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Trial to Reduce Cardiovascular Events With Aranesp® Therapy (TREAT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00093015
Recruitment Status : Completed
First Posted : September 29, 2004
Results First Posted : September 2, 2010
Last Update Posted : November 8, 2022
Sponsor:
Information provided by (Responsible Party):
Amgen

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Kidney Disease
Diabetes Mellitus
Anemia
Interventions Drug: Placebo
Drug: darbepoetin alfa
Enrollment 4038
Recruitment Details First Subject Enrolled: 25 Aug 2004 Last Subject Enrolled: 04 Dec 2007
Pre-assignment Details  
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was <9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL. Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Period Title: Overall Study
Started 2026 2012
Received Study Medication 2019 2004
Completed 1361 1348
Not Completed 665 664
Reason Not Completed
Withdrawal by Subject             194             171
Lost to Follow-up             96             108
Death             375             385
Arm/Group Title Darbepoetin Alfa Placebo Total
Hide Arm/Group Description Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed. Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was <9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL. Total of all reporting groups
Overall Number of Baseline Participants 2012 2026 4038
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 2012 participants 2026 participants 4038 participants
67.2  (10.7) 67.5  (10.6) 67.4  (10.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 2012 participants 2026 participants 4038 participants
Female
1178
  58.5%
1134
  56.0%
2312
  57.3%
Male
834
  41.5%
892
  44.0%
1726
  42.7%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 2012 participants 2026 participants 4038 participants
White or Caucasian 1270 1300 2570
Black or African American 414 401 815
Hispanic or Latino 273 265 538
Asian 35 43 78
Japanese 8 3 11
American Indian or Alaska Native 1 4 5
Native Hawaiian or Other Pacific Islander 4 5 9
Aborigine 2 1 3
Other 5 4 9
History of cardiovascular disease   [1] 
Measure Type: Number
Unit of measure:  Participant
 Number Analyzed 2012 participants 2026 participants 4038 participants
With history of cardiovascular disease 1287 1355 2642
Without history of cardiovascular disease 725 671 1396
[1]
Measure Description: Cardiovascular disease history is based on the cardiovascular medical history case report form.
Baseline proteinuria level   [1] 
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 2012 participants 2026 participants 4038 participants
>= 1 g/g creat 686 711 1397
< 1 g/g creat 1324 1315 2639
[1]
Measure Description: Baseline proteinuria level (g/g creat). Baseline proteinuria is defined as the last non-missing measurement prior or on the day of first investigational product.
1.Primary Outcome
Title Time to All-cause Mortality or Cardiovascular (CV) Events Including Hospitalization Due to Acute Myocardial Ischemia, Congestive Heart Failure (CHF), Myocardial Infarction (MI), and Cerebrovascular Accident (CVA)
Hide Description Time from randomization to the first confirmed composite event. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time Frame Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was <9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.
Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Overall Number of Participants Analyzed 2026 2012
Measure Type: Number
Unit of Measure: Participants
602 632
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.41
Comments Nominal p-value from a 2-sided log rank test is presented. The primary cardiovascular composite endpoint was tested at the 0.04056 significance level at final analysis after accounting for 4 planned interim analyses (overall alpha = 0.048).
Method Log Rank
Comments A 2-sided log-rank test comparing the survival functions of the 2 groups stratified by baseline proteinuria and CV disease (CVD) history.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.05
Confidence Interval 95%
0.94 to 1.17
Estimation Comments Treatment effect was estimated using a hazards ratio and 95% confidence interval (CI) obtained from a Cox proportional hazards model stratified by baseline proteinuria and CVD history. Hazard ratio (darbepoetin alfa / placebo)
2.Primary Outcome
Title Time to All-cause Mortality or End Stage Renal Disease (ESRD)
Hide Description Time from randomization to first event of all-cause mortality or ESRD. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time Frame Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was <9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.
Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Overall Number of Participants Analyzed 2026 2012
Measure Type: Number
Unit of Measure: Participants
618 652
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.29
Comments Nominal p-value from a 2-sided log rank test is presented. The primary renal composite endpoint was tested at the 0.002 significance level at final analysis.
Method Log Rank
Comments A 2-sided log-rank test comparing the survival functions of the 2 groups stratified by baseline proteinuria and CV disease (CVD) history.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.06
Confidence Interval 95%
0.95 to 1.19
Estimation Comments Treatment effect was estimated using a hazards ratio and 95% confidence interval (CI) obtained from a Cox proportional hazards model stratified by baseline proteinuria and CVD history. Hazard ratio (darbepoetin alfa / placebo)
3.Secondary Outcome
Title Time to All-cause Mortality
Hide Description Time from randomization to all-cause mortality. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time Frame Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was <9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.
Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Overall Number of Participants Analyzed 2026 2012
Measure Type: Number
Unit of Measure: Participants
395 412
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.48
Comments Nominal p-value from a 2-sided log rank test is presented.
Method Log Rank
Comments A 2-sided log-rank test comparing the survival functions of the 2 groups stratified by baseline proteinuria and CV disease (CVD) history.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.05
Confidence Interval 95%
0.92 to 1.21
Estimation Comments Treatment effect was estimated using a hazards ratio and 95% confidence interval (CI) obtained from a Cox proportional hazards model stratified by baseline proteinuria and CVD history. Hazard ratio (darbepoetin alfa / placebo)
4.Secondary Outcome
Title Time to Cardiovascular Mortality
Hide Description Time from randomization to cardiovascular (CV) mortality. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time Frame Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was <9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.
Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Overall Number of Participants Analyzed 2026 2012
Measure Type: Number
Unit of Measure: Participants
250 259
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.61
Comments Nominal p-value from a 2-sided log rank test is presented.
Method Log Rank
Comments A 2-sided log-rank test comparing the survival functions of the 2 groups stratified by baseline proteinuria and CV disease (CVD) history.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.05
Confidence Interval 95%
0.88 to 1.25
Estimation Comments Treatment effect was estimated using a hazards ratio and 95% confidence interval (CI) obtained from a Cox proportional hazards model stratified by baseline proteinuria and CVD history. Hazard ratio (darbepoetin alfa / placebo)
5.Secondary Outcome
Title Time to Myocardial Infarction
Hide Description Time from randomization to fatal or non-fatal myocardial infarction (MI). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time Frame Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was <9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.
Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Overall Number of Participants Analyzed 2026 2012
Measure Type: Number
Unit of Measure: Participants
129 124
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.73
Comments Nominal p-value from a 2-sided log rank test is presented.
Method Log Rank
Comments A 2-sided log-rank test comparing the survival functions of the 2 groups stratified by baseline proteinuria and CV disease (CVD) history.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.96
Confidence Interval 95%
0.75 to 1.23
Estimation Comments Treatment effect was estimated using a hazards ratio and 95% confidence interval (CI) obtained from a Cox proportional hazards model stratified by baseline proteinuria and CVD history. Hazard ratio (darbepoetin alfa / placebo)
6.Secondary Outcome
Title Time to Cerebrovascular Accident
Hide Description Time from randomization to fatal or non-fatal cerebrovascular accident (CVA). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time Frame Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was <9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.
Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Overall Number of Participants Analyzed 2026 2012
Measure Type: Number
Unit of Measure: Participants
53 101
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Nominal p-value from a 2-sided log rank test is presented.
Method Log Rank
Comments A 2-sided log-rank test comparing the survival functions of the 2 groups stratified by baseline proteinuria and CV disease (CVD) history.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.92
Confidence Interval 95%
1.38 to 2.68
Estimation Comments Treatment effect was estimated using a hazards ratio and 95% confidence interval (CI) obtained from a Cox proportional hazards model stratified by baseline proteinuria and CVD history. Hazard ratio (darbepoetin alfa / placebo)
7.Secondary Outcome
Title Time to Congestive Heart Failure
Hide Description Time from randomization to fatal or non-fatal congestive heart failure(CHF). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time Frame Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was <9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.
Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Overall Number of Participants Analyzed 2026 2012
Measure Type: Number
Unit of Measure: Participants
229 205
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.24
Comments Nominal p-value from a 2-sided log rank test is presented.
Method Log Rank
Comments A 2-sided log-rank test comparing the survival functions of the 2 groups stratified by baseline proteinuria and CV disease (CVD) history.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.89
Confidence Interval 95%
0.74 to 1.08
Estimation Comments Treatment effect was estimated using a hazards ratio and 95% confidence interval (CI) obtained from a Cox proportional hazards model stratified by baseline proteinuria and CVD history. Hazard ratio (darbepoetin alfa / placebo)
8.Secondary Outcome
Title Time to End Stage Renal Disease
Hide Description Time from randomization to end stage renal disease (ESRD). Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time Frame Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was <9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.
Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Overall Number of Participants Analyzed 2026 2012
Measure Type: Number
Unit of Measure: Participants
330 338
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.83
Comments Nominal p-value from a 2-sided log rank test is presented.
Method Log Rank
Comments A 2-sided log-rank test comparing the survival functions of the 2 groups stratified by baseline proteinuria and CV disease (CVD) history.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 1.02
Confidence Interval 95%
0.87 to 1.18
Estimation Comments Treatment effect was estimated using a hazards ratio and 95% confidence interval (CI) obtained from a Cox proportional hazards model stratified by baseline proteinuria and CVD history. Hazard ratio (darbepoetin alfa / placebo)
9.Secondary Outcome
Title Rate of Decline in Estimated Glomerular Filtration Rate (eGFR) Relative to Baseline
Hide Description GFR was estimated using the following MDRD formula: 186 x [Serum creatinine]^(-1.154) x [Age]^(-0.203) x [0.742 if subject is female] x [1.210 if subject is black]. Change from baseline in eGFR at week 49 for each treatment group are presented. The treatment effect of the rate of decline in eGFR per year was estimated using the mixed model.
Time Frame Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects were analyzed as randomized using all available eGFR measurements, except eGFR measurements measured after subjects develop ESRD since creatinine measurements were no longer reliable or meaningful for eGFR calculation.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was <9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.
Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Overall Number of Participants Analyzed 2026 2012
Mean (Standard Deviation)
Unit of Measure: mL/min/1.73m^2
-1.89  (10.60) -1.30  (10.81)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.54
Comments Nominal p-value is from the term treatment group*visit in the mixed model.
Method Mixed Models Analysis
Comments Adjusted for baseline eGFR and the stratification factors of proteinuria and CVD history.
Method of Estimation Estimation Parameter Slope
Estimated Value -0.12
Confidence Interval 95%
-0.51 to 0.26
Estimation Comments Estimated difference in rate of decline in eGFR per year between darbepoetin alfa and placebo.
10.Secondary Outcome
Title Change in Patient Reported Fatigue Relative to Baseline at Week 25
Hide Description Change in patient reported fatigue measured by the Functional Assessment of Cancer Therapy (FACT) - Fatigue scale from baseline to week 25. Range and direction of scale: 0 = most fatigue; 52 = least fatigue
Time Frame Baseline and week 25
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects with both the baseline and at least post-baseline measurement at week 25 for FACT-fatigue were included in the analysis and were analyzed as randomized. Last observation carried forward (LOCF) using last non-missing post-baseline value was used for missing post-baseline data for subjects who were still on study.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was <9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.
Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Overall Number of Participants Analyzed 1769 1762
Mean (Standard Deviation)
Unit of Measure: Units on a scale
2.8  (10.3) 4.2  (10.5)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Nominal p-value is presented.
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.33
Confidence Interval 95%
0.64 to 2.02
Parameter Dispersion
Type: Standard Deviation
Value: 0.35
Estimation Comments Difference (darbepoetin alfa - placebo)
11.Secondary Outcome
Title Time to Hospitalization Due to Acute Myocardial Ischemia
Hide Description Time from randomization to hospitalization due to acute myocardial ischemia. Kaplan-Meier estimate of the median time was not estimable due to low proportion of participants experiencing at least one events, therefore participants experiencing at least one event were summarized.
Time Frame Until a primary cardiovascular event (death, myocardial ischemia, congestive heart failure, myocardial infarction or cerebrovascular accident) occurred or 28 March 2009, whichever occurred first
Hide Outcome Measure Data
Hide Analysis Population Description
The analysis followed intent-to-treat principles. Subjects were analyzed as randomized using all available follow-up information.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Subcutaneous placebo when hemoglobin concentration was ≥ 9.0 g/dL. Received subcutaneous rescue therapy (once monthly) with darbepoetin alfa in a blinded fashion if the hemoglobin concentration was <9.0 g/dL until the hemoglobin concentration was ≥ 9.0 g/dL.
Subcutaneous darbepoetin alfa at a starting dose of 75 mcg/kg once every 2 weeks, titrated to maintain a hemoglobin concentration of 13.0 g/dL. Dosing was switched to once monthly when two consecutive hemoglobin concentrations between 12.0 and 13.5 g/dL were observed.
Overall Number of Participants Analyzed 2026 2012
Measure Type: Number
Unit of Measure: Participants
49 41
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.40
Comments Nominal p-value from a 2-sided log rank test is presented.
Method Log Rank
Comments A 2-sided log-rank test comparing the survival functions of the 2 groups stratified by baseline proteinuria and CV disease (CVD) history.
Method of Estimation Estimation Parameter Cox Proportional Hazard
Estimated Value 0.84
Confidence Interval 95%
0.55 to 1.27
Estimation Comments Treatment effect was estimated using a hazards ratio and 95% confidence interval (CI) obtained from a Cox proportional hazards model stratified by baseline proteinuria and CVD history. Hazard ratio (darbepoetin alfa / placebo)
Time Frame Differential follow-up up to 4.6 years
Adverse Event Reporting Description The table of Other Adverse Events summarizes the most frequent non-serious occurrences of adverse events.
 
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description [Not Specified] [Not Specified]
All-Cause Mortality
Placebo Darbepoetin Alfa
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Placebo Darbepoetin Alfa
Affected / at Risk (%) Affected / at Risk (%)
Total   1219/2019 (60.38%)   1235/2004 (61.63%) 
Blood and lymphatic system disorders     
Anaemia † 1  155/2019 (7.68%)  65/2004 (3.24%) 
Anaemia of chronic disease † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Coagulopathy † 1  2/2019 (0.10%)  4/2004 (0.20%) 
Disseminated intravascular coagulation † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Haemorrhagic anaemia † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Hypercoagulation † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Hypersplenism † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Iron deficiency anaemia † 1  3/2019 (0.15%)  1/2004 (0.05%) 
Leukocytosis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Lymphadenopathy † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Nephrogenic anaemia † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Normochromic normocytic anaemia † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pancytopenia † 1  2/2019 (0.10%)  4/2004 (0.20%) 
Splenomegaly † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Thrombocytopenia † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Thrombocytopenic purpura † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cardiac disorders     
AV dissociation † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Acute coronary syndrome † 1  17/2019 (0.84%)  18/2004 (0.90%) 
Acute myocardial infarction † 1  28/2019 (1.39%)  33/2004 (1.65%) 
Angina pectoris † 1  28/2019 (1.39%)  19/2004 (0.95%) 
Angina unstable † 1  22/2019 (1.09%)  17/2004 (0.85%) 
Aortic valve incompetence † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Aortic valve stenosis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Arrhythmia † 1  8/2019 (0.40%)  7/2004 (0.35%) 
Arrhythmia supraventricular † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Arteriosclerosis coronary artery † 1  4/2019 (0.20%)  3/2004 (0.15%) 
Atrial fibrillation † 1  42/2019 (2.08%)  39/2004 (1.95%) 
Atrial flutter † 1  5/2019 (0.25%)  6/2004 (0.30%) 
Atrioventricular block † 1  3/2019 (0.15%)  2/2004 (0.10%) 
Atrioventricular block complete † 1  8/2019 (0.40%)  7/2004 (0.35%) 
Atrioventricular block second degree † 1  3/2019 (0.15%)  1/2004 (0.05%) 
Bradyarrhythmia † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Bradycardia † 1  15/2019 (0.74%)  8/2004 (0.40%) 
Cardiac arrest † 1  23/2019 (1.14%)  31/2004 (1.55%) 
Cardiac disorder † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Cardiac failure † 1  40/2019 (1.98%)  38/2004 (1.90%) 
Cardiac failure acute † 1  6/2019 (0.30%)  1/2004 (0.05%) 
Cardiac failure chronic † 1  6/2019 (0.30%)  10/2004 (0.50%) 
Cardiac failure congestive † 1  214/2019 (10.60%)  178/2004 (8.88%) 
Cardiac tamponade † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Cardiac valve disease † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Cardiac valve sclerosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cardiac valve vegetation † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cardio-respiratory arrest † 1  19/2019 (0.94%)  17/2004 (0.85%) 
Cardiogenic shock † 1  5/2019 (0.25%)  4/2004 (0.20%) 
Cardiomyopathy † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Cardiopulmonary failure † 1  3/2019 (0.15%)  1/2004 (0.05%) 
Congestive cardiomyopathy † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Cor pulmonale † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Coronary artery disease † 1  62/2019 (3.07%)  41/2004 (2.05%) 
Coronary artery occlusion † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Coronary artery stenosis † 1  6/2019 (0.30%)  2/2004 (0.10%) 
Diastolic dysfunction † 1  3/2019 (0.15%)  0/2004 (0.00%) 
Electromechanical dissociation † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Extrasystoles † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hypertensive heart disease † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Ischaemic cardiomyopathy † 1  10/2019 (0.50%)  6/2004 (0.30%) 
Left ventricular dysfunction † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Microvascular angina † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Mitral valve disease † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Mitral valve incompetence † 1  3/2019 (0.15%)  2/2004 (0.10%) 
Myocardial infarction † 1  63/2019 (3.12%)  78/2004 (3.89%) 
Myocardial ischaemia † 1  18/2019 (0.89%)  10/2004 (0.50%) 
Nodal arrhythmia † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Nodal rhythm † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pacemaker generated arrhythmia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Palpitations † 1  4/2019 (0.20%)  1/2004 (0.05%) 
Pericardial effusion † 1  3/2019 (0.15%)  2/2004 (0.10%) 
Pericarditis † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Pleuropericarditis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Right ventricular failure † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Sick sinus syndrome † 1  7/2019 (0.35%)  5/2004 (0.25%) 
Sinus arrhythmia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Sinus bradycardia † 1  3/2019 (0.15%)  1/2004 (0.05%) 
