AG-013736 In Combination With Gemcitabine Versus Gemcitabine Alone For Patients With Metastatic Pancreatic Cancer

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT00219557
First received: September 13, 2005
Last updated: July 23, 2012
Last verified: July 2012
Results First Received: February 25, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Pancreatic Neoplasms
Interventions: Drug: Gemcitabine
Drug: AG-013736

  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
No text entered.

Reporting Groups
  Description
Axitinib + Gemcitabine (Phase 1 Lead-In) Axitinib (AG-013736) 5 milligram (mg) tablet orally twice daily (BID) starting from Day 3 of Cycle 1, in cycles of 4 weeks. Gemcitabine 1000 milligram/square meter (mg/m^2) 30 minutes intravenous (IV) infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.
Axitinib + Gemcitabine Axitinib (AG-013736) 5 mg tablet orally BID starting from Day 1 of Cycle 1, in cycles of 4 weeks. Gemcitabine 1000 mg/m^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.
Gemcitabine Gemcitabine 1000 mg/m^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.

Participant Flow for 2 periods

Period 1:   Phase 1
    Axitinib + Gemcitabine (Phase 1 Lead-In)     Axitinib + Gemcitabine     Gemcitabine  
STARTED     8     0     0  
COMPLETED     1     0     0  
NOT COMPLETED     7     0     0  
Lack of Efficacy                 3                 0                 0  
Adverse Event                 2                 0                 0  
Withdrawal by Subject                 1                 0                 0  
Started chemotherapy at other institute                 1                 0                 0  

Period 2:   Phase 2
    Axitinib + Gemcitabine (Phase 1 Lead-In)     Axitinib + Gemcitabine     Gemcitabine  
STARTED     0     69     34  
Treated     0     68     31  
COMPLETED     0     0     1  
NOT COMPLETED     0     69     33  
Lack of Efficacy                 0                 21                 15  
Adverse Event                 0                 22                 2  
Death                 0                 8                 2  
Unspecified                 0                 8                 6  
Withdrawal by Subject                 0                 9                 5  
Treatment not received                 0                 1                 3  



  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
Axitinib + Gemcitabine (Phase 1 Lead-In) Axitinib (AG-013736) 5 milligram (mg) tablet orally twice daily (BID) starting from Day 3 of Cycle 1, in cycles of 4 weeks. Gemcitabine 1000 milligram/square meter (mg/m^2) 30 minutes intravenous (IV) infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.
Axitinib + Gemcitabine Axitinib (AG-013736) 5 mg tablet orally BID starting from Day 1 of Cycle 1, in cycles of 4 weeks. Gemcitabine 1000 mg/m^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.
Gemcitabine Gemcitabine 1000 mg/m^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.
Total Total of all reporting groups

Baseline Measures
    Axitinib + Gemcitabine (Phase 1 Lead-In)     Axitinib + Gemcitabine     Gemcitabine     Total  
Number of Participants  
[units: participants]
  8     69     34     111  
Age, Customized  
[units: Participants]
       
18 years to 44 years     0     2     4     6  
45 years to 64 years     5     31     20     56  
Greater than or equal to 65 years     3     36     10     49  
Gender  
[units: Participants]
       
Female     1     34     18     53  
Male     7     35     16     58  



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Overall Survival (OS)   [ Time Frame: Baseline of Phase 2 to death or until at least 1 year after the randomization of the last participant ]

2.  Secondary:   Dose Confirmation of Axitinib (AG-013736) on Basis of Number of Participants With Dose Limiting Toxicity (DLT)   [ Time Frame: Phase 1 baseline up to Week 4 ]

3.  Secondary:   Dose Confirmation of Gemcitabine on Basis of Number of Participants With Dose Limiting Toxicity (DLT)   [ Time Frame: Phase 1 Baseline up to Week 4 ]

4.  Secondary:   Maximum Observed Plasma Concentration (Cmax) for Axitinib (AG-013736)   [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3.5, 4.5, 9.5, and 12.5 hours (hr) post-dose on Day 15 of Phase 1 Cycle 1 ]

5.  Secondary:   Area Under the Curve From Time Zero to 24 Hours [AUC (0-24)] of Axitinib (AG-013736)   [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3.5, 4.5, 9.5, and 12.5 hr post-dose on Day 15 of Pase 1 Cycle 1 ]

