Everolimus and Octreotide in Patients With Advanced Carcinoid Tumor (RADIANT-2)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00412061
First received: December 13, 2006
Last updated: March 5, 2014
Last verified: March 2014
Results First Received: October 25, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Conditions: Carcinoid Tumor
Malignant Carcinoid Syndrome
Interventions: Drug: Octreotide
Drug: Placebo
Drug: Everolimus

  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
Total 429 patients were randomized to double blind phase of treatment.

Reporting Groups
  Description
Octreotide+ Everolimus Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.
Octreotide+ Placebo Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.

Participant Flow:   Overall Study
    Octreotide+ Everolimus     Octreotide+ Placebo  
STARTED     216     213  
Safety Population     215     211  
COMPLETED     95 [1]   146  
NOT COMPLETED     121     67  
Ongoing, on study drug                 37                 34  
Adverse Event                 57                 14  
Withdrawn consent                 17                 11  
Death                 6                 2  
Protocol Violation                 3                 4  
New cancer therapy                 1                 1  
Lost to Follow-up                 0                 1  
[1] Patients listed as completed discontinued due to disease progression.



  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
Octreotide+ Everolimus Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.
Octreotide+ Placebo Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.
Total Total of all reporting groups

Baseline Measures
    Octreotide+ Everolimus     Octreotide+ Placebo     Total  
Number of Participants  
[units: participants]
  216     213     429  
Age  
[units: years]
Mean ± Standard Deviation
  60.1  ± 10.72     59.4  ± 11.13     59.8  ± 10.92  
Gender  
[units: patients]
     
Female     119     89     208  
Male     97     124     221  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Progression Free Survival (PFS) as Per Adjudicated Central Radiology Review   [ Time Frame: Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010 ]

2.  Secondary:   Best Overall Response Rate as Per Adjudicated Central Radiology Review Based on Response Evaluation Criteria in Solid Tumors (RECIST)   [ Time Frame: Time from randomisation to dates of disease progression, death from any cause or last tumor assessment, reported between day of first patient randomised, 10 January 2007, until cut-off date 02 April 2010 ]

3.  Secondary:   Number of Patients With Adverse Events (AEs), Clinically Notable AE, Death, Serious Adverse Events (SAEs)   [ Time Frame: From first day of treatment up to 28 days after last day of treatment in double blind (safety data collected till data cut off date i.e. 2nd April 2010) ]

4.  Secondary:   Progression Free Survival (PFS) as Per Adjudicated Central Review by Change From Baseline Chromogranin A (CgA) and 5-hydroxyindoleacetic Acid (5-HIAA)   [ Time Frame: If elevated at baseline, evaluated every cycle visit (28 days/cycle) ]
Results not yet posted.   Anticipated Posting Date:   08/2013   Safety Issue:   No

5.  Secondary:   Overall Survival Using Kaplan-Meier Methodology   [ Time Frame: The date of randomization to the date of death ]
Results not yet posted.   Anticipated Posting Date:   08/2013   Safety Issue:   No

6.  Secondary:   Evaluation of Pharmacokinetics (PK)Parameters   [ Time Frame: Day 1 of every cycle (28 days/cycle) throughout the study ]
Results not yet posted.   Anticipated Posting Date:   08/2013   Safety Issue:   No


  Serious Adverse Events
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Time Frame No text entered.
Additional Description The Safety Set consists of all patients who received at least one dose of study drug and who had at least one valid post-baseline safety assessment. The “other adverse events” table includes only non-serious adverse events.

Reporting Groups
  Description
Octreotide+ Everolimus Everolimus was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity. Each treatment cycle lasted 28 days. Patients received their first dose of everolimus at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1, Day 1.
Octreotide + Placebo Matching placebo was administered in accordance with a 10-mg daily dosing regimen (two 5-mg tablets) in conjunction with octreotide 30 mg intramuscularly (i.m.) every 28 days. Patients were treated until progression or unacceptable toxicity; Each treatment cycle lasted 28 days. Patients received their first dose of matching placebo at Cycle 1, Day 1. Administration of octreotide was performed every 28 days (± 4 days) starting on Cycle 1 Day 1.