Sinus tachycardia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Supraventricular tachycardia † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Tachycardia † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Torsade de pointes † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Ventricular arrhythmia † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Ventricular extrasystoles † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Ventricular fibrillation † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Ventricular tachycardia † 1  5/2019 (0.25%)  6/2004 (0.30%) 
Congenital, familial and genetic disorders     
Arteriovenous malformation † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Gastrointestinal angiodysplasia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Gastrointestinal arteriovenous malformation † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hypospadias † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Phimosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Urachal abnormality † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Ear and labyrinth disorders     
Deafness unilateral † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Haematotympanum † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Otosalpingitis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Vertigo † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Vestibular disorder † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Vestibular neuronitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Endocrine disorders     
Adrenal insufficiency † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Adrenal mass † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Adrenocortical insufficiency acute † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Goitre † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hyperparathyroidism † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Hyperthyroidism † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Hypothyroidism † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Eye disorders     
Cataract † 1  8/2019 (0.40%)  8/2004 (0.40%) 
Cataract cortical † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cataract diabetic † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Diabetic blindness † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Diabetic retinopathy † 1  3/2019 (0.15%)  5/2004 (0.25%) 
Eye haemorrhage † 1  3/2019 (0.15%)  3/2004 (0.15%) 
Glaucoma † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Iridocyclitis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Maculopathy † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Retinal artery thrombosis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Retinal detachment † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Retinal haemorrhage † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Retinopathy † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Retinopathy proliferative † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Ulcerative keratitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Uveitis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Vitreous haemorrhage † 1  3/2019 (0.15%)  4/2004 (0.20%) 
Gastrointestinal disorders     
Abdominal distension † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Abdominal hernia † 1  3/2019 (0.15%)  3/2004 (0.15%) 
Abdominal pain † 1  16/2019 (0.79%)  14/2004 (0.70%) 
Abdominal pain lower † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Abdominal pain upper † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Abdominal strangulated hernia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Abdominal wall haematoma † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Appendicitis perforated † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Ascites † 1  3/2019 (0.15%)  2/2004 (0.10%) 
Barrett's oesophagus † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Bezoar † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Cheilitis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Colitis † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Colitis ischaemic † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Colitis ulcerative † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Colonic atony † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Colonic polyp † 1  3/2019 (0.15%)  5/2004 (0.25%) 
Constipation † 1  2/2019 (0.10%)  6/2004 (0.30%) 
Diabetic gastroparesis † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Diarrhoea † 1  7/2019 (0.35%)  11/2004 (0.55%) 
Diarrhoea haemorrhagic † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Diverticular perforation † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Diverticulum † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Diverticulum intestinal haemorrhagic † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Duodenal ulcer † 1  3/2019 (0.15%)  1/2004 (0.05%) 
Duodenal ulcer haemorrhage † 1  4/2019 (0.20%)  1/2004 (0.05%) 
Duodenitis † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Dyspepsia † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Dysphagia † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Enterocutaneous fistula † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Enterovesical fistula † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Erosive oesophagitis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Faecaloma † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Food poisoning † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Gastric haemorrhage † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Gastric perforation † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Gastric polyps † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Gastric ulcer † 1  8/2019 (0.40%)  7/2004 (0.35%) 
Gastric ulcer haemorrhage † 1  0/2019 (0.00%)  3/2004 (0.15%) 
Gastritis † 1  9/2019 (0.45%)  10/2004 (0.50%) 
Gastritis erosive † 1  1/2019 (0.05%)  3/2004 (0.15%) 
Gastritis haemorrhagic † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Gastroduodenal ulcer † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Gastrointestinal haemorrhage † 1  28/2019 (1.39%)  21/2004 (1.05%) 
Gastrointestinal inflammation † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Gastrointestinal ulcer † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Gastrooesophageal reflux disease † 1  5/2019 (0.25%)  10/2004 (0.50%) 
Haematemesis † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Haemorrhoidal haemorrhage † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Haemorrhoids † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Ileus † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Ileus paralytic † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Impaired gastric emptying † 1  0/2019 (0.00%)  6/2004 (0.30%) 
Inguinal hernia † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Inguinal hernia, obstructive † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Intestinal infarction † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Intestinal ischaemia † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Intestinal mass † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Intestinal obstruction † 1  3/2019 (0.15%)  0/2004 (0.00%) 
Intestinal perforation † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Intra-abdominal haematoma † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Large intestinal ulcer † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Large intestine perforation † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Lower gastrointestinal haemorrhage † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Mallory-Weiss syndrome † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Melaena † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Mesenteric artery stenosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Nausea † 1  4/2019 (0.20%)  3/2004 (0.15%) 
Oedematous pancreatitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Oesophageal achalasia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Oesophageal polyp † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Oesophageal spasm † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Oesophageal stenosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Oesophageal varices haemorrhage † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Oesophagitis † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Oesophagitis ulcerative † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pancreatic cyst † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pancreatitis † 1  5/2019 (0.25%)  8/2004 (0.40%) 