6.  Secondary:   Time to Reach Maximum Observed Plasma Concentration (Tmax) of Axitinib (AG-013736)   [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3.5, 4.5, 9.5, and 12.5 hr post-dose on Day 15 of Phase 1 Cycle 1 ]

7.  Secondary:   Plasma Decay Half-life (t1/2) of Axitinib (AG-013736)   [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3.5, 4.5, 9.5, and 12.5 hr post-dose on Day 15 of Phase 1 Cycle 1 ]

8.  Secondary:   Maximum Observed Plasma Concentration (Cmax) of Gemcitabine   [ Time Frame: 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 9 and 12 hr after start of infusion on Day 15 of Phase 1 Cycle 1 ]

9.  Secondary:   Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of Gemcitabine   [ Time Frame: 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 9 and 12 hr after start of infusion on Day 15 of Phase 1 Cycle 1 ]

10.  Secondary:   Plasma Decay Half-life (t1/2) of Gemcitabine   [ Time Frame: 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 9 and 12 hr after start of infusion on Day 15 of Phase 1 Cycle 1 ]

11.  Secondary:   Percentage of Participants With Overall Response (OR)   [ Time Frame: Phase 2 baseline to disease progression or discontinuation from study, assessed every 8 weeks up to 80 weeks ]

12.  Secondary:   Duration of Response (DR)   [ Time Frame: Phase 2 baseline to disease progression or discontinuation from study due to any cause, assessed every 8 weeks up to 80 weeks ]

13.  Secondary:   Progression-free Survival (PFS)   [ Time Frame: Phase 2 baseline until the date of first documented progression or death due to any cause, assessed every 8 weeks up to 80 weeks ]

14.  Secondary:   One Year Survival Probability   [ Time Frame: Phase 2 baseline to disease progression or death due to any cause or at least 1 year after the first dose for the last participant ]

15.  Secondary:   Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score at Day 1 of Every Cycle and End of Study   [ Time Frame: Phase 2 baseline [Day (D)1 of Cycle (C)1], Day 1 of all subsequent cycles up to Cycle 14 and end of study (EoS). ]

16.  Secondary:   Change From Baseline in 26-item Pancreatic Cancer-specific Quality of Life Questionnaire (QLQ-PAN26) Score at Day 1 of Every Cycle and End of Study   [ Time Frame: Phase 2 baseline [Day (D) 1 of Cycle (C)1], Day 1 of all subsequent cycles up to Cycle 14 and end of study (EoS). ]

17.  Secondary:   Population Pharmacokinetics of Axitinib (AG-013736) in Phase 2   [ Time Frame: Phase 2 Day 1 (Pre-dose), Day 29, Day 57 and then every 8 weeks until disease progression or discontinuation from study or up to 80 weeks ]
Results not yet reported.   Anticipated Reporting Date:   No text entered.   Safety Issue:   No


  Serious Adverse Events


  Other Adverse Events
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Time Frame No text entered.
Additional Description The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Frequency Threshold
Threshold above which other adverse events are reported   0%  

Reporting Groups
  Description
Axitinib + Gemcitabine (Phase 1 Lead-In) Axitinib (AG-013736) 5 milligram (mg) tablet orally twice daily (BID) starting from Day 3 of Cycle 1, in cycles of 4 weeks. Gemcitabine 1000 milligram/square meter (mg/m^2) 30 minutes intravenous (IV) infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.
Axitinib + Gemcitabine Axitinib (AG-013736) 5 mg tablet orally twice daily (BID) from Day 1 of Cycle 1 (28 days) and all subsequent cycles (28 days). Gemcitabine 1000 mg/m^2 30-minute infusion on Day 1, 8 and 15 of each cycle.
Gemcitabine Gemcitabine 1000 mg/m^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.

