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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00410124
First received: December 11, 2006
Last updated: December 7, 2012
Last verified: December 2012
Results First Received: October 23, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Metastatic Renal Cell Carcinoma
Interventions: Drug: RAD001
Drug: Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Core period was terminated due to early achievements of efficacy targets and patients who were receiving study drug and patients receiving placebo in double blind phase had option to continue into the extension phase to receive open label RAD001.

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

Participant Flow for 2 periods

Period 1:   Core Phase Double Blind (15 Months)
    RAD001 +BSC     Placebo + BSC / RAD001  
STARTED     277 [1]   139  
Ongoing     13     4  
Completed Double Blind Treatment     62     2  
COMPLETED     75 [2]   6 [3]
NOT COMPLETED     202     133  
Adverse Event                 36                 2  
Abnormal Laboratory Value                 1                 0  
Protocol Violation                 2                 1  
Withdrawal by Subject                 13                 2  
Lost to Follow-up                 4                 0  
Administrative Problems                 2                 0  
Death                 7                 4  
Disease Progression                 137                 124  
[1] Started indicates randomized (FAS) and treated
[2] Patients ongoing/completed double blind phase had option entering extension phase continuing RAD001.
[3] All patients ongoing/completed/not completed in core had option to enter extension taking RAD001.

Period 2:   Extension Phase - Open Label (45 Months)
    RAD001 +BSC     Placebo + BSC / RAD001  
STARTED     67     111 [1]
COMPLETED     0     0  
NOT COMPLETED     67     111  
Adverse Event                 7                 19  
Abnormal Laboratory Values                 0                 1  
Abnormal Test Procedures                 0                 1  
Withdrawal by Subject                 1                 1  
Death                 2                 10  
Disease Progression                 56                 78  
Patient no longer required study drug                 1                 0  
Final Primary Analysis                 0                 1  
[1] Patients on placebo in core received RAD001 in extension phase.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

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

Baseline Measures
    RAD001 +BSC     Placebo + BSC     Total  
Number of Participants  
[units: participants]
  277     139     416  
Age, Customized  
[units: participants]
     
<65 years     165     98     263  
>=65 years     112     41     153  
Gender  
[units: participants]
     
Female     61     33     94  
Male     216     106     322  



  Outcome Measures
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1.  Primary:   Progressive Free Survival (PFS) in Patients Who Receive RAD001 Plus Best Supportive Care(BSC) Versus Patients Who Receive Matching Placebo Plus BSC   [ Time Frame: Time from randomization to dates of disease progression, death from any cause or last tumor assessment reported between date of first patient randomized until 28Feb2008 cut of date. ]

2.  Secondary:   Overall Survival (OS) Assessed by the Monthly Overall Survival Assessments   [ Time Frame: Assessed every month up to 2 years after the last patient was randomized into the study from the date of randomization to the time of death. (Data cutoff was 15Nov2009) ]

3.  Secondary:   Best Overall Response Rate in Patients Who Receive RAD001 Plus BSC Versus Matching Placebo Plus BSC   [ Time Frame: Time from randomization to dates of disease progression, death from any cause or last tumor assessment reported, between date of first patient randomized until 28Feb2008 cutoff date ]

4.  Secondary:   Duration of Response in Patients Who Receive RAD001 Plus BSC Versus Placebo Plus BSC   [ Time Frame: Time from randomization to dates of disease progression, death from any cause or last tumor assessment reported, between date of first patient randomized until 28Feb2008 cutoff date ]

5.  Secondary:   Analysis of Time to Definitive Deterioration of the Global Health Status/QoL Scale(QL) Scores of the EORTC QLQ-30 Questionnaire by at Least 10 Percent Using Kaplan Meier Method, by Treatment.   [ Time Frame: Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date ]

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

7.  Secondary:   Time to Definitive Deterioration of the Physical Functioning Scale (PF)Score of the EORTC QLQ-C30 Questionnaire by at Least 10 Percent Using Kaplan_Meier Method, by Treatment.   [ Time Frame: Baseline and every 28 days under treatment and at discontinuation from RAD001" until 28Feb2008 cutoff date ]

