thrombocytopenia  1  4/361 (1.11%)  0/182 (0.00%) 
Cardiac disorders     
Angina pectoris  1  1/361 (0.28%)  0/182 (0.00%) 
Angina unstable  1  1/361 (0.28%)  0/182 (0.00%) 
Atrial fibrillation  1  4/361 (1.11%)  0/182 (0.00%) 
Cardiac arrest  1  0/361 (0.00%)  2/182 (1.10%) 
Cardiac failure  1  1/361 (0.28%)  0/182 (0.00%) 
Cardiac failure congestive  1  0/361 (0.00%)  1/182 (0.55%) 
Cardio-respiratory arrest  1  1/361 (0.28%)  0/182 (0.00%) 
Ischaemic cardiomyopathy  1  1/361 (0.28%)  0/182 (0.00%) 
Mitral valve incompetence  1  1/361 (0.28%)  0/182 (0.00%) 
Myocardial ischaemia  1  1/361 (0.28%)  0/182 (0.00%) 
Pericardial effusion  1  0/361 (0.00%)  1/182 (0.55%) 
Congenital, familial and genetic disorders     
Pyloric stenosis  1  0/361 (0.00%)  1/182 (0.55%) 
Eye disorders     
Cataract  1  0/361 (0.00%)  1/182 (0.55%) 
Ocular icterus  1  0/361 (0.00%)  1/182 (0.55%) 
Retinal detachment  1  0/361 (0.00%)  1/182 (0.55%) 
Gastrointestinal disorders     
Abdominal distension  1  1/361 (0.28%)  0/182 (0.00%) 
Abdominal pain  1  9/361 (2.49%)  8/182 (4.40%) 
Abdominal pain upper  1  4/361 (1.11%)  0/182 (0.00%) 
Ascites  1  13/361 (3.60%)  11/182 (6.04%) 
Colitis  1  1/361 (0.28%)  0/182 (0.00%) 
Colitis ischaemic  1  1/361 (0.28%)  0/182 (0.00%) 
Colonic obstruction  1  1/361 (0.28%)  0/182 (0.00%) 
Constipation  1  0/361 (0.00%)  1/182 (0.55%) 
Dysphagia  1  1/361 (0.28%)  0/182 (0.00%) 
Enteritis  1  1/361 (0.28%)  0/182 (0.00%) 
Faeces discoloured  1  1/361 (0.28%)  0/182 (0.00%) 
Gastric antral vascular ectasia  1  1/361 (0.28%)  0/182 (0.00%) 
Gastric haemorrhage  1  1/361 (0.28%)  0/182 (0.00%) 
Gastric ulcer  1  0/361 (0.00%)  1/182 (0.55%) 
Gastric ulcer haemorrhage  1  1/361 (0.28%)  0/182 (0.00%) 
Gastrointestinal haemorrhage  1  5/361 (1.39%)  1/182 (0.55%) 
Haematemesis  1  1/361 (0.28%)  2/182 (1.10%) 
Ileal ulcer  1  0/361 (0.00%)  1/182 (0.55%) 
Intestinal obstruction  1  2/361 (0.55%)  1/182 (0.55%) 
Intra-abdominal haemorrhage  1  0/361 (0.00%)  1/182 (0.55%) 
Large intestine perforation  1  0/361 (0.00%)  1/182 (0.55%) 
Melaena  1  0/361 (0.00%)  1/182 (0.55%) 
Mouth ulceration  1  1/361 (0.28%)  0/182 (0.00%) 
Oesophageal haemorrhage  1  0/361 (0.00%)  1/182 (0.55%) 
Oesophageal varices haemorrhage  1  1/361 (0.28%)  3/182 (1.65%) 
Peritoneal haemorrhage  1  0/361 (0.00%)  1/182 (0.55%) 
Small intestinal haemorrhage  1  0/361 (0.00%)  1/182 (0.55%) 
Stomatitis  1  1/361 (0.28%)  0/182 (0.00%) 
Subileus  1  1/361 (0.28%)  0/182 (0.00%) 
Upper gastrointestinal haemorrhage  1  3/361 (0.83%)  2/182 (1.10%) 
Varices oesophageal  1  0/361 (0.00%)  1/182 (0.55%) 
Vomiting  1  2/361 (0.55%)  3/182 (1.65%) 
General disorders     
Asthenia  1  9/361 (2.49%)  3/182 (1.65%) 
Chills  1  2/361 (0.55%)  0/182 (0.00%) 
Death  1  1/361 (0.28%)  0/182 (0.00%) 
Face oedema  1  1/361 (0.28%)  0/182 (0.00%) 
Fatigue  1  1/361 (0.28%)  0/182 (0.00%) 
General physical health deterioration  1  5/361 (1.39%)  4/182 (2.20%) 
Hyperpyrexia  1  1/361 (0.28%)  0/182 (0.00%) 