Other Adverse Events
    Axitinib + Gemcitabine (Phase 1 Lead-In)     Axitinib + Gemcitabine     Gemcitabine  
Total, other (not including serious) adverse events        
# participants affected / at risk     7/8     67/68     26/31  
Blood and lymphatic system disorders        
Anaemia * 1      
# participants affected / at risk     4/8 (50.00%)     16/68 (23.53%)     7/31 (22.58%)  
Granulocytopenia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Iron deficiency anaemia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Leukopenia * 1      
# participants affected / at risk     2/8 (25.00%)     3/68 (4.41%)     0/31 (0.00%)  
Neutropenia * 1      
# participants affected / at risk     2/8 (25.00%)     15/68 (22.06%)     6/31 (19.35%)  
Thrombocytopenia * 1      
# participants affected / at risk     4/8 (50.00%)     10/68 (14.71%)     2/31 (6.45%)  
Thrombocytosis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Lymphopenia * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Cardiac disorders        
Atrial fibrillation * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Cardiogenic shock * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Cyanosis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Pericardial effusion * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Sinus tachycardia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Tachycardia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     2/31 (6.45%)  
Ear and labyrinth disorders        
Ear pain * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Tinnitus * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Vertigo * 1      
# participants affected / at risk     1/8 (12.50%)     1/68 (1.47%)     0/31 (0.00%)  
Eye disorders        
Blepharitis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Conjunctivitis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Eyelid oedema * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Photopsia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Vitreous floaters * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Gastrointestinal disorders        
Abdominal discomfort * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     2/31 (6.45%)  
Abdominal distension * 1      
# participants affected / at risk     0/8 (0.00%)     4/68 (5.88%)     1/31 (3.23%)  
Abdominal hernia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Abdominal pain * 1      
# participants affected / at risk     2/8 (25.00%)     16/68 (23.53%)     8/31 (25.81%)  
Abdominal pain upper * 1      
# participants affected / at risk     1/8 (12.50%)     11/68 (16.18%)     1/31 (3.23%)  
Abdominal tenderness * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Aphthous stomatitis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Ascites * 1      
# participants affected / at risk     1/8 (12.50%)     3/68 (4.41%)     5/31 (16.13%)  
Constipation * 1      
# participants affected / at risk     2/8 (25.00%)     18/68 (26.47%)     7/31 (22.58%)  
Diarrhoea * 1      
# participants affected / at risk     4/8 (50.00%)     35/68 (51.47%)     8/31 (25.81%)  
Dry mouth * 1      
# participants affected / at risk     0/8 (0.00%)     5/68 (7.35%)     1/31 (3.23%)  
Duodenal ulcer * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Dyspepsia * 1      
# participants affected / at risk     0/8 (0.00%)     9/68 (13.24%)     4/31 (12.90%)  
Dysphagia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Flatulence * 1      
# participants affected / at risk     1/8 (12.50%)     5/68 (7.35%)     2/31 (6.45%)  
Gastric Ulcer * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Gastritis * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     1/31 (3.23%)  
Gastrointestinal haemorrhage * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Gastrooesophageal reflux disease * 1      
# participants affected / at risk     2/8 (25.00%)     1/68 (1.47%)     1/31 (3.23%)  
Gingival pain * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Gingival swelling * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Haematochezia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Haemorrhoids * 1      
# participants affected / at risk     0/8 (0.00%)     5/68 (7.35%)     0/31 (0.00%)  
Inguinal hernia * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Intestinal haemorrhage * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Lip ulceration * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Mesenteric artery stenosis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Nausea * 1      
# participants affected / at risk     3/8 (37.50%)     30/68 (44.12%)     15/31 (48.39%)  
Oral pain * 1      
# participants affected / at risk     0/8 (0.00%)     6/68 (8.82%)     0/31 (0.00%)  
Peptic ulcer haemorrhage * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Proctalgia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Rectal haemorrhage * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     1/31 (3.23%)  
Sensitivity of teeth * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Small intestinal obstruction * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Steatorrhoea * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Stomatitis * 1      
# participants affected / at risk     1/8 (12.50%)     12/68 (17.65%)     2/31 (6.45%)  
Tongue coated * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Tongue disorder * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Toothache * 1      
# participants affected / at risk     2/8 (25.00%)     2/68 (2.94%)     0/31 (0.00%)  
Vomiting * 1      
# participants affected / at risk     2/8 (25.00%)     29/68 (42.65%)     12/31 (38.71%)  
General disorders        
Adverse drug reaction * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Asthenia * 1      
# participants affected / at risk     1/8 (12.50%)     22/68 (32.35%)     4/31 (12.90%)  
Catheter site pain * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Chest pain * 1      
# participants affected / at risk     1/8 (12.50%)     5/68 (7.35%)     0/31 (0.00%)  
Chills * 1      
