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Safety and Efficacy of RAD001 (Everolimus) Monotherapy Plus Best Supportive Care in Patients With Advanced Gastric Cancer (AGC) (GRANITE-1)

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ClinicalTrials.gov Identifier: NCT00879333
Recruitment Status : Completed
First Posted : April 10, 2009
Results First Posted : April 6, 2015
Last Update Posted : November 3, 2015
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
Condition Advanced Gastric Cancer
Interventions Drug: Everolimus
Drug: Everolimus placebo
Drug: Best Supportive Care (BSC)
Enrollment 656
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Everolimus 10mg/Daily Placebo
Hide Arm/Group Description All patients were randomized to receive everolimus + BSC. All patients orally took two 5 mg tablets of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments. All patients were randomized to receive placebo + BSC. All patients orally took two 5 mg tablets of matching placebo once daily. Therefore, all patients in the placebo receive matching tablets of total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
Period Title: Overall Study
Started 439 217
Discontinued Study Treatment 428 217
Completed 11 [1] 0
Not Completed 428 217
Reason Not Completed
Adverse Event             94             34
Abnormal Laboratory Value             1             0
Withdrawal by Subject             20             7
Lost to Follow-up             2             1
Administrative Problems             2             0
Death             16             5
Disease Progression             292             169
Protocol Violation             1             1
[1]
Completed=Patients Still on Treatment; At data cutoff final analysis, 11 patients were on treatment
Arm/Group Title Everolimus 10mg/Daily Placebo Total
Hide Arm/Group Description All patients were randomized to receive everolimus + BSC. All patients orally took two 5 mg tablets of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments. All patients were randomized to receive placebo + BSC. All patients orally took two 5 mg tablets of matching placebo once daily. Therefore, all patients in the placebo receive matching tablets of total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments. Total of all reporting groups
Overall Number of Baseline Participants 439 217 656
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 439 participants 217 participants 656 participants
60.3  (11.59) 60.8  (11.61) 60.4  (11.59)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 439 participants 217 participants 656 participants
< 65 years 260 129 389
>=65 years 179 88 267
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 439 participants 217 participants 656 participants
Female
117
  26.7%
56
  25.8%
173
  26.4%
Male
322
  73.3%
161
  74.2%
483
  73.6%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 439 participants 217 participants 656 participants
Caucasian 166 75 241
Black 3 1 4
Asian 251 126 377
Native American 0 1 1
Other 19 14 33
1.Primary Outcome
Title Overall Survival (OS)
Hide Description The primary objective of this study was to compare OS between everolimus + best supportive care (BSC) and placebo + BSC. OS, was defined as the time from date of randomization to the date of death due to any cause. If at the analysis cut-off date a patient was not known to have died, survival was censored at the date of the last contact. OS was analyzed using the Kaplan Meier estimates method.
Time Frame 2.5 years
Hide Outcome Measure Data
Hide 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 and stratum that they were assigned to at randomization.
Arm/Group Title Everolimus 10mg/Daily Placebo
Hide Arm/Group Description:
All patients were randomized to receive everolimus + BSC. All patients orally took two 5 mg tablets of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
All patients were randomized to receive placebo + BSC. All patients orally took two 5 mg tablets of matching placebo once daily. Therefore, all patients in the placebo receive matching tablets of total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
Overall Number of Participants Analyzed 439 217
Median (95% Confidence Interval)
Unit of Measure: Months
5.39
(4.80 to 6.01)
4.34
(3.81 to 5.49)
2.Secondary Outcome
Title Progression Free Survival (PFS)
Hide Description Progression free survival was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause, where progression was based on Investigator assessment of baseline and post-baseline scans according to RECIST. Progression free survival was censored if no PFS event was observed before the first to occur out of (i) the cut-off date, or (ii) the date when a further anticancer therapy was started. The censoring date was the date of the last adequate tumor assessment before either of these two events occurred. If a PFS event was observed after two or more missing or non-evaluable tumor assessments, then the date of progression was censored at the date of the last adequate tumor assessment; for a PFS event observed after a single missing or non-evaluable tumor assessment, the actual date of disease progression was used. Anslsis was done using Kaplan-Meier estimates method.
Time Frame 2.5 years
Hide Outcome Measure Data
Hide 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 and stratum that they were assigned to at randomization.