8.  Secondary:   Pharmacokinetics of RAD001:Peak Concentration in a Dosing Interval (C-max); Pre-dose Concentration at 24-h Time Point in Dosing Interval (C-min) and Average Concentration in a Dosing Interval =(C-avg)   [ Time Frame: At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day1, Cycle 1 Day 15 and at pre-dose from Cycle 2(day1) and all subsequent treatment cycles up until data cut-off 28 Feb 2008. ]

9.  Secondary:   Pharmacokinetics of RAD001: Time at Which C-Max Occurs (t-Max)   [ Time Frame: At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose of From Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008. ]

10.  Secondary:   Pharmacokinetics of RAD001: Area Under Curve (AUC) in a Dosing Interval From Time-zero to Time of the Last Quantifiable Concentration. (AUC 0-tlast)   [ Time Frame: At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008. ]

11.  Secondary:   Pharmacokinetics of RAD001: Time of the Last Quantifiable Concentration in a Dosing Interval - (Tlast)   [ Time Frame: At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008. ]

12.  Secondary:   Pharmacokinetics of RAD001: Apparent Systemic Clearance From Blood Following Extravascular Administration (CL/F)   [ Time Frame: At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008. ]

13.  Secondary:   Pharmacokinetics of RAD001: Normalized to Body Surface Area (CL/F)   [ Time Frame: At pre-dose and post-dose: 1 hour, 2 hour, 5 hour, 24 hour of Cycle 1 Day 1, Cycle 1 Day 15 and at pre-dose from Cycle 2 (Day 1) and all subsequent treatment cycles until data cut-off 28Feb2008. ]


  Serious Adverse Events
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Time Frame No text entered.
Additional Description The Safety population consists of all patients who received at least one dose of study drug and who had at least one valid post-baseline safety assessment. Patients were analyzed according to the treatment actually received.