# participants affected / at risk     0/8 (0.00%)     5/68 (7.35%)     3/31 (9.68%)  
Device occlusion * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Disease progression * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Face oedema * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Fatigue * 1      
# participants affected / at risk     7/8 (87.50%)     29/68 (42.65%)     10/31 (32.26%)  
Feeling cold * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
General physical health deterioration * 1      
# participants affected / at risk     1/8 (12.50%)     1/68 (1.47%)     0/31 (0.00%)  
Hyperpyrexia * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Influenza like illness * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Infusion related reaction * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Infusion site pain * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Malaise * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Mass * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Mucosal dryness * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Mucosal inflammation * 1      
# participants affected / at risk     3/8 (37.50%)     12/68 (17.65%)     2/31 (6.45%)  
Oedema * 1      
# participants affected / at risk     0/8 (0.00%)     6/68 (8.82%)     0/31 (0.00%)  
Oedema peripheral * 1      
# participants affected / at risk     1/8 (12.50%)     11/68 (16.18%)     8/31 (25.81%)  
Pain * 1      
# participants affected / at risk     0/8 (0.00%)     10/68 (14.71%)     2/31 (6.45%)  
Performance status decreased * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Pyrexia * 1      
# participants affected / at risk     1/8 (12.50%)     12/68 (17.65%)     7/31 (22.58%)  
Hepatobiliary disorders        
Bile duct obstruction * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Bile duct stenosis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Cholangitis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Cholecystitis * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Cholestasis * 1      
# participants affected / at risk     1/8 (12.50%)     1/68 (1.47%)     1/31 (3.23%)  
Cytolytic hepatitis * 1      
# participants affected / at risk     3/8 (37.50%)     1/68 (1.47%)     1/31 (3.23%)  
Hepatotoxicity * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Hyperbilirubinaemia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Jaundice * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     1/31 (3.23%)  
Immune system disorders        
Hypersensitivity * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Infections and infestations        
Bacteraemia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Bronchitis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Candidiasis * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     1/31 (3.23%)  
Cellulitis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Diverticulitis * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Escherichia sepsis * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Folliculitis * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Gastroenteritis * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Gingival abscess * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Herpes ophthalmic * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Hordeolum * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Infected skin ulcer * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Infection * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Influenza * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Localised infection * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Nasopharyngitis * 1      
# participants affected / at risk     2/8 (25.00%)     1/68 (1.47%)     0/31 (0.00%)  
Oral candidiasis * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Oral herpes * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Oropharyngeal candidiasis * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Periodontal infection * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Pneumonia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Staphylococcal infection * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Upper respiratory tract infection * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Urinary tract infection * 1      
# participants affected / at risk     1/8 (12.50%)     9/68 (13.24%)     3/31 (9.68%)  
Vulvovaginal candidiasis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Wound infection * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Injury, poisoning and procedural complications        
Contusion * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Drug toxicity * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Excoriation * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Fall * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Joint sprain * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Muscle strain * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Periorbital haematoma * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Procedural pain * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Sunburn * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Investigations        
Alanine aminotransferase * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Alanine aminotransferase increased * 1      
# participants affected / at risk     0/8 (0.00%)     3/68 (4.41%)     1/31 (3.23%)  
Aspartate aminotransferase * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Aspartate aminotransferase increased * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     2/31 (6.45%)  
Blood albumin decreased * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Blood albumin increased * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Blood alkaline phosphatase * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Blood alkaline phosphatase increased * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     1/31 (3.23%)  