Arm/Group Title Everolimus 10mg/Daily Placebo
Hide Arm/Group Description:
All patients were randomized to receive everolimus + BSC. All patients orally took two 5 mg tablets of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
All patients were randomized to receive placebo + BSC. All patients orally took two 5 mg tablets of matching placebo once daily. Therefore, all patients in the placebo receive matching tablets of total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
Overall Number of Participants Analyzed 439 217
Median (95% Confidence Interval)
Unit of Measure: Months
1.68
(1.51 to 1.94)
1.41
(1.38 to 1.45)
3.Secondary Outcome
Title Patient Reported Outcome (PRO): Time to Definitive Deterioration of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) Scores
Hide Description The EORTC QLQ-C30 global health status/quality of life sub-scale (QL) was pre-specified as the primary domain of interest, followed by physical functioning (PF), social functioning (SF) and emotional functioning (EF).The EORTC QLQ-C30 questionnaire, along with a module specific for gastric cancer patients (EORTC QLQ-STO22), was used to evaluate PRO. The QLQ-C30 has five function scales (physical, role, cognitive, emotional and social), three symptom scales (fatigue, pain and nausea/vomiting) and a global health status/quality of life scale. In addition, there are questions that assess specific symptoms. The QLQ-STO22 consists of 22 questions that make up five multi-item scales (dysphagia, pain, reflux, eating and anxiety) and four single-item scales (dry mouth, tasting, body image and hair loss).
Time Frame 2.5 years
Hide Outcome Measure Data
Hide 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 and stratum that they were assigned to at randomization.
Arm/Group Title Everolimus 10mg/Daily Placebo
Hide Arm/Group Description:
All patients were randomized to receive everolimus + BSC. All patients orally took two 5 mg tablets of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
All patients were randomized to receive placebo + BSC. All patients orally took two 5 mg tablets of matching placebo once daily. Therefore, all patients in the placebo receive matching tablets of total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
Overall Number of Participants Analyzed 439 217
Median (95% Confidence Interval)
Unit of Measure: Months
In QL score by at least 5 % compared to baseline
1.51
(1.28 to 1.84)
1.45
(1.05 to 1.68)
In PF score by at least 5 % compared to baseline
1.35
(1.12 to 1.54)
1.15
(1.02 to 1.64)
In SF score by at least 5 % compared to baseline
1.87
(1.84 to 2.30)
1.87
(1.64 to 2.46)
In EF score by at least 5 % compared to baseline
1.84
(1.61 to 2.10)
1.71
(1.41 to 1.87)
4.Secondary Outcome
Title Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) Score
Hide Description The ECOG PS scale was used to classify patients according to their functional impairment, with scores ranging from 0 (fully active) to 5 (dead). An analysis of the time to definitive deterioration of the ECOG PS by one category of the score from baseline was performed. Definitive deterioration was defined as a definitive increase by one category from baseline in ECOG PS, with no later improvements observed during the course of the study. A single measure reporting an increase in ECOG PS is sufficient to consider it as a definitive worsening only if it was the last one available for the patient. Kaplan-Meier method was used to estimate the distribution function of time to definitive worsening.
Time Frame 2.5 years
Hide Outcome Measure Data
Hide 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 and stratum that they were assigned to at randomization.
Arm/Group Title Everolimus 10mg/Daily Placebo
Hide Arm/Group Description:
All patients were randomized to receive everolimus + BSC. All patients orally took two 5 mg tablets of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
All patients were randomized to receive placebo + BSC. All patients orally took two 5 mg tablets of matching placebo once daily. Therefore, all patients in the placebo receive matching tablets of total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
Overall Number of Participants Analyzed 439 217
Median (95% Confidence Interval)
Unit of Measure: Months
2.30
(1.97 to 2.79)
2.23
(1.87 to 2.92)
5.Secondary Outcome
Title Overall Response Rate (ORR)
Hide Description ORR was defined as the proportion of patients with measurable disease in whom best overall response (OR) was either complete response (CR) or partial response (PR) according to RECIST criteria.
Time Frame 2.5 years
Hide Outcome Measure Data
Hide 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 and stratum that they were assigned to at randomization.