Malaise  1  2/361 (0.55%)  0/182 (0.00%) 
Multi-organ failure  1  3/361 (0.83%)  1/182 (0.55%) 
Non-cardiac chest pain  1  1/361 (0.28%)  1/182 (0.55%) 
Oedema peripheral  1  4/361 (1.11%)  2/182 (1.10%) 
Performance status decreased  1  1/361 (0.28%)  0/182 (0.00%) 
Pyrexia  1  14/361 (3.88%)  2/182 (1.10%) 
Sudden death  1  1/361 (0.28%)  0/182 (0.00%) 
Hepatobiliary disorders     
Bile duct obstruction  1  0/361 (0.00%)  1/182 (0.55%) 
Bile duct stenosis  1  1/361 (0.28%)  1/182 (0.55%) 
Cholangitis  1  2/361 (0.55%)  0/182 (0.00%) 
Cholecystitis  1  2/361 (0.55%)  0/182 (0.00%) 
Cirrhosis alcoholic  1  1/361 (0.28%)  0/182 (0.00%) 
Hepatic cirrhosis  1  8/361 (2.22%)  3/182 (1.65%) 
Hepatic failure  1  5/361 (1.39%)  4/182 (2.20%) 
Hepatic pain  1  1/361 (0.28%)  0/182 (0.00%) 
Hepatorenal syndrome  1  1/361 (0.28%)  1/182 (0.55%) 
Hyperbilirubinaemia  1  5/361 (1.39%)  5/182 (2.75%) 
Jaundice  1  1/361 (0.28%)  2/182 (1.10%) 
Jaundice cholestatic  1  1/361 (0.28%)  1/182 (0.55%) 
Immune system disorders     
Allergic oedema  1  1/361 (0.28%)  0/182 (0.00%) 
Infections and infestations     
Atypical pneumonia  1  1/361 (0.28%)  0/182 (0.00%) 
Bacteraemia  1  2/361 (0.55%)  0/182 (0.00%) 
Bacterial toxaemia  1  1/361 (0.28%)  0/182 (0.00%) 
Bronchitis  1  1/361 (0.28%)  0/182 (0.00%) 
Bronchopneumonia  1  1/361 (0.28%)  0/182 (0.00%) 
Candidiasis  1  1/361 (0.28%)  0/182 (0.00%) 
Cellulitis  1  1/361 (0.28%)  0/182 (0.00%) 
Cholangitis suppurative  1  1/361 (0.28%)  0/182 (0.00%) 
Citrobacter infection  1  1/361 (0.28%)  0/182 (0.00%) 
Dengue fever  1  1/361 (0.28%)  0/182 (0.00%) 
Erysipelas  1  1/361 (0.28%)  0/182 (0.00%) 
Escherichia sepsis  1  1/361 (0.28%)  0/182 (0.00%) 
Gastroenteritis  1  2/361 (0.55%)  0/182 (0.00%) 
Gastroenteritis bacterial  1  0/361 (0.00%)  1/182 (0.55%) 
Infection  1  0/361 (0.00%)  1/182 (0.55%) 
Listeriosis  1  1/361 (0.28%)  0/182 (0.00%) 
Lung infection  1  1/361 (0.28%)  0/182 (0.00%) 
Morganella infection  1  1/361 (0.28%)  0/182 (0.00%) 
Peritonitis  1  4/361 (1.11%)  1/182 (0.55%) 
Pneumocystis jiroveci pneumonia  1  1/361 (0.28%)  0/182 (0.00%) 
Pneumonia  1  18/361 (4.99%)  1/182 (0.55%) 
Sepsis  1  6/361 (1.66%)  1/182 (0.55%) 
Septic shock  1  1/361 (0.28%)  0/182 (0.00%) 
Urinary tract infection  1  1/361 (0.28%)  1/182 (0.55%) 
Injury, poisoning and procedural complications     
Facial bones fracture  1  1/361 (0.28%)  0/182 (0.00%) 
Fall  1  1/361 (0.28%)  0/182 (0.00%) 
Hand fracture  1  1/361 (0.28%)  0/182 (0.00%) 
Humerus fracture  1  0/361 (0.00%)  1/182 (0.55%) 
Overdose  1  1/361 (0.28%)  2/182 (1.10%) 
Radius fracture  1  1/361 (0.28%)  0/182 (0.00%) 
Thoracic vertebral fracture  1  1/361 (0.28%)  0/182 (0.00%) 
Investigations     
Aspartate aminotransferase increased  1  1/361 (0.28%)  0/182 (0.00%) 
Blood bilirubin increased  1  1/361 (0.28%)  0/182 (0.00%) 
Blood creatinine increased  1  1/361 (0.28%)  1/182 (0.55%) 
Blood uric acid increased  1  1/361 (0.28%)  0/182 (0.00%) 