Serious Adverse Events
    Octreotide+ Everolimus     Octreotide + Placebo  
Total, serious adverse events      
# participants affected / at risk     122/215 (56.74%)     73/211 (34.60%)  
Blood and lymphatic system disorders      
Anaemia † 1    
# participants affected / at risk     4/215 (1.86%)     2/211 (0.95%)  
Disseminated intravascular coagulation † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Febrile neutropenia † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Haemorrhagic anaemia † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Thrombocytopenia † 1    
# participants affected / at risk     3/215 (1.40%)     0/211 (0.00%)  
Cardiac disorders      
Acute myocardial infarction † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Angina pectoris † 1    
# participants affected / at risk     2/215 (0.93%)     3/211 (1.42%)  
Aortic valve incompetence † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Arrhythmia † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Atrial fibrillation † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Atrial flutter † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Carcinoid heart disease † 1    
# participants affected / at risk     2/215 (0.93%)     2/211 (0.95%)  
Cardiac failure † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Cardiac failure congestive † 1    
# participants affected / at risk     2/215 (0.93%)     2/211 (0.95%)  
Cardiac valve disease † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Cardio-respiratory arrest † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Cardiopulmonary failure † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Coronary artery disease † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Coronary artery occlusion † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Dilatation ventricular † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Left ventricular dysfunction † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Mitral valve stenosis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Myocardial infarction † 1    
# participants affected / at risk     1/215 (0.47%)     2/211 (0.95%)  
Myocardial ischaemia † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Palpitations † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Pericardial effusion † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Pulmonary valve incompetence † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Pulmonary valve stenosis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Right ventricular failure † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Stress cardiomyopathy † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Tricuspid valve disease † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Tricuspid valve incompetence † 1    
# participants affected / at risk     1/215 (0.47%)     2/211 (0.95%)  
Tricuspid valve prolapse † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Tricuspid valve stenosis † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Congenital, familial and genetic disorders      
Atrial septal defect † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Gastrointestinal angiodysplasia † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Ear and labyrinth disorders      
Vertigo † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Endocrine disorders      
Adrenocortical insufficiency acute † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Carcinoid syndrome † 1    
# participants affected / at risk     3/215 (1.40%)     1/211 (0.47%)  
Eye disorders      
Diplopia † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Gastrointestinal disorders      
Abdominal adhesions † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Abdominal distension † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Abdominal hernia † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Abdominal pain † 1    
# participants affected / at risk     13/215 (6.05%)     11/211 (5.21%)  
Abdominal pain lower † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Abdominal pain upper † 1    
# participants affected / at risk     1/215 (0.47%)     2/211 (0.95%)  
Ascites † 1    
# participants affected / at risk     0/215 (0.00%)     5/211 (2.37%)  
Colitis † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Diarrhoea † 1    
# participants affected / at risk     8/215 (3.72%)     5/211 (2.37%)  
Duodenal obstruction † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Duodenal stenosis † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Enteritis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Faeces discoloured † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Food poisoning † 1    
# participants affected / at risk     0/215 (0.00%)     2/211 (0.95%)  
Gastric haemorrhage † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Gastrointestinal fistula † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Gastrointestinal haemorrhage † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Gastrooesophageal reflux disease † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Haematemesis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Haematochezia † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Haemorrhoids † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Ileus † 1    
# participants affected / at risk     5/215 (2.33%)     1/211 (0.47%)  
Inguinal hernia, obstructive † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Intestinal obstruction † 1    
# participants affected / at risk     2/215 (0.93%)     4/211 (1.90%)  
Lip oedema † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Melaena † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Nausea † 1    
# participants affected / at risk     3/215 (1.40%)     4/211 (1.90%)  
Oesophageal spasm † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Pancreatitis acute † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Pneumatosis intestinalis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Rectal haemorrhage † 1    
# participants affected / at risk     3/215 (1.40%)     0/211 (0.00%)  
Small intestinal haemorrhage † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Small intestinal obstruction † 1    
# participants affected / at risk     7/215 (3.26%)     3/211 (1.42%)  
Small intestinal stenosis † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Stomatitis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Subileus † 1    