Arm/Group Title Everolimus 10mg/Daily Placebo
Hide Arm/Group Description:
All patients were randomized to receive everolimus + BSC. All patients orally took two 5 mg tablets of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
All patients were randomized to receive placebo + BSC. All patients orally took two 5 mg tablets of matching placebo once daily. Therefore, all patients in the placebo receive matching tablets of total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
Overall Number of Participants Analyzed 439 217
Measure Type: Number
Unit of Measure: Participants
Measurable Disease 379 191
Complete Response (CR) 1 0
Partial Response (PR) 16 4
Overall Response Rate (ORR) 17 4
6.Secondary Outcome
Title Everolimus Steady State Concentraions at Predose (Cmin) and Cmax at Week 5
Hide Description Cmin is the minimum (trough) steady-state drug concentration in the blood during multiple dosing and Cmax is the maximum (peak) blood drug concentration after dose administration. Cmax is estimated as the maximum of C1h and C2H. C1h is 1 hour post-dose blood concentration and C2h is 2 hour post-dose blood concentration. Only valid pre-dose (Cmin), C1h, and C2h everolimus samples were included in the analysis. Valid pre-dose samples were confirmed blood samples collected at steady-state, collected immediately prior to dosing on the same study day, and collected at approximately 24 ± 4 hours after the previous dose and with no vomiting within the first 4 hours following the last dose. Valid C1h and C2h samples were confirmed blood samples collected at steady-state and within ± 1 hour window and with no vomiting within the first 4 hours following the current and previous dose.
Time Frame Week 5
Hide Outcome Measure Data
Hide Analysis Population Description
PK analyses were based on the safety population in patients with evaluable samples. Only valid pre-dose (Cmin) & Cmax everolimus samples were included. For patients who were unable to tolerate the protocol-specified dosing schedule, dose adjustments were allowed to keep the patient on study drug. Some patients had dose reductions to 5mg daily.
Arm/Group Title Everolimus 10mg/Daily Everolimus 5 mg/Day
Hide Arm/Group Description:
All patients were randomized to receive everolimus + BSC. All patients orally took two 5 mg tablets of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
Patients were randomized to receive everolimus + BSC. Patients orally took 1 5 mg tablet of everolimus once daily. Two of the 18 patients on the 5 mg arm, only had pre-dose evaluable samples.
Overall Number of Participants Analyzed 218 18
Mean (Standard Deviation)
Unit of Measure: ng/mL
Pre-dose (Cmin) (n: 201,18) 16.143  (10.7723) 10.498  (6.1432)
Cmax (n: 218,16) 72.775  (36.5435) 37.269  (27.2086)
7.Secondary Outcome
Title Everolimus Steady State Concentraions at Predose (Cmin) and Cmax by Region Asia vs. Rest of the World (ROW) at Week 5
Hide Description Cmin is the minimum (trough) steady-state drug concentration in the blood during multiple dosing and Cmax is the maximum (peak) blood drug concentration after dose administration. Cmax is estimated as the maximum of C1h and C2H. C1h is 1 hour post-dose blood concentration and C2h is 2 hour post-dose blood concentration. Only valid pre-dose (Cmin), C1h, and C2h everolimus samples were included in the analysis. Valid pre-dose samples were confirmed blood samples collected at steady-state, collected immediately prior to dosing on the same study day, and collected at approximately 24 ± 4 hours after the previous dose and with no vomiting within the first 4 hours following the last dose. Valid C1h and C2h samples were confirmed blood samples collected at steady-state and within ± 1 hour window and with no vomiting within the first 4 hours following the current and previous dose.
Time Frame Week 5
Hide Outcome Measure Data
Hide Analysis Population Description
PK analyses were based on the safety population in patients with evaluable samples. Only valid pre-dose (Cmin) & Cmax everolimus samples were included. For patients who were unable to tolerate the protocol-specified dosing schedule, dose adjustments were allowed to keep the patient on study drug. Some patients had dose reductions to 5mg daily.
Arm/Group Title Everolimus 10mg/Daily Everolimus 5mg/Day
Hide Arm/Group Description:
All patients were randomized to receive everolimus + BSC. All patients orally took two 5 mg tablets of everolimus once daily. Therefore, all patients in the everolimus arm took a total daily dose of 10 mg. Best supportive care was in accordance with the local practice of an individual institution or center, and specifically excluded anti-cancer treatments.
Patients were randomized to receive everolimus + BSC. Patients orally took 5 mg tablet of everolimus once daily. One of the 11 patients on the 5 mg arm, only had a pre-dose evaluable sample.