Pancreatitis acute † 1  4/2019 (0.20%)  5/2004 (0.25%) 
Peptic ulcer † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Peptic ulcer haemorrhage † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Peritoneal haemorrhage † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Peritonitis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Rectal haemorrhage † 1  3/2019 (0.15%)  2/2004 (0.10%) 
Rectal prolapse † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Reflux oesophagitis † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Retroperitoneal haematoma † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Retroperitoneal haemorrhage † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Small intestinal obstruction † 1  7/2019 (0.35%)  1/2004 (0.05%) 
Small intestinal perforation † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Tongue oedema † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Umbilical hernia † 1  3/2019 (0.15%)  1/2004 (0.05%) 
Umbilical hernia, obstructive † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Upper gastrointestinal haemorrhage † 1  5/2019 (0.25%)  3/2004 (0.15%) 
Volvulus † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Vomiting † 1  8/2019 (0.40%)  7/2004 (0.35%) 
General disorders     
Adverse drug reaction † 1  4/2019 (0.20%)  7/2004 (0.35%) 
Adverse event † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Asthenia † 1  9/2019 (0.45%)  9/2004 (0.45%) 
Brain death † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Cardiac death † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Catheter site haemorrhage † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Catheter site inflammation † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Chest discomfort † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Chest pain † 1  11/2019 (0.54%)  12/2004 (0.60%) 
Death † 1  38/2019 (1.88%)  39/2004 (1.95%) 
Facial pain † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Fatigue † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Gait disturbance † 1  1/2019 (0.05%)  4/2004 (0.20%) 
Generalised oedema † 1  4/2019 (0.20%)  3/2004 (0.15%) 
Hernia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Hernia obstructive † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Inflammation † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Ischaemic ulcer † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Malaise † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Multi-organ failure † 1  7/2019 (0.35%)  3/2004 (0.15%) 
Necrobiosis † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Non-cardiac chest pain † 1  22/2019 (1.09%)  29/2004 (1.45%) 
Oedema † 1  2/2019 (0.10%)  4/2004 (0.20%) 
Oedema peripheral † 1  7/2019 (0.35%)  6/2004 (0.30%) 
Pain † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Polyp † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Pyrexia † 1  6/2019 (0.30%)  3/2004 (0.15%) 
Sudden cardiac death † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Sudden death † 1  11/2019 (0.54%)  12/2004 (0.60%) 
Ulcer † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Wound necrosis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Hepatobiliary disorders     
Bile duct stenosis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Bile duct stone † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Biliary colic † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Biliary dyskinesia † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Cholangitis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cholecystitis † 1  9/2019 (0.45%)  8/2004 (0.40%) 
Cholecystitis acute † 1  6/2019 (0.30%)  5/2004 (0.25%) 
Cholecystitis chronic † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Cholelithiasis † 1  7/2019 (0.35%)  17/2004 (0.85%) 
Gallbladder polyp † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Hepatic cirrhosis † 1  1/2019 (0.05%)  4/2004 (0.20%) 
Hepatic congestion † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Hepatic failure † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Hepatic steatosis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hepatomegaly † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hepatorenal failure † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Jaundice † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Jaundice cholestatic † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Liver disorder † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Portal hypertension † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Immune system disorders     
Anaphylactic reaction † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Anaphylactic shock † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Drug hypersensitivity † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hypersensitivity † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Sarcoidosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Infections and infestations     
Abdominal abscess † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Abdominal wall abscess † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Abscess † 1  0/2019 (0.00%)  4/2004 (0.20%) 
Abscess limb † 1  5/2019 (0.25%)  3/2004 (0.15%) 
Acute endocarditis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Anal abscess † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Appendicitis † 1  2/2019 (0.10%)  4/2004 (0.20%) 
Arteriovenous fistula site infection † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Arteriovenous graft site infection † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Arthritis bacterial † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Arthritis infective † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Bacteraemia † 1  4/2019 (0.20%)  3/2004 (0.15%) 
Bacterial disease carrier † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Bacterial sepsis † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Breast cellulitis † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Bronchiectasis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Bronchitis † 1  20/2019 (0.99%)  32/2004 (1.60%) 
Bronchitis bacterial † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Bronchitis fungal † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Bronchitis viral † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Bronchopneumonia † 1  13/2019 (0.64%)  9/2004 (0.45%) 
Campylobacter gastroenteritis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Catheter related infection † 1  0/2019 (0.00%)  3/2004 (0.15%) 
Catheter site infection † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Cellulitis † 1  41/2019 (2.03%)  59/2004 (2.94%) 
Cellulitis gangrenous † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cervicitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Cholecystitis infective † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Clostridial infection † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Clostridium difficile colitis † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Corynebacterium infection † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Creutzfeldt-Jakob disease † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cystitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Dacryocystitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Dengue fever † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Device related infection † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Diabetic foot infection † 1  8/2019 (0.40%)  11/2004 (0.55%) 
Diabetic gangrene † 1  0/2019 (0.00%)  4/2004 (0.20%) 
Diarrhoea infectious † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Diverticulitis † 1  4/2019 (0.20%)  8/2004 (0.40%) 
Embolic pneumonia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Emphysematous cystitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Empyema † 1  0/2019 (0.00%)  3/2004 (0.15%) 
Encephalitis viral † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Endocarditis † 1  3/2019 (0.15%)  3/2004 (0.15%) 