# participants affected / at risk     3/215 (1.40%)     2/211 (0.95%)  
Upper gastrointestinal haemorrhage † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Vomiting † 1    
# participants affected / at risk     5/215 (2.33%)     6/211 (2.84%)  
General disorders      
Asthenia † 1    
# participants affected / at risk     2/215 (0.93%)     3/211 (1.42%)  
Brain death † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Chest pain † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Chills † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Fatigue † 1    
# participants affected / at risk     2/215 (0.93%)     1/211 (0.47%)  
General physical health deterioration † 1    
# participants affected / at risk     6/215 (2.79%)     2/211 (0.95%)  
Generalised oedema † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Hypothermia † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Malaise † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Non-cardiac chest pain † 1    
# participants affected / at risk     3/215 (1.40%)     0/211 (0.00%)  
Oedema peripheral † 1    
# participants affected / at risk     3/215 (1.40%)     4/211 (1.90%)  
Pain † 1    
# participants affected / at risk     1/215 (0.47%)     2/211 (0.95%)  
Pyrexia † 1    
# participants affected / at risk     7/215 (3.26%)     3/211 (1.42%)  
Hepatobiliary disorders      
Cholangitis † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Cholangitis acute † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Cholecystitis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Cholecystitis acute † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Cholestasis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Cytolytic hepatitis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Hepatic failure † 1    
# participants affected / at risk     2/215 (0.93%)     2/211 (0.95%)  
Hepatic function abnormal † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Hyperbilirubinaemia † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Jaundice † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Infections and infestations      
Abdominal wall abscess † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Abscess intestinal † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Arthritis infective † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Bacteraemia † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Cellulitis † 1    
# participants affected / at risk     3/215 (1.40%)     0/211 (0.00%)  
Cholecystitis infective † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Clostridium difficile colitis † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Diverticulitis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Escherichia sepsis † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Gastroenteritis † 1    
# participants affected / at risk     2/215 (0.93%)     1/211 (0.47%)  
Gastroenteritis viral † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Herpes zoster † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Infected skin ulcer † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Influenza † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Lung infection † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Pneumonia † 1    
# participants affected / at risk     9/215 (4.19%)     1/211 (0.47%)  
Pneumonia viral † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Sepsis † 1    
# participants affected / at risk     2/215 (0.93%)     1/211 (0.47%)  
Sinusitis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Staphylococcal infection † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Urinary tract infection † 1    
# participants affected / at risk     2/215 (0.93%)     2/211 (0.95%)  
Urinary tract infection bacterial † 1    
# participants affected / at risk     0/215 (0.00%)     2/211 (0.95%)  
Urosepsis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Injury, poisoning and procedural complications      
Femoral neck fracture † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Fractured sacrum † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Heat exhaustion † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Hip fracture † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Humerus fracture † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Joint injury † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Post procedural complication † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Post procedural haemorrhage † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Rib fracture † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Scapula fracture † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Seroma † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Traumatic lung injury † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Investigations      
Alanine aminotransferase increased † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Aspartate aminotransferase increased † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Blood creatinine increased † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Blood urea increased † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Cardiac murmur † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Coagulation time shortened † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Heart rate increased † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Lipase increased † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Weight decreased † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Metabolism and nutrition disorders      
Cachexia † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Decreased appetite † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Dehydration † 1    
# participants affected / at risk     7/215 (3.26%)     1/211 (0.47%)  
Failure to thrive † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Hypercalcaemia † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Hyperglycaemia † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Hypocalcaemia † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Hypoglycaemia † 1    
# participants affected / at risk     2/215 (0.93%)     1/211 (0.47%)  
Hypokalaemia † 1    