C-reactive protein abnormal  1  1/361 (0.28%)  0/182 (0.00%) 
Cardiac enzymes increased  1  1/361 (0.28%)  0/182 (0.00%) 
General physical condition abnormal  1  1/361 (0.28%)  0/182 (0.00%) 
Haemoglobin decreased  1  2/361 (0.55%)  0/182 (0.00%) 
International normalised ratio increased  1  1/361 (0.28%)  0/182 (0.00%) 
Platelet count decreased  1  1/361 (0.28%)  0/182 (0.00%) 
Troponin increased  1  1/361 (0.28%)  0/182 (0.00%) 
Weight decreased  1  2/361 (0.55%)  0/182 (0.00%) 
White blood cell count decreased  1  1/361 (0.28%)  0/182 (0.00%) 
White blood cell count increased  1  0/361 (0.00%)  1/182 (0.55%) 
Metabolism and nutrition disorders     
Cachexia  1  1/361 (0.28%)  1/182 (0.55%) 
Decreased appetite  1  8/361 (2.22%)  0/182 (0.00%) 
Dehydration  1  1/361 (0.28%)  2/182 (1.10%) 
Diabetes mellitus  1  2/361 (0.55%)  1/182 (0.55%) 
Diabetes mellitus inadequate control  1  1/361 (0.28%)  0/182 (0.00%) 
Failure to thrive  1  1/361 (0.28%)  0/182 (0.00%) 
Hyperammonaemia  1  1/361 (0.28%)  0/182 (0.00%) 
Hypercalcaemia  1  2/361 (0.55%)  0/182 (0.00%) 
Hypercholesterolaemia  1  1/361 (0.28%)  0/182 (0.00%) 
Hyperglycaemia  1  1/361 (0.28%)  1/182 (0.55%) 
Hyperkalaemia  1  2/361 (0.55%)  3/182 (1.65%) 
Hypoglycaemia  1  2/361 (0.55%)  1/182 (0.55%) 
Hypokalaemia  1  1/361 (0.28%)  0/182 (0.00%) 
Hyponatraemia  1  6/361 (1.66%)  1/182 (0.55%) 
Malnutrition  1  0/361 (0.00%)  1/182 (0.55%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  2/361 (0.55%)  0/182 (0.00%) 
Back pain  1  1/361 (0.28%)  0/182 (0.00%) 
Bone pain  1  1/361 (0.28%)  0/182 (0.00%) 
Mobility decreased  1  1/361 (0.28%)  0/182 (0.00%) 
Myalgia  1  1/361 (0.28%)  0/182 (0.00%) 
Neck pain  1  1/361 (0.28%)  0/182 (0.00%) 
Pain in extremity  1  1/361 (0.28%)  0/182 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Cancer pain  1  1/361 (0.28%)  0/182 (0.00%) 
Hepatocellular carcinoma  1  0/361 (0.00%)  1/182 (0.55%) 
Metastases to peritoneum  1  1/361 (0.28%)  0/182 (0.00%) 
Metastatic pain  1  1/361 (0.28%)  0/182 (0.00%) 
Oesophageal carcinoma  1  1/361 (0.28%)  0/182 (0.00%) 
Tumour haemorrhage  1  1/361 (0.28%)  0/182 (0.00%) 
Nervous system disorders     
Altered state of consciousness  1  1/361 (0.28%)  0/182 (0.00%) 
Amnesia  1  1/361 (0.28%)  0/182 (0.00%) 
Cerebellar haemorrhage  1  1/361 (0.28%)  0/182 (0.00%) 
Cerebral haemorrhage  1  2/361 (0.55%)  1/182 (0.55%) 
Cerebral infarction  1  0/361 (0.00%)  2/182 (1.10%) 
Cerebrovascular accident  1  1/361 (0.28%)  0/182 (0.00%) 
Cognitive disorder  1  1/361 (0.28%)  0/182 (0.00%) 
Dementia  1  0/361 (0.00%)  1/182 (0.55%) 
Depressed level of consciousness  1  0/361 (0.00%)  1/182 (0.55%) 
Diabetic hyperosmolar coma  1  1/361 (0.28%)  0/182 (0.00%) 
Dysarthria  1  1/361 (0.28%)  0/182 (0.00%) 
Encephalopathy  1  2/361 (0.55%)  2/182 (1.10%) 
Haemorrhage intracranial  1  0/361 (0.00%)  1/182 (0.55%) 
Haemorrhagic stroke  1  1/361 (0.28%)  0/182 (0.00%) 
Hemiplegia  1  2/361 (0.55%)  0/182 (0.00%) 