Blood bilirubin increased * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Blood creatinine increased * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Blood glucose * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Blood glucose increased * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Blood lactate dehydrogenase increased * 1      
# participants affected / at risk     1/8 (12.50%)     1/68 (1.47%)     0/31 (0.00%)  
Blood potassium decreased * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Blood pressure increased * 1      
# participants affected / at risk     0/8 (0.00%)     3/68 (4.41%)     0/31 (0.00%)  
Blood sodium decreased * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Blood thyroid stimulating hormone increased * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Haemoglobin * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Haemoglobin decreased * 1      
# participants affected / at risk     0/8 (0.00%)     5/68 (7.35%)     2/31 (6.45%)  
Heart rate increased * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
International normalised ratio * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Neutrophil count * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Neutrophil count decreased * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Platelet count decreased * 1      
# participants affected / at risk     0/8 (0.00%)     4/68 (5.88%)     0/31 (0.00%)  
Prothrombin time prolonged * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Transaminases increased * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     1/31 (3.23%)  
Weight decreased * 1      
# participants affected / at risk     1/8 (12.50%)     16/68 (23.53%)     4/31 (12.90%)  
Metabolism and nutrition disorders        
Anorexia * 1      
# participants affected / at risk     3/8 (37.50%)     0/68 (0.00%)     0/31 (0.00%)  
Cachexia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Decreased appetite * 1      
# participants affected / at risk     1/8 (12.50%)     29/68 (42.65%)     10/31 (32.26%)  
Dehydration * 1      
# participants affected / at risk     1/8 (12.50%)     4/68 (5.88%)     0/31 (0.00%)  
Diabetes mellitus inadequate control * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Failure to thrive * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Hyperglycaemia * 1      
# participants affected / at risk     0/8 (0.00%)     3/68 (4.41%)     0/31 (0.00%)  
Hyperkalaemia * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     2/31 (6.45%)  
Hypernatraemia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Hypoalbuminaemia * 1      
# participants affected / at risk     1/8 (12.50%)     2/68 (2.94%)     0/31 (0.00%)  
Hypocalcaemia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Hypoglycaemia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Hypokalaemia * 1      
# participants affected / at risk     0/8 (0.00%)     11/68 (16.18%)     4/31 (12.90%)  
Hypomagnesaemia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Musculoskeletal and connective tissue disorders        
Arthralgia * 1      
# participants affected / at risk     1/8 (12.50%)     1/68 (1.47%)     0/31 (0.00%)  
Back pain * 1      
# participants affected / at risk     2/8 (25.00%)     12/68 (17.65%)     2/31 (6.45%)  
Bone pain * 1      
# participants affected / at risk     1/8 (12.50%)     2/68 (2.94%)     0/31 (0.00%)  
Flank pain * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Joint swelling * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Mobility decreased * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Muscle atrophy * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Muscle spasms * 1      
# participants affected / at risk     1/8 (12.50%)     1/68 (1.47%)     0/31 (0.00%)  
Muscular weakness * 1      
# participants affected / at risk     1/8 (12.50%)     3/68 (4.41%)     0/31 (0.00%)  
Musculoskeletal chest pain * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Musculoskeletal pain * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Myalgia * 1      
# participants affected / at risk     0/8 (0.00%)     3/68 (4.41%)     0/31 (0.00%)  
Myositis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Pain in extremity * 1      
# participants affected / at risk     0/8 (0.00%)     6/68 (8.82%)     3/31 (9.68%)  
Spinal osteoarthritis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Trigger finger * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Neoplasms benign, malignant and unspecified (incl cysts and polyps)        
Malignant pleural effusion * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Tumour pain * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Nervous system disorders        
Aphasia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Ataxia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Balance disorder * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Cerebral ischaemia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Dizziness * 1      
# participants affected / at risk     0/8 (0.00%)     8/68 (11.76%)     3/31 (9.68%)  
Dysarthria * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Dysgeusia * 1      
# participants affected / at risk     1/8 (12.50%)     7/68 (10.29%)     2/31 (6.45%)  
Dyskinesia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Facial paresis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Headache * 1      
# participants affected / at risk     1/8 (12.50%)     9/68 (13.24%)     2/31 (6.45%)  
Hypoaesthesia * 1      
# participants affected / at risk     0/8 (0.00%)     5/68 (7.35%)     0/31 (0.00%)  
Lethargy * 1      
# participants affected / at risk     0/8 (0.00%)     6/68 (8.82%)     0/31 (0.00%)  
Neuropathy * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Neuropathy peripheral * 1      
# participants affected / at risk     1/8 (12.50%)     3/68 (4.41%)     0/31 (0.00%)  
Paraesthesia * 1      
# participants affected / at risk     1/8 (12.50%)     1/68 (1.47%)     1/31 (3.23%)  
Peripheral sensory neuropathy * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     1/31 (3.23%)  