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

Serious Adverse Events
    Randomized to RAD001+ BSC ( Blinded + Open Label)     Randomized to Placebo + BSC (Open Label)     Randomized to Placebo + BSC (Double Blind Only)  
Total, serious adverse events        
# participants affected / at risk     135/274 (49.27%)     60/111 (54.05%)     17/26 (65.38%)  
Blood and lymphatic system disorders        
Anaemia † 1      
# participants affected / at risk     13/274 (4.74%)     5/111 (4.50%)     0/26 (0.00%)  
Bone marrow reticulin fibrosis † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Haemolysis † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Thrombocytopenia † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Cardiac disorders        
Aortic valve incompetence † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Cardiac disorder † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Cardiac failure † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     0/26 (0.00%)  
Cardiac failure congestive † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Left ventricular dysfunction † 1      
# participants affected / at risk     1/274 (0.36%)     1/111 (0.90%)     0/26 (0.00%)  
Myocardial infarction † 1      
# participants affected / at risk     0/274 (0.00%)     0/111 (0.00%)     1/26 (3.85%)  
Myocardial ischaemia † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Pericardial effusion † 1      
# participants affected / at risk     1/274 (0.36%)     1/111 (0.90%)     0/26 (0.00%)  
Tachycardia † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Endocrine disorders        
Adrenal insufficiency † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Hypothyroidism † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Eye disorders        
Eye pain † 1      
# participants affected / at risk     0/274 (0.00%)     0/111 (0.00%)     1/26 (3.85%)  
Gastrointestinal disorders        
Abdominal distension † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     1/26 (3.85%)  
Abdominal pain † 1      
# participants affected / at risk     7/274 (2.55%)     1/111 (0.90%)     0/26 (0.00%)  
Abdominal pain lower † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Ascites † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Constipation † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     0/26 (0.00%)  
Diarrhoea † 1      
# participants affected / at risk     2/274 (0.73%)     1/111 (0.90%)     0/26 (0.00%)  
Dysphagia † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Faecaloma † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     1/26 (3.85%)  
Gastrointestinal haemorrhage † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Gastrointestinal sounds abnormal † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Haematochezia † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Inguinal hernia † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Intestinal obstruction † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Nausea † 1      
# participants affected / at risk     3/274 (1.09%)     1/111 (0.90%)     0/26 (0.00%)  
Pancreatitis acute † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Peritoneal effusion † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Peritonitis † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Proctalgia † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Small intestinal obstruction † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Stomatitis † 1      
# participants affected / at risk     3/274 (1.09%)     0/111 (0.00%)     0/26 (0.00%)  
Tongue oedema † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Vomiting † 1      
# participants affected / at risk     4/274 (1.46%)     1/111 (0.90%)     0/26 (0.00%)  
General disorders        
Asthenia † 1      
# participants affected / at risk     4/274 (1.46%)     1/111 (0.90%)     2/26 (7.69%)  
Chest discomfort † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Chest pain † 1      
# participants affected / at risk     4/274 (1.46%)     0/111 (0.00%)     0/26 (0.00%)  
Disease progression † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Fatigue † 1      
# participants affected / at risk     7/274 (2.55%)     0/111 (0.00%)     0/26 (0.00%)  
General physical health deterioration † 1      
# participants affected / at risk     3/274 (1.09%)     1/111 (0.90%)     2/26 (7.69%)  
Generalised oedema † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Malaise † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     0/26 (0.00%)  
Mucosal inflammation † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Non-cardiac chest pain † 1      
# participants affected / at risk     4/274 (1.46%)     0/111 (0.00%)     0/26 (0.00%)  
Oedema peripheral † 1      
# participants affected / at risk     3/274 (1.09%)     1/111 (0.90%)     0/26 (0.00%)  
Pain † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Performance status decreased † 1      
# participants affected / at risk     1/274 (0.36%)     2/111 (1.80%)     0/26 (0.00%)  
Pyrexia † 1      
# participants affected / at risk     13/274 (4.74%)     5/111 (4.50%)     0/26 (0.00%)  
Hepatobiliary disorders        
Bile duct obstruction † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Biloma † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Cholangitis † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     0/26 (0.00%)  
Cholangitis acute † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Cholecystitis † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Cholelithiasis † 1      
# participants affected / at risk     1/274 (0.36%)     2/111 (1.80%)     0/26 (0.00%)  
Cholestasis † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     0/26 (0.00%)  
Hepatic failure † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Hepatic steatosis † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Hyperbilirubinaemia † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Jaundice † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     0/26 (0.00%)  
Liver disorder † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Immune system disorders        
Hypersensitivity † 1      
# participants affected / at risk     1/274 (0.36%)     1/111 (0.90%)     0/26 (0.00%)  
Infections and infestations        
Appendicitis † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     0/26 (0.00%)  
Bronchitis † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Bronchopulmonary aspergillosis † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     0/26 (0.00%)  
Cellulitis † 1      