Endocarditis bacterial † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Endocarditis staphylococcal † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Enterovirus infection † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Erysipelas † 1  3/2019 (0.15%)  1/2004 (0.05%) 
Escherichia bacteraemia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Escherichia sepsis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Escherichia urinary tract infection † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Extradural abscess † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Folliculitis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Furuncle † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Gangrene † 1  11/2019 (0.54%)  19/2004 (0.95%) 
Gas gangrene † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Gastroenteritis † 1  27/2019 (1.34%)  31/2004 (1.55%) 
Gastroenteritis viral † 1  3/2019 (0.15%)  6/2004 (0.30%) 
Gastrointestinal infection † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Groin abscess † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Helicobacter gastritis † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Hepatitis C † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Herpes zoster † 1  3/2019 (0.15%)  5/2004 (0.25%) 
Herpes zoster ophthalmic † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Infected bunion † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Infected skin ulcer † 1  1/2019 (0.05%)  5/2004 (0.25%) 
Infection † 1  3/2019 (0.15%)  4/2004 (0.20%) 
Influenza † 1  0/2019 (0.00%)  5/2004 (0.25%) 
Intervertebral discitis † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Intraspinal abscess † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Lobar pneumonia † 1  9/2019 (0.45%)  5/2004 (0.25%) 
Localised infection † 1  4/2019 (0.20%)  14/2004 (0.70%) 
Lower respiratory tract infection † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Lung infection † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Lung infection pseudomonal † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Mastitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Meningitis pneumococcal † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Muscle abscess † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Necrotising fasciitis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Orchitis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Osteomyelitis † 1  18/2019 (0.89%)  24/2004 (1.20%) 
Osteomyelitis acute † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Osteomyelitis chronic † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Otitis externa † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Otitis media † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Paronychia † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Parotitis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Perirectal abscess † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Peritonitis bacterial † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Pharyngitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pneumonia † 1  120/2019 (5.94%)  90/2004 (4.49%) 
Pneumonia bacterial † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Pneumonia legionella † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Pneumonia pneumococcal † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Pneumonia primary atypical † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pneumonia streptococcal † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pneumonia viral † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Post procedural infection † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Postoperative abscess † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Postoperative wound infection † 1  1/2019 (0.05%)  6/2004 (0.30%) 
Pseudomembranous colitis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Pseudomonas infection † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Pulmonary sepsis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pyelonephritis † 1  2/2019 (0.10%)  7/2004 (0.35%) 
Pyelonephritis acute † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pyelonephritis chronic † 1  5/2019 (0.25%)  2/2004 (0.10%) 
Pyelonephritis fungal † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pyothorax † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Rectal abscess † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Respiratory tract infection † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Respiratory tract infection viral † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Salmonellosis † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Scrotal abscess † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Sepsis † 1  32/2019 (1.58%)  30/2004 (1.50%) 
Sepsis syndrome † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Septic shock † 1  9/2019 (0.45%)  9/2004 (0.45%) 
Sinusitis † 1  2/2019 (0.10%)  6/2004 (0.30%) 
Skin infection † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Staphylococcal bacteraemia † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Staphylococcal infection † 1  3/2019 (0.15%)  3/2004 (0.15%) 
Staphylococcal osteomyelitis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Staphylococcal sepsis † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Staphylococcal skin infection † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Streptococcal bacteraemia † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Streptococcal sepsis † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Subacute endocarditis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Subcutaneous abscess † 1  3/2019 (0.15%)  4/2004 (0.20%) 
Tooth abscess † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Toxic shock syndrome † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Tracheobronchitis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Upper respiratory tract infection † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Urinary tract infection † 1  50/2019 (2.48%)  58/2004 (2.89%) 
Urinary tract infection bacterial † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Urinary tract infection fungal † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Urosepsis † 1  9/2019 (0.45%)  14/2004 (0.70%) 
Uterine abscess † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Viraemia † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Viral infection † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Wound abscess † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Wound infection † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Wound infection staphylococcal † 1  0/2019 (0.00%)  3/2004 (0.15%) 
Injury, poisoning and procedural complications     
Accidental overdose † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Alcohol poisoning † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Anaemia postoperative † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Ankle fracture † 1  6/2019 (0.30%)  4/2004 (0.20%) 
Arteriovenous fistula occlusion † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Arteriovenous fistula site complication † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Brain contusion † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Burns third degree † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Carbon monoxide poisoning † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Cardiac pacemaker malfunction † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cardiac procedure complication † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Cervical vertebral fracture † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Chest injury † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Clavicle fracture † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Compression fracture † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Concussion † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Contusion † 1  1/2019 (0.05%)  4/2004 (0.20%) 
Crush injury † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Dialysis device complication † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Dislocation of joint prosthesis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Drug toxicity † 1  0/2019 (0.00%)  3/2004 (0.15%) 