# participants affected / at risk     4/215 (1.86%)     0/211 (0.00%)  
Hypomagnesaemia † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Hypophosphataemia † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Malnutrition † 1    
# participants affected / at risk     1/215 (0.47%)     2/211 (0.95%)  
Metabolic acidosis † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Type 2 diabetes mellitus † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Musculoskeletal and connective tissue disorders      
Arthralgia † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Arthritis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Back pain † 1    
# participants affected / at risk     0/215 (0.00%)     4/211 (1.90%)  
Bone pain † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Flank pain † 1    
# participants affected / at risk     2/215 (0.93%)     1/211 (0.47%)  
Muscle spasms † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Musculoskeletal chest pain † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Neck pain † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Osteoarthritis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Osteoporosis † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Pain in extremity † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)      
B-cell type acute leukaemia † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Brain neoplasm malignant † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Cancer pain † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Lung infiltration malignant † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Malignant pleural effusion † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Nervous system disorders      
Cerebrovascular accident † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Depressed level of consciousness † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Dizziness postural † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Encephalopathy † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Facial paresis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Headache † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Hemicephalalgia † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Hypoaesthesia † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Intracranial haematoma † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Lethargy † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Mental impairment † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Metabolic encephalopathy † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Radiculopathy † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Sciatica † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Subarachnoid haemorrhage † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Syncope † 1    
# participants affected / at risk     2/215 (0.93%)     1/211 (0.47%)  
Psychiatric disorders      
Confusional state † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Hallucination † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Renal and urinary disorders      
Bladder tamponade † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Calculus ureteric † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Calculus urinary † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Haematuria † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Nephrolithiasis † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Renal failure † 1    
# participants affected / at risk     4/215 (1.86%)     0/211 (0.00%)  
Renal failure acute † 1    
# participants affected / at risk     3/215 (1.40%)     1/211 (0.47%)  
Renal impairment † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Renal infarct † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Ureteric obstruction † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Urinary bladder haemorrhage † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Urinary retention † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Reproductive system and breast disorders      
Testicular swelling † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Respiratory, thoracic and mediastinal disorders      
Acute respiratory failure † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Atelectasis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Cough † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Dyspnoea † 1    
# participants affected / at risk     8/215 (3.72%)     2/211 (0.95%)  
Hypoxia † 1    
# participants affected / at risk     3/215 (1.40%)     1/211 (0.47%)  
Interstitial lung disease † 1    
# participants affected / at risk     3/215 (1.40%)     0/211 (0.00%)  
Lung infiltration † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Organising pneumonia † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Pleural effusion † 1    
# participants affected / at risk     3/215 (1.40%)     0/211 (0.00%)  
Pneumonitis † 1    
# participants affected / at risk     2/215 (0.93%)     0/211 (0.00%)  
Pulmonary embolism † 1    
# participants affected / at risk     6/215 (2.79%)     1/211 (0.47%)  
Respiratory failure † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Tachypnoea † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Skin and subcutaneous tissue disorders      
Angioedema † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Palmar-plantar erythrodysaesthesia syndrome † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Vascular disorders      
Aortic dissection † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Deep vein thrombosis † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Flushing † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Haematoma † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Hypertension † 1    
# participants affected / at risk     1/215 (0.47%)     1/211 (0.47%)  
Hypotension † 1    
# participants affected / at risk     0/215 (0.00%)     1/211 (0.47%)  
Jugular vein thrombosis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Orthostatic hypotension † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Phlebitis † 1    
# participants affected / at risk     1/215 (0.47%)     0/211 (0.00%)  
Events were collected by systematic assessment
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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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