# participants affected / at risk     0/274 (0.00%)     2/111 (1.80%)     0/26 (0.00%)  
Enterococcal infection † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Escherichia infection † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Fungal infection † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Gastroenteritis † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Incision site infection † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Klebsiella infection † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Klebsiella sepsis † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Lung abscess † 1      
# participants affected / at risk     1/274 (0.36%)     2/111 (1.80%)     0/26 (0.00%)  
Lung infection † 1      
# participants affected / at risk     4/274 (1.46%)     0/111 (0.00%)     0/26 (0.00%)  
Pelvic abscess † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Pleural infection † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Pneumonia † 1      
# participants affected / at risk     10/274 (3.65%)     1/111 (0.90%)     0/26 (0.00%)  
Pneumonia bacterial † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Pneumonia viral † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Pyelonephritis † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Rectal abscess † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     0/26 (0.00%)  
Respiratory tract infection † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Salmonellosis † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Sepsis † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     0/26 (0.00%)  
Septic shock † 1      
# participants affected / at risk     3/274 (1.09%)     1/111 (0.90%)     0/26 (0.00%)  
Sinusitis † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Staphylococcal sepsis † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Upper respiratory tract infection † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Viral infection † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Wound abscess † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Injury, poisoning and procedural complications        
Cervical vertebral fracture † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Device dislocation † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Femur fracture † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     1/26 (3.85%)  
Fracture † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Humerus fracture † 1      
# participants affected / at risk     0/274 (0.00%)     0/111 (0.00%)     1/26 (3.85%)  
Ilium fracture † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Lower limb fracture † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Medical device complication † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Post procedural bile leak † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Radiation skin injury † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Rib fracture † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Spinal fracture † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Stent occlusion † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Subdural haematoma † 1      
# participants affected / at risk     0/274 (0.00%)     0/111 (0.00%)     1/26 (3.85%)  
Subdural haemorrhage † 1      
# participants affected / at risk     0/274 (0.00%)     0/111 (0.00%)     1/26 (3.85%)  
Tracheal haemorrhage † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Wound dehiscence † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Investigations        
Bile duct pressure increased † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Blood alkaline phosphatase increased † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Blood amylase increased † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Blood bilirubin increased † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Blood chloride decreased † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Blood creatine phosphokinase increased † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Blood creatinine increased † 1      
# participants affected / at risk     4/274 (1.46%)     1/111 (0.90%)     0/26 (0.00%)  
Blood urea increased † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Ejection fraction decreased † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Lipase increased † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Metabolism and nutrition disorders        
Cachexia † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Cell death † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Decreased appetite † 1      
# participants affected / at risk     3/274 (1.09%)     1/111 (0.90%)     0/26 (0.00%)  
Dehydration † 1      
# participants affected / at risk     9/274 (3.28%)     2/111 (1.80%)     1/26 (3.85%)  
Diabetes mellitus † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     0/26 (0.00%)  
Diabetes mellitus inadequate control † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Diabetic ketoacidosis † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Hypercalcaemia † 1      
# participants affected / at risk     3/274 (1.09%)     0/111 (0.00%)     2/26 (7.69%)  
Hyperkalaemia † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Hypomagnesaemia † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Hyponatraemia † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Musculoskeletal and connective tissue disorders        
Arthralgia † 1      
# participants affected / at risk     1/274 (0.36%)     1/111 (0.90%)     0/26 (0.00%)  
Back pain † 1      
# participants affected / at risk     4/274 (1.46%)     1/111 (0.90%)     1/26 (3.85%)  
Bone pain † 1      
# participants affected / at risk     4/274 (1.46%)     0/111 (0.00%)     0/26 (0.00%)  
Hypercreatinaemia † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Muscular weakness † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Musculoskeletal chest pain † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Osteonecrosis † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Pathological fracture † 1      
# participants affected / at risk     2/274 (0.73%)     1/111 (0.90%)     1/26 (3.85%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)        
Breast cancer † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Cancer pain † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     0/26 (0.00%)  
Infected neoplasm † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Lung neoplasm † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Lymphangiosis carcinomatosa † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Metastases to bone † 1      
# participants affected / at risk     0/274 (0.00%)     0/111 (0.00%)     1/26 (3.85%)  
Metastases to central nervous system † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Metastases to liver † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Metastases to lung † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Metastases to spine † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Pleura carcinoma † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Renal cancer metastatic † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Transitional cell carcinoma † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Tumour haemorrhage † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Tumour pain † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Nervous system disorders        