Eschar † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Eyeball rupture † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Facial bones fracture † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Fall † 1  6/2019 (0.30%)  5/2004 (0.25%) 
Feeding tube complication † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Femoral neck fracture † 1  3/2019 (0.15%)  2/2004 (0.10%) 
Femur fracture † 1  9/2019 (0.45%)  10/2004 (0.50%) 
Fibula fracture † 1  3/2019 (0.15%)  0/2004 (0.00%) 
Foot fracture † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Forearm fracture † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Fracture † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Fractured coccyx † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Gastroenteritis radiation † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Graft thrombosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Haematuria traumatic † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hand fracture † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Head injury † 1  5/2019 (0.25%)  1/2004 (0.05%) 
Heart injury † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Hip fracture † 1  17/2019 (0.84%)  22/2004 (1.10%) 
Humerus fracture † 1  8/2019 (0.40%)  4/2004 (0.20%) 
Implantable defibrillator malfunction † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Incision site haemorrhage † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Incisional hernia † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Injury † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Intervertebral disc injury † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Intraocular lens dislocation † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Joint dislocation † 1  3/2019 (0.15%)  1/2004 (0.05%) 
Joint sprain † 1  4/2019 (0.20%)  1/2004 (0.05%) 
Limb injury † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Lower limb fracture † 1  0/2019 (0.00%)  4/2004 (0.20%) 
Lumbar vertebral fracture † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Meniscus lesion † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Neck injury † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Overdose † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Pacemaker complication † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Pelvic fracture † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pneumothorax traumatic † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Post procedural complication † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Post procedural haematoma † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Post procedural haemorrhage † 1  1/2019 (0.05%)  3/2004 (0.15%) 
Post procedural swelling † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Post-traumatic pain † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Postoperative fever † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Postoperative ileus † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Radius fracture † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Rib fracture † 1  1/2019 (0.05%)  5/2004 (0.25%) 
Skin injury † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Skin laceration † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Skull fractured base † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Soft tissue injury † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Spinal compression fracture † 1  3/2019 (0.15%)  6/2004 (0.30%) 
Spinal cord injury cervical † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Spinal fracture † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Subcutaneous haematoma † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Subdural haematoma † 1  5/2019 (0.25%)  6/2004 (0.30%) 
Subdural haemorrhage † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Synovial rupture † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Tendon rupture † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Therapeutic agent toxicity † 1  6/2019 (0.30%)  2/2004 (0.10%) 
Thermal burn † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Tibia fracture † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Traumatic fracture † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Traumatic haematoma † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Upper limb fracture † 1  3/2019 (0.15%)  2/2004 (0.10%) 
Vascular graft complication † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Vascular pseudoaneurysm † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Wound dehiscence † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Wrist fracture † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Investigations     
Blood albumin decreased † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Blood glucose increased † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Blood potassium increased † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Blood pressure increased † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Blood sodium decreased † 1  1/2019 (0.05%)  0/2004 (0.00%) 
C-reactive protein increased † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Carotid bruit † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Coagulation time prolonged † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Haemoglobin decreased † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Heart rate increased † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Heart rate irregular † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Laboratory test abnormal † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Lipase increased † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Medical observation † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Methicillin-resistant staphylococcal aureus test positive † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Transaminases increased † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Troponin increased † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Urine output decreased † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Metabolism and nutrition disorders     
Acidosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Acidosis hyperchloraemic † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Dehydration † 1  40/2019 (1.98%)  29/2004 (1.45%) 
Diabetes mellitus † 1  30/2019 (1.49%)  24/2004 (1.20%) 
Diabetes mellitus inadequate control † 1  22/2019 (1.09%)  26/2004 (1.30%) 
Diabetic complication † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Diabetic foot † 1  5/2019 (0.25%)  12/2004 (0.60%) 
Diabetic ketoacidosis † 1  6/2019 (0.30%)  9/2004 (0.45%) 
Electrolyte imbalance † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Enzyme abnormality † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Failure to thrive † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Fluid overload † 1  6/2019 (0.30%)  1/2004 (0.05%) 
Fluid retention † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Gout † 1  5/2019 (0.25%)  10/2004 (0.50%) 
Hypercalcaemia † 1  0/2019 (0.00%)  3/2004 (0.15%) 
Hypercholesterolaemia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Hyperglycaemia † 1  18/2019 (0.89%)  33/2004 (1.65%) 
Hyperglycaemic hyperosmolar nonketotic syndrome † 1  3/2019 (0.15%)  2/2004 (0.10%) 
Hyperkalaemia † 1  51/2019 (2.53%)  48/2004 (2.40%) 
Hypernatraemia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Hyperosmolar state † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hyperphosphataemia † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hyperuricaemia † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Hypervolaemia † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hypocalcaemia † 1  0/2019 (0.00%)  4/2004 (0.20%) 
Hypoglycaemia † 1  58/2019 (2.87%)  81/2004 (4.04%) 
Hypoglycaemic unconsciousness † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hypokalaemia † 1  3/2019 (0.15%)  7/2004 (0.35%) 
Hypomagnesaemia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Hyponatraemia † 1  3/2019 (0.15%)  7/2004 (0.35%) 
Hypovolaemia † 1  5/2019 (0.25%)  5/2004 (0.25%) 
Iron deficiency † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Lactic acidosis † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Malnutrition † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Metabolic acidosis † 1  4/2019 (0.20%)  1/2004 (0.05%) 