Overall Number of Participants Analyzed 218 18
Mean (Standard Deviation)
Unit of Measure: ng/mL
Asia: Pre-dose (n:127, 11) 16.804  (9.6163) 9.921  (5.1565)
Asia: Cmax (n:132, 10) 73.568  (34.1898) 34.580  (26.8110)
Rest of the World: Pre-dose (n:74, 7) 15.009  (12.5000) 11.406  (7.8128)
Rest of the World: Cmax (n:86, 6) 71.558  (40.0655) 41.750  (29.8074)
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Everolimus 10mg / Daily Placebo
Hide Arm/Group Description Everolimus 10mg / daily Placebo
All-Cause Mortality
Everolimus 10mg / Daily Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Everolimus 10mg / Daily Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   210/437 (48.05%)   89/215 (41.40%) 
Blood and lymphatic system disorders     
Anaemia  1  15/437 (3.43%)  2/215 (0.93%) 
Coagulopathy  1  1/437 (0.23%)  0/215 (0.00%) 
Disseminated intravascular coagulation  1  2/437 (0.46%)  0/215 (0.00%) 
Febrile neutropenia  1  2/437 (0.46%)  0/215 (0.00%) 
Iron deficiency anaemia  1  1/437 (0.23%)  0/215 (0.00%) 
Neutropenia  1  3/437 (0.69%)  0/215 (0.00%) 
Pancytopenia  1  1/437 (0.23%)  0/215 (0.00%) 
Thrombocytopenia  1  4/437 (0.92%)  1/215 (0.47%) 
Cardiac disorders     
Atrial fibrillation  1  1/437 (0.23%)  0/215 (0.00%) 
Cardiac arrest  1  2/437 (0.46%)  0/215 (0.00%) 
Cardiac disorder  1  0/437 (0.00%)  1/215 (0.47%) 
Cardio-respiratory arrest  1  1/437 (0.23%)  0/215 (0.00%) 
Myocardial ischaemia  1  1/437 (0.23%)  0/215 (0.00%) 
Palpitations  1  1/437 (0.23%)  0/215 (0.00%) 
Congenital, familial and genetic disorders     
Pyloric stenosis  1  1/437 (0.23%)  1/215 (0.47%) 
Eye disorders     
Retinal detachment  1  1/437 (0.23%)  0/215 (0.00%) 
Gastrointestinal disorders     
Abdominal adhesions  1  1/437 (0.23%)  0/215 (0.00%) 
Abdominal compartment syndrome  1  1/437 (0.23%)  0/215 (0.00%) 
Abdominal distension  1  2/437 (0.46%)  1/215 (0.47%) 
Abdominal pain  1  21/437 (4.81%)  12/215 (5.58%) 
Abdominal pain upper  1  2/437 (0.46%)  2/215 (0.93%) 
Abdominal rigidity  1  0/437 (0.00%)  1/215 (0.47%) 
Ascites  1  9/437 (2.06%)  4/215 (1.86%) 
Chronic gastrointestinal bleeding  1  1/437 (0.23%)  0/215 (0.00%) 
Colitis  1  1/437 (0.23%)  0/215 (0.00%) 
Constipation  1  0/437 (0.00%)  2/215 (0.93%) 
Diarrhoea  1  6/437 (1.37%)  0/215 (0.00%) 
Duodenal perforation  1  1/437 (0.23%)  0/215 (0.00%) 
Dyspepsia  1  3/437 (0.69%)  1/215 (0.47%) 
Dysphagia  1  5/437 (1.14%)  2/215 (0.93%) 
Enteritis  1  1/437 (0.23%)  0/215 (0.00%) 
Faecaloma  1  2/437 (0.46%)  0/215 (0.00%) 
Flatulence  1  0/437 (0.00%)  1/215 (0.47%) 
Gastric haemorrhage  1  1/437 (0.23%)  0/215 (0.00%) 
Gastric perforation  1  2/437 (0.46%)  1/215 (0.47%) 
Gastric stenosis  1  0/437 (0.00%)  1/215 (0.47%) 
Gastric ulcer haemorrhage  1  1/437 (0.23%)  0/215 (0.00%) 
Gastrointestinal haemorrhage  1  13/437 (2.97%)  3/215 (1.40%) 
Gastrointestinal obstruction  1  1/437 (0.23%)  0/215 (0.00%) 
Gastrointestinal pain  1  1/437 (0.23%)  0/215 (0.00%) 
Gastrointestinal toxicity  1  1/437 (0.23%)  0/215 (0.00%) 
Haematemesis  1  2/437 (0.46%)  3/215 (1.40%) 
Ileus  1  5/437 (1.14%)  0/215 (0.00%) 