Hepatic encephalopathy  1  5/361 (1.39%)  0/182 (0.00%) 
Metabolic encephalopathy  1  0/361 (0.00%)  1/182 (0.55%) 
Nervous system disorder  1  1/361 (0.28%)  0/182 (0.00%) 
Peripheral motor neuropathy  1  0/361 (0.00%)  1/182 (0.55%) 
Sciatica  1  0/361 (0.00%)  1/182 (0.55%) 
Syncope  1  1/361 (0.28%)  0/182 (0.00%) 
Psychiatric disorders     
Anxiety  1  0/361 (0.00%)  1/182 (0.55%) 
Confusional state  1  2/361 (0.55%)  3/182 (1.65%) 
Disorientation  1  1/361 (0.28%)  0/182 (0.00%) 
Mental status changes  1  1/361 (0.28%)  0/182 (0.00%) 
Renal and urinary disorders     
Anuria  1  2/361 (0.55%)  0/182 (0.00%) 
Haematuria  1  1/361 (0.28%)  0/182 (0.00%) 
Renal disorder  1  1/361 (0.28%)  0/182 (0.00%) 
Renal failure  1  11/361 (3.05%)  2/182 (1.10%) 
Renal failure acute  1  8/361 (2.22%)  2/182 (1.10%) 
Renal failure chronic  1  1/361 (0.28%)  0/182 (0.00%) 
Reproductive system and breast disorders     
Testicular swelling  1  1/361 (0.28%)  0/182 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema  1  2/361 (0.55%)  0/182 (0.00%) 
Acute respiratory distress syndrome  1  0/361 (0.00%)  1/182 (0.55%) 
Asthma  1  1/361 (0.28%)  0/182 (0.00%) 
Bronchial haemorrhage  1  0/361 (0.00%)  1/182 (0.55%) 
Bronchostenosis  1  0/361 (0.00%)  1/182 (0.55%) 
Cough  1  1/361 (0.28%)  1/182 (0.55%) 
Dyspnoea  1  9/361 (2.49%)  4/182 (2.20%) 
Epistaxis  1  9/361 (2.49%)  0/182 (0.00%) 
Haemoptysis  1  1/361 (0.28%)  0/182 (0.00%) 
Interstitial lung disease  1  5/361 (1.39%)  0/182 (0.00%) 
Lung disorder  1  1/361 (0.28%)  0/182 (0.00%) 
Lung infiltration  1  2/361 (0.55%)  0/182 (0.00%) 
Pleural effusion  1  3/361 (0.83%)  1/182 (0.55%) 
Pleurisy  1  1/361 (0.28%)  0/182 (0.00%) 
Pneumonia aspiration  1  1/361 (0.28%)  1/182 (0.55%) 
Pneumonitis  1  5/361 (1.39%)  1/182 (0.55%) 
Pneumothorax  1  1/361 (0.28%)  0/182 (0.00%) 
Productive cough  1  1/361 (0.28%)  0/182 (0.00%) 
Pulmonary embolism  1  2/361 (0.55%)  1/182 (0.55%) 
Pulmonary oedema  1  0/361 (0.00%)  1/182 (0.55%) 
Respiratory arrest  1  0/361 (0.00%)  1/182 (0.55%) 
Respiratory failure  1  3/361 (0.83%)  0/182 (0.00%) 
Sleep apnoea syndrome  1  1/361 (0.28%)  0/182 (0.00%) 
Upper respiratory tract inflammation  1  1/361 (0.28%)  0/182 (0.00%) 
Skin and subcutaneous tissue disorders     
Angioedema  1  1/361 (0.28%)  0/182 (0.00%) 
Pruritus  1  1/361 (0.28%)  0/182 (0.00%) 
Rash  1  1/361 (0.28%)  0/182 (0.00%) 
Skin ulcer  1  1/361 (0.28%)  0/182 (0.00%) 
Social circumstances     
Immobilisation prolonged  1  1/361 (0.28%)  0/182 (0.00%) 
Vascular disorders     
Deep vein thrombosis  1  1/361 (0.28%)  0/182 (0.00%) 
Haematoma  1  1/361 (0.28%)  0/182 (0.00%) 
Post thrombotic syndrome  1  1/361 (0.28%)  0/182 (0.00%) 
Shock haemorrhagic  1  0/361 (0.00%)  2/182 (1.10%) 
Vascular compression  1  1/361 (0.28%)  0/182 (0.00%) 
Vena cava thrombosis  1  1/361 (0.28%)  0/182 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Everolimus + Best Supportive Care (BSC) Placebo + Best Supportive Care