Obesity † 1  4/2019 (0.20%)  0/2004 (0.00%) 
Type 2 diabetes mellitus † 1  6/2019 (0.30%)  1/2004 (0.05%) 
Musculoskeletal and connective tissue disorders     
Ankylosing spondylitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Arthralgia † 1  4/2019 (0.20%)  3/2004 (0.15%) 
Arthritis † 1  3/2019 (0.15%)  4/2004 (0.20%) 
Arthropathy † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Back pain † 1  5/2019 (0.25%)  7/2004 (0.35%) 
Bone pain † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Bursitis † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Cervical spinal stenosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Costochondritis † 1  1/2019 (0.05%)  4/2004 (0.20%) 
Fasciitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Fistula † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Foot deformity † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Fracture nonunion † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Gouty arthritis † 1  3/2019 (0.15%)  6/2004 (0.30%) 
Haemarthrosis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Intervertebral disc degeneration † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Intervertebral disc displacement † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Intervertebral disc protrusion † 1  4/2019 (0.20%)  2/2004 (0.10%) 
Joint effusion † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Lumbar spinal stenosis † 1  2/2019 (0.10%)  6/2004 (0.30%) 
Mobility decreased † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Muscular weakness † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Musculoskeletal chest pain † 1  7/2019 (0.35%)  7/2004 (0.35%) 
Musculoskeletal disorder † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Musculoskeletal pain † 1  1/2019 (0.05%)  3/2004 (0.15%) 
Myalgia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Neck pain † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Neuropathic arthropathy † 1  3/2019 (0.15%)  1/2004 (0.05%) 
Osteitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Osteoarthritis † 1  18/2019 (0.89%)  24/2004 (1.20%) 
Osteoporosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Pain in extremity † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Pathological fracture † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Periarthritis † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Rhabdomyolysis † 1  5/2019 (0.25%)  0/2004 (0.00%) 
Rheumatoid arthritis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Rotator cuff syndrome † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Scoliosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Soft tissue necrosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Spinal column stenosis † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Spinal osteoarthritis † 1  3/2019 (0.15%)  6/2004 (0.30%) 
Spondylolisthesis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Synovitis † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Abdominal neoplasm † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Acute myeloid leukaemia † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Adenocarcinoma † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Adenocarcinoma of the cervix † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Adrenal adenoma † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Adrenal neoplasm † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Basal cell carcinoma † 1  3/2019 (0.15%)  3/2004 (0.15%) 
Benign pancreatic neoplasm † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Bile duct cancer † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Bladder cancer † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Bladder neoplasm † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Bladder transitional cell carcinoma recurrent † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Breast cancer † 1  7/2019 (0.35%)  5/2004 (0.25%) 
Breast cancer metastatic † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Bronchioloalveolar carcinoma † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Central nervous system lymphoma † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Chronic lymphocytic leukaemia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Colon adenoma † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Colon cancer † 1  6/2019 (0.30%)  8/2004 (0.40%) 
Colon cancer metastatic † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Diffuse large B-cell lymphoma † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Endometrial cancer † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Endometrial cancer metastatic † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Gammopathy † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Gastric cancer † 1  5/2019 (0.25%)  0/2004 (0.00%) 
Glioblastoma † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Haemangioma † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hepatic cancer metastatic † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hepatic neoplasm † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Hepatic neoplasm malignant † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Intraductal papilloma of breast † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Laryngeal cancer † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Lentigo maligna stage unspecified † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Lung adenocarcinoma † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Lung adenocarcinoma metastatic † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Lung adenocarcinoma stage III † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Lung cancer metastatic † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Lung neoplasm † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Lung neoplasm malignant † 1  5/2019 (0.25%)  7/2004 (0.35%) 
Lymphoma † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Malignant melanoma † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Meningioma † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Metastases to central nervous system † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Metastases to liver † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Metastases to lung † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Metastatic neoplasm † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Metastatic renal cell carcinoma † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Multiple myeloma † 1  4/2019 (0.20%)  4/2004 (0.20%) 
Myelodysplastic syndrome † 1  3/2019 (0.15%)  0/2004 (0.00%) 
Myelofibrosis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Neoplasm malignant † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Neoplasm skin † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Non-Hodgkin's lymphoma † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Non-Hodgkin's lymphoma stage III † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Non-small cell lung cancer † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Non-small cell lung cancer metastatic † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Non-small cell lung cancer stage III † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Oesophageal carcinoma † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Ovarian fibroma † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Ovarian neoplasm † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Paget's disease of the breast † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pancreatic carcinoma † 1  1/2019 (0.05%)  4/2004 (0.20%) 
Pancreatic carcinoma metastatic † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pancreatic neoplasm † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Parathyroid tumour benign † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Prostate cancer † 1  4/2019 (0.20%)  3/2004 (0.15%) 
Prostate cancer metastatic † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Prostatic adenoma † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Rectal cancer † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Rectal cancer stage 0 † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Renal cancer † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Renal cancer metastatic † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