Internal hernia  1  1/437 (0.23%)  0/215 (0.00%) 
Intestinal obstruction  1  5/437 (1.14%)  5/215 (2.33%) 
Intestinal perforation  1  3/437 (0.69%)  0/215 (0.00%) 
Mallory-Weiss syndrome  1  1/437 (0.23%)  0/215 (0.00%) 
Melaena  1  1/437 (0.23%)  3/215 (1.40%) 
Nausea  1  9/437 (2.06%)  9/215 (4.19%) 
Obstruction gastric  1  2/437 (0.46%)  2/215 (0.93%) 
Oesophageal perforation  1  1/437 (0.23%)  0/215 (0.00%) 
Oesophageal stenosis  1  1/437 (0.23%)  0/215 (0.00%) 
Oesophagitis  1  0/437 (0.00%)  1/215 (0.47%) 
Peritoneal adhesions  1  1/437 (0.23%)  0/215 (0.00%) 
Peritoneal disorder  1  1/437 (0.23%)  0/215 (0.00%) 
Peritoneal haemorrhage  1  0/437 (0.00%)  1/215 (0.47%) 
Rectal haemorrhage  1  0/437 (0.00%)  1/215 (0.47%) 
Rectal obstruction  1  1/437 (0.23%)  0/215 (0.00%) 
Small intestinal obstruction  1  0/437 (0.00%)  3/215 (1.40%) 
Stomatitis  1  3/437 (0.69%)  1/215 (0.47%) 
Subileus  1  2/437 (0.46%)  1/215 (0.47%) 
Upper gastrointestinal haemorrhage  1  3/437 (0.69%)  0/215 (0.00%) 
Vomiting  1  14/437 (3.20%)  10/215 (4.65%) 
General disorders     
Asthenia  1  12/437 (2.75%)  6/215 (2.79%) 
Chest discomfort  1  1/437 (0.23%)  0/215 (0.00%) 
Device dislocation  1  1/437 (0.23%)  0/215 (0.00%) 
Device malfunction  1  0/437 (0.00%)  1/215 (0.47%) 
Device occlusion  1  2/437 (0.46%)  0/215 (0.00%) 
Drug intolerance  1  1/437 (0.23%)  0/215 (0.00%) 
Facial pain  1  1/437 (0.23%)  0/215 (0.00%) 
Fatigue  1  8/437 (1.83%)  4/215 (1.86%) 
General physical health deterioration  1  14/437 (3.20%)  4/215 (1.86%) 
Hyperthermia  1  2/437 (0.46%)  0/215 (0.00%) 
Local swelling  1  1/437 (0.23%)  0/215 (0.00%) 
Malaise  1  2/437 (0.46%)  0/215 (0.00%) 
Multi-organ failure  1  1/437 (0.23%)  1/215 (0.47%) 
Non-cardiac chest pain  1  2/437 (0.46%)  0/215 (0.00%) 
Oedema peripheral  1  0/437 (0.00%)  2/215 (0.93%) 
Performance status decreased  1  1/437 (0.23%)  0/215 (0.00%) 
Pyrexia  1  10/437 (2.29%)  1/215 (0.47%) 
Stent malfunction  1  0/437 (0.00%)  1/215 (0.47%) 
Systemic inflammatory response syndrome  1  1/437 (0.23%)  0/215 (0.00%) 
Hepatobiliary disorders     
Bile duct obstruction  1  2/437 (0.46%)  1/215 (0.47%) 
Cholangitis  1  3/437 (0.69%)  0/215 (0.00%) 
Cholangitis acute  1  1/437 (0.23%)  0/215 (0.00%) 
Cholestasis  1  0/437 (0.00%)  1/215 (0.47%) 
Hepatic failure  1  1/437 (0.23%)  1/215 (0.47%) 
Hepatic function abnormal  1  1/437 (0.23%)  1/215 (0.47%) 
Hepatitis  1  1/437 (0.23%)  0/215 (0.00%) 
Hyperbilirubinaemia  1  4/437 (0.92%)  5/215 (2.33%) 
Jaundice cholestatic  1  2/437 (0.46%)  0/215 (0.00%) 
Infections and infestations     
Acinetobacter infection  1  1/437 (0.23%)  0/215 (0.00%) 
Biliary sepsis  1  1/437 (0.23%)  0/215 (0.00%) 
Bronchopneumonia  1  0/437 (0.00%)  1/215 (0.47%) 
Clostridium difficile colitis  1  1/437 (0.23%)  0/215 (0.00%) 
Device related infection  1  2/437 (0.46%)  0/215 (0.00%) 
Escherichia urinary tract infection  1  0/437 (0.00%)  1/215 (0.47%) 
Gastric infection  1  1/437 (0.23%)  0/215 (0.00%) 
Gastroenteritis  1  1/437 (0.23%)  0/215 (0.00%) 
Herpes zoster  1  1/437 (0.23%)  1/215 (0.47%) 