Affected / at Risk (%) Affected / at Risk (%)
Total   343/361 (95.01%)   147/182 (80.77%) 
Blood and lymphatic system disorders     
Anaemia  1  56/361 (15.51%)  13/182 (7.14%) 
Thrombocytopenia  1  40/361 (11.08%)  2/182 (1.10%) 
Gastrointestinal disorders     
Abdominal pain  1  54/361 (14.96%)  27/182 (14.84%) 
Abdominal pain upper  1  28/361 (7.76%)  17/182 (9.34%) 
Ascites  1  51/361 (14.13%)  23/182 (12.64%) 
Constipation  1  31/361 (8.59%)  23/182 (12.64%) 
Diarrhoea  1  94/361 (26.04%)  25/182 (13.74%) 
Dry mouth  1  23/361 (6.37%)  5/182 (2.75%) 
Nausea  1  60/361 (16.62%)  25/182 (13.74%) 
Stomatitis  1  142/361 (39.34%)  9/182 (4.95%) 
Vomiting  1  55/361 (15.24%)  17/182 (9.34%) 
General disorders     
Asthenia  1  59/361 (16.34%)  31/182 (17.03%) 
Fatigue  1  90/361 (24.93%)  30/182 (16.48%) 
Oedema peripheral  1  100/361 (27.70%)  25/182 (13.74%) 
Pyrexia  1  86/361 (23.82%)  13/182 (7.14%) 
Infections and infestations     
Hepatitis B  1  25/361 (6.93%)  8/182 (4.40%) 
Investigations     
Alanine aminotransferase increased  1  11/361 (3.05%)  11/182 (6.04%) 
Aspartate aminotransferase increased  1  23/361 (6.37%)  19/182 (10.44%) 
Gamma-glutamyltransferase increased  1  18/361 (4.99%)  12/182 (6.59%) 
Platelet count decreased  1  21/361 (5.82%)  0/182 (0.00%) 
Weight decreased  1  34/361 (9.42%)  8/182 (4.40%) 
Metabolism and nutrition disorders     
Decreased appetite  1  114/361 (31.58%)  27/182 (14.84%) 
Hyperglycaemia  1  20/361 (5.54%)  3/182 (1.65%) 
Hypokalaemia  1  19/361 (5.26%)  1/182 (0.55%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  24/361 (6.65%)  13/182 (7.14%) 
Pain in extremity  1  19/361 (5.26%)  9/182 (4.95%) 
Nervous system disorders     
Dysgeusia  1  31/361 (8.59%)  4/182 (2.20%) 
Headache  1  26/361 (7.20%)  9/182 (4.95%) 
Psychiatric disorders     
Insomnia  1  37/361 (10.25%)  15/182 (8.24%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  79/361 (21.88%)  23/182 (12.64%) 
Dyspnoea  1  45/361 (12.47%)  21/182 (11.54%) 
Epistaxis  1  78/361 (21.61%)  5/182 (2.75%) 
Pleural effusion  1  19/361 (5.26%)  3/182 (1.65%) 
Skin and subcutaneous tissue disorders     
Dry skin  1  24/361 (6.65%)  6/182 (3.30%) 
Pruritus  1  64/361 (17.73%)  29/182 (15.93%) 
Rash  1  76/361 (21.05%)  16/182 (8.79%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 16.0
Three patients (1 in the everolimus arm and 2 in the placebo arm were excluded from the Safety Set. These three patients were randomized but never received any study treatment.
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 the pooled data (i.e., data from all sites) in the clinical trial.
Results Point of Contact
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01035229     History of Changes
Other Study ID Numbers: CRAD001O2301
2009-010196-25 ( EudraCT Number )
First Submitted: December 17, 2009
First Posted: December 18, 2009
Results First Submitted: September 24, 2014
Results First Posted: October 27, 2014
Last Update Posted: September 22, 2016