Sensory loss * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Somnolence * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     1/31 (3.23%)  
Syncope * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Tremor * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Psychiatric disorders        
Agitation * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     1/31 (3.23%)  
Anxiety * 1      
# participants affected / at risk     0/8 (0.00%)     9/68 (13.24%)     3/31 (9.68%)  
Confusional state * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     2/31 (6.45%)  
Delirium * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Depressed mood * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Depression * 1      
# participants affected / at risk     2/8 (25.00%)     7/68 (10.29%)     2/31 (6.45%)  
Insomnia * 1      
# participants affected / at risk     2/8 (25.00%)     6/68 (8.82%)     0/31 (0.00%)  
Restlessness * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Sleep disorder * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Renal and urinary disorders        
Chromaturia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Dysuria * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Haematuria * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Haemoglobinuria * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Nocturia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Oliguria * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Proteinuria * 1      
# participants affected / at risk     0/8 (0.00%)     6/68 (8.82%)     0/31 (0.00%)  
Renal failure acute * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Urinary incontinence * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Urinary retention * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Urine flow decreased * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Reproductive system and breast disorders        
Erectile dysfunction * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Metrorrhagia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Vaginal haemorrhage * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Vulvovaginal dryness * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Vulvovaginal erythema * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Respiratory, thoracic and mediastinal disorders        
Cough * 1      
# participants affected / at risk     2/8 (25.00%)     5/68 (7.35%)     3/31 (9.68%)  
Dysphonia * 1      
# participants affected / at risk     6/8 (75.00%)     11/68 (16.18%)     1/31 (3.23%)  
Dyspnoea * 1      
# participants affected / at risk     2/8 (25.00%)     15/68 (22.06%)     5/31 (16.13%)  
Dyspnoea exertional * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Epistaxis * 1      
# participants affected / at risk     2/8 (25.00%)     8/68 (11.76%)     0/31 (0.00%)  
Haemoptysis * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Hiccups * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Nasal dryness * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Orthopnoea * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Pleural effusion * 1      
# participants affected / at risk     0/8 (0.00%)     3/68 (4.41%)     1/31 (3.23%)  
Pleuritic pain * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Pneumonitis * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Pulmonary oedema * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Respiratory distress * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Rhinorrhoea * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Upper-airway cough syndrome * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Skin and subcutaneous tissue disorders        
Alopecia * 1      
# participants affected / at risk     1/8 (12.50%)     10/68 (14.71%)     0/31 (0.00%)  
Decubitus ulcer * 1      
# participants affected / at risk     0/8 (0.00%)     4/68 (5.88%)     0/31 (0.00%)  
Dry Skin * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Erythema * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     1/31 (3.23%)  
Hyperhidrosis * 1      
# participants affected / at risk     1/8 (12.50%)     2/68 (2.94%)     3/31 (9.68%)  
Livedo reticularis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Night sweats * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Palmar erythema * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Palmar-plantar erythrodysaesthesia syndrome * 1      
# participants affected / at risk     2/8 (25.00%)     1/68 (1.47%)     0/31 (0.00%)  
Petechiae * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Photosensitivity reaction * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Pruritus * 1      
# participants affected / at risk     2/8 (25.00%)     6/68 (8.82%)     1/31 (3.23%)  
Pruritus generalised * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Rash * 1      
# participants affected / at risk     0/8 (0.00%)     12/68 (17.65%)     2/31 (6.45%)  
Rash generalised * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Skin lesion * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Urticaria * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Surgical and medical procedures        
Pancreaticoduodenectomy * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Vascular disorders        
Deep vein thrombosis * 1      
# participants affected / at risk     0/8 (0.00%)     4/68 (5.88%)     2/31 (6.45%)  
Haemorrhage * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Hot flush * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Hypertension * 1      
# participants affected / at risk     4/8 (50.00%)     16/68 (23.53%)     0/31 (0.00%)  
Pallor * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Shock * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Thrombophlebitis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Thrombosis * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA v13.1



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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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