Infection  1  0/437 (0.00%)  1/215 (0.47%) 
Liver abscess  1  2/437 (0.46%)  0/215 (0.00%) 
Lower respiratory tract infection  1  3/437 (0.69%)  0/215 (0.00%) 
Lung infection  1  1/437 (0.23%)  0/215 (0.00%) 
Oral herpes  1  1/437 (0.23%)  0/215 (0.00%) 
Peritonitis  1  2/437 (0.46%)  0/215 (0.00%) 
Peritonitis bacterial  1  1/437 (0.23%)  0/215 (0.00%) 
Pneumocystis jirovecii pneumonia  1  2/437 (0.46%)  0/215 (0.00%) 
Pneumonia  1  12/437 (2.75%)  4/215 (1.86%) 
Pulmonary tuberculosis  1  1/437 (0.23%)  0/215 (0.00%) 
Pyelonephritis acute  1  1/437 (0.23%)  0/215 (0.00%) 
Sepsis  1  2/437 (0.46%)  2/215 (0.93%) 
Septic shock  1  4/437 (0.92%)  0/215 (0.00%) 
Skin infection  1  1/437 (0.23%)  0/215 (0.00%) 
Streptococcal sepsis  1  0/437 (0.00%)  1/215 (0.47%) 
Urinary tract infection  1  4/437 (0.92%)  0/215 (0.00%) 
Urosepsis  1  0/437 (0.00%)  2/215 (0.93%) 
Injury, poisoning and procedural complications     
Colon injury  1  1/437 (0.23%)  0/215 (0.00%) 
Compression fracture  1  1/437 (0.23%)  0/215 (0.00%) 
Hepatic rupture  1  0/437 (0.00%)  1/215 (0.47%) 
Ligament sprain  1  1/437 (0.23%)  0/215 (0.00%) 
Muscle injury  1  1/437 (0.23%)  0/215 (0.00%) 
Oesophageal injury  1  1/437 (0.23%)  0/215 (0.00%) 
Post procedural haematuria  1  1/437 (0.23%)  0/215 (0.00%) 
Procedural pain  1  1/437 (0.23%)  0/215 (0.00%) 
Subdural haemorrhage  1  1/437 (0.23%)  0/215 (0.00%) 
Investigations     
Alanine aminotransferase increased  1  1/437 (0.23%)  0/215 (0.00%) 
Aspartate aminotransferase increased  1  1/437 (0.23%)  0/215 (0.00%) 
Blood creatinine increased  1  1/437 (0.23%)  1/215 (0.47%) 
C-reactive protein increased  1  1/437 (0.23%)  0/215 (0.00%) 
General physical condition abnormal  1  1/437 (0.23%)  0/215 (0.00%) 
Haemoglobin decreased  1  1/437 (0.23%)  0/215 (0.00%) 
International normalised ratio increased  1  1/437 (0.23%)  0/215 (0.00%) 
Transaminases increased  1  1/437 (0.23%)  0/215 (0.00%) 
Metabolism and nutrition disorders     
Cachexia  1  1/437 (0.23%)  1/215 (0.47%) 
Decreased appetite  1  21/437 (4.81%)  8/215 (3.72%) 
Dehydration  1  3/437 (0.69%)  2/215 (0.93%) 
Diabetes mellitus  1  1/437 (0.23%)  0/215 (0.00%) 
Failure to thrive  1  1/437 (0.23%)  0/215 (0.00%) 
Feeding disorder  1  0/437 (0.00%)  1/215 (0.47%) 
Fluid intake reduced  1  1/437 (0.23%)  0/215 (0.00%) 
Food intolerance  1  1/437 (0.23%)  1/215 (0.47%) 
Hypercalcaemia  1  1/437 (0.23%)  0/215 (0.00%) 
Hyperglycaemia  1  1/437 (0.23%)  0/215 (0.00%) 
Hypoglycaemia  1  1/437 (0.23%)  0/215 (0.00%) 
Hyponatraemia  1  1/437 (0.23%)  0/215 (0.00%) 
Hypophagia  1  1/437 (0.23%)  1/215 (0.47%) 
Malnutrition  1  1/437 (0.23%)  0/215 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/437 (0.23%)  0/215 (0.00%) 
Back pain  1  5/437 (1.14%)  2/215 (0.93%) 
Bone pain  1  1/437 (0.23%)  0/215 (0.00%) 
Flank pain  1  1/437 (0.23%)  1/215 (0.47%) 
Intervertebral disc protrusion  1  1/437 (0.23%)  0/215 (0.00%) 
Musculoskeletal chest pain  1  1/437 (0.23%)  0/215 (0.00%) 
Pain in extremity  1  1/437 (0.23%)  0/215 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Cancer pain  1  2/437 (0.46%)  0/215 (0.00%) 