Aphasia † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     1/26 (3.85%)  
Balance disorder † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Cerebral haemorrhage † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Coma † 1      
# participants affected / at risk     0/274 (0.00%)     0/111 (0.00%)     1/26 (3.85%)  
Convulsion † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     1/26 (3.85%)  
Depressed level of consciousness † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Dizziness † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Encephalopathy † 1      
# participants affected / at risk     0/274 (0.00%)     0/111 (0.00%)     1/26 (3.85%)  
Grand mal convulsion † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     1/26 (3.85%)  
Headache † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     1/26 (3.85%)  
Hemiplegia † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Lethargy † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Loss of consciousness † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Paraesthesia † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Spinal cord compression † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     0/26 (0.00%)  
Status epilepticus † 1      
# participants affected / at risk     0/274 (0.00%)     0/111 (0.00%)     1/26 (3.85%)  
Tremor † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Trigeminal neuralgia † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Psychiatric disorders        
Agitation † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     1/26 (3.85%)  
Confusional state † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     1/26 (3.85%)  
Delirium † 1      
# participants affected / at risk     1/274 (0.36%)     1/111 (0.90%)     0/26 (0.00%)  
Depression † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Hallucination † 1      
# participants affected / at risk     0/274 (0.00%)     0/111 (0.00%)     1/26 (3.85%)  
Intentional self-injury † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Mental status changes † 1      
# participants affected / at risk     2/274 (0.73%)     1/111 (0.90%)     0/26 (0.00%)  
Psychotic disorder † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Suicide attempt † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Renal and urinary disorders        
Haematuria † 1      
# participants affected / at risk     2/274 (0.73%)     1/111 (0.90%)     1/26 (3.85%)  
Hydronephrosis † 1      
# participants affected / at risk     0/274 (0.00%)     2/111 (1.80%)     0/26 (0.00%)  
Renal failure † 1      
# participants affected / at risk     5/274 (1.82%)     4/111 (3.60%)     0/26 (0.00%)  
Renal failure acute † 1      
# participants affected / at risk     3/274 (1.09%)     3/111 (2.70%)     1/26 (3.85%)  
Renal impairment † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Ureteric dilatation † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Ureteric obstruction † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Ureteric stenosis † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Urinary retention † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Reproductive system and breast disorders        
Pelvic pain † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Respiratory, thoracic and mediastinal disorders        
Acute respiratory failure † 1      
# participants affected / at risk     3/274 (1.09%)     0/111 (0.00%)     0/26 (0.00%)  
Asphyxia † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Atelectasis † 1      
# participants affected / at risk     2/274 (0.73%)     0/111 (0.00%)     0/26 (0.00%)  
Cough † 1      
# participants affected / at risk     4/274 (1.46%)     1/111 (0.90%)     0/26 (0.00%)  
Dyspnoea † 1      
# participants affected / at risk     25/274 (9.12%)     11/111 (9.91%)     1/26 (3.85%)  
Dyspnoea exertional † 1      
# participants affected / at risk     1/274 (0.36%)     1/111 (0.90%)     0/26 (0.00%)  
Haemoptysis † 1      
# participants affected / at risk     3/274 (1.09%)     1/111 (0.90%)     0/26 (0.00%)  
Hydrothorax † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Hypoxia † 1      
# participants affected / at risk     2/274 (0.73%)     1/111 (0.90%)     0/26 (0.00%)  
Interstitial lung disease † 1      
# participants affected / at risk     6/274 (2.19%)     3/111 (2.70%)     0/26 (0.00%)  
Lung disorder † 1      
# participants affected / at risk     3/274 (1.09%)     2/111 (1.80%)     0/26 (0.00%)  
Lung infiltration † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Pleural effusion † 1      
# participants affected / at risk     11/274 (4.01%)     8/111 (7.21%)     0/26 (0.00%)  
Pleuritic pain † 1      
# participants affected / at risk     0/274 (0.00%)     2/111 (1.80%)     0/26 (0.00%)  
Pneumonitis † 1      
# participants affected / at risk     11/274 (4.01%)     2/111 (1.80%)     0/26 (0.00%)  
Pulmonary alveolar haemorrhage † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Pulmonary embolism † 1      
# participants affected / at risk     2/274 (0.73%)     2/111 (1.80%)     0/26 (0.00%)  
Pulmonary infarction † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Pulmonary toxicity † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Respiratory distress † 1      
# participants affected / at risk     0/274 (0.00%)     1/111 (0.90%)     0/26 (0.00%)  
Respiratory failure † 1      
# participants affected / at risk     2/274 (0.73%)     3/111 (2.70%)     1/26 (3.85%)  
Skin and subcutaneous tissue disorders        
Night sweats † 1      
# participants affected / at risk     0/274 (0.00%)     0/111 (0.00%)     1/26 (3.85%)  
Pruritus † 1      
# participants affected / at risk     1/274 (0.36%)     1/111 (0.90%)     0/26 (0.00%)  
Vascular disorders        
Circulatory collapse † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Deep vein thrombosis † 1      
# participants affected / at risk     1/274 (0.36%)     1/111 (0.90%)     0/26 (0.00%)  
Haematoma † 1      
# participants affected / at risk     0/274 (0.00%)     0/111 (0.00%)     1/26 (3.85%)  
Shock † 1      
# participants affected / at risk     1/274 (0.36%)     0/111 (0.00%)     0/26 (0.00%)  
Thrombosis † 1      
# participants affected / at risk     0/274 (0.00%)     0/111 (0.00%)     1/26 (3.85%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA




  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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