Lymphangiosis carcinomatosa  1  1/437 (0.23%)  0/215 (0.00%) 
Malignant melanoma  1  1/437 (0.23%)  0/215 (0.00%) 
Tumour associated fever  1  1/437 (0.23%)  0/215 (0.00%) 
Tumour haemorrhage  1  3/437 (0.69%)  0/215 (0.00%) 
Tumour perforation  1  1/437 (0.23%)  0/215 (0.00%) 
Nervous system disorders     
Brain stem infarction  1  0/437 (0.00%)  1/215 (0.47%) 
Cerebrovascular accident  1  0/437 (0.00%)  1/215 (0.47%) 
Depressed level of consciousness  1  0/437 (0.00%)  1/215 (0.47%) 
Dizziness  1  1/437 (0.23%)  2/215 (0.93%) 
Headache  1  1/437 (0.23%)  0/215 (0.00%) 
Hemiplegia  1  0/437 (0.00%)  1/215 (0.47%) 
Loss of consciousness  1  0/437 (0.00%)  1/215 (0.47%) 
Paraparesis  1  0/437 (0.00%)  1/215 (0.47%) 
Syncope  1  2/437 (0.46%)  0/215 (0.00%) 
Psychiatric disorders     
Anxiety  1  1/437 (0.23%)  0/215 (0.00%) 
Confusional state  1  2/437 (0.46%)  0/215 (0.00%) 
Expressive language disorder  1  0/437 (0.00%)  1/215 (0.47%) 
Renal and urinary disorders     
Haematuria  1  1/437 (0.23%)  0/215 (0.00%) 
Hydronephrosis  1  1/437 (0.23%)  0/215 (0.00%) 
Renal failure  1  2/437 (0.46%)  0/215 (0.00%) 
Renal failure acute  1  0/437 (0.00%)  1/215 (0.47%) 
Renal impairment  1  1/437 (0.23%)  4/215 (1.86%) 
Ureteric obstruction  1  1/437 (0.23%)  0/215 (0.00%) 
Urinary incontinence  1  1/437 (0.23%)  0/215 (0.00%) 
Reproductive system and breast disorders     
Scrotal oedema  1  1/437 (0.23%)  0/215 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema  1  1/437 (0.23%)  0/215 (0.00%) 
Dyspnoea  1  9/437 (2.06%)  3/215 (1.40%) 
Hypoxia  1  2/437 (0.46%)  2/215 (0.93%) 
Interstitial lung disease  1  2/437 (0.46%)  0/215 (0.00%) 
Pleural effusion  1  9/437 (2.06%)  3/215 (1.40%) 
Pneumonia aspiration  1  0/437 (0.00%)  1/215 (0.47%) 
Pneumonitis  1  3/437 (0.69%)  0/215 (0.00%) 
Productive cough  1  1/437 (0.23%)  0/215 (0.00%) 
Pulmonary embolism  1  2/437 (0.46%)  2/215 (0.93%) 
Pulmonary fibrosis  1  1/437 (0.23%)  0/215 (0.00%) 
Pulmonary oedema  1  1/437 (0.23%)  0/215 (0.00%) 
Respiratory arrest  1  1/437 (0.23%)  0/215 (0.00%) 
Respiratory failure  1  4/437 (0.92%)  0/215 (0.00%) 
Respiratory tract congestion  1  0/437 (0.00%)  1/215 (0.47%) 
Skin and subcutaneous tissue disorders     
Angioedema  1  0/437 (0.00%)  1/215 (0.47%) 
Rash  1  2/437 (0.46%)  0/215 (0.00%) 
Vascular disorders     
Circulatory collapse  1  1/437 (0.23%)  0/215 (0.00%) 
Deep vein thrombosis  1  1/437 (0.23%)  0/215 (0.00%) 
Extremity necrosis  1  1/437 (0.23%)  0/215 (0.00%) 
Hypertension  1  1/437 (0.23%)  0/215 (0.00%) 
Hypotension  1  3/437 (0.69%)  1/215 (0.47%) 
Hypovolaemic shock  1  0/437 (0.00%)  1/215 (0.47%) 
Lymphoedema  1  1/437 (0.23%)  0/215 (0.00%) 
Pallor  1  0/437 (0.00%)  1/215 (0.47%) 
Pelvic venous thrombosis  1  1/437 (0.23%)  0/215 (0.00%) 
Peripheral ischaemia  1  1/437 (0.23%)  0/215 (0.00%) 
Thrombophlebitis  1  0/437 (0.00%)  1/215 (0.47%) 
Thrombosis  1  0/437 (0.00%)  1/215 (0.47%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Everolimus 10mg / Daily Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   416/437 (95.19%)   193/215 (89.77%) 
Blood and lymphatic system disorders     
Anaemia  1  108/437 (24.71%)  42/215 (19.53%) 
Leukopenia  1  30/437 (6.86%)  3/215 (1.40%) 
Neutropenia  1  47/437 (10.76%)  6/215 (2.79%) 
Thrombocytopenia  1  77/437 (17.62%)  4/215 (1.86%) 
Gastrointestinal disorders     
Abdominal distension  1  39/437 (8.92%)  20/215 (9.30%) 
Abdominal pain  1  90/437 (20.59%)  49/215 (22.79%) 
Abdominal pain upper  1  51/437 (11.67%)  26/215 (12.09%) 
Constipation  1  92/437 (21.05%)  41/215 (19.07%) 
Diarrhoea  1  112/437 (25.63%)  33/215 (15.35%) 
Dyspepsia  1  22/437 (5.03%)  8/215 (3.72%) 
Nausea  1  129/437 (29.52%)  63/215 (29.30%) 
Stomatitis  1  173/437 (39.59%)  22/215 (10.23%) 
Vomiting  1  98/437 (22.43%)  54/215 (25.12%) 
General disorders     
Asthenia  1  67/437 (15.33%)  18/215 (8.37%) 
Fatigue  1  146/437 (33.41%)  63/215 (29.30%) 
Oedema peripheral  1  49/437 (11.21%)  21/215 (9.77%) 
Pyrexia  1  77/437 (17.62%)  24/215 (11.16%) 
Investigations     
Alanine aminotransferase increased  1  28/437 (6.41%)  9/215 (4.19%) 
Aspartate aminotransferase increased  1  34/437 (7.78%)  8/215 (3.72%) 
Blood alkaline phosphatase increased  1  34/437 (7.78%)  6/215 (2.79%) 
Weight decreased  1  87/437 (19.91%)  19/215 (8.84%) 
Metabolism and nutrition disorders     
Decreased appetite  1  202/437 (46.22%)  76/215 (35.35%) 
Hyperglycaemia  1  31/437 (7.09%)  6/215 (2.79%) 
Hypoalbuminaemia  1  25/437 (5.72%)  12/215 (5.58%) 
Hypokalaemia  1  52/437 (11.90%)  9/215 (4.19%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  46/437 (10.53%)  16/215 (7.44%) 
Nervous system disorders     
Dizziness  1  22/437 (5.03%)  12/215 (5.58%) 
Dysgeusia  1  26/437 (5.95%)  7/215 (3.26%) 
Headache  1  32/437 (7.32%)  8/215 (3.72%) 
Psychiatric disorders     
Insomnia  1  51/437 (11.67%)  22/215 (10.23%) 
Renal and urinary disorders     
Proteinuria  1  24/437 (5.49%)  5/215 (2.33%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  50/437 (11.44%)  17/215 (7.91%) 
Dyspnoea  1  54/437 (12.36%)  21/215 (9.77%) 
Epistaxis  1  29/437 (6.64%)  1/215 (0.47%) 
Skin and subcutaneous tissue disorders     
Dry skin  1  23/437 (5.26%)  7/215 (3.26%) 
Palmar-plantar erythrodysaesthesia syndrome  1  22/437 (5.03%)  2/215 (0.93%) 
Pruritus  1  47/437 (10.76%)  9/215 (4.19%) 
Rash  1  86/437 (19.68%)  19/215 (8.84%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.0
4 randomized patients, 2 patients each from the everolimus and placebo arms were excluded from the safety analyses as they did not receive any dose of study treatment.
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.
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.
Results Point of Contact
Name/Title: Study Director
Organization: Novartis Pharmaceuticals
Phone: 862-778-8300
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00879333     History of Changes
Other Study ID Numbers: CRAD001R2301
2008-006544-20 ( EudraCT Number )
First Submitted: April 8, 2009
First Posted: April 10, 2009
Results First Submitted: January 28, 2015
Results First Posted: April 6, 2015
Last Update Posted: November 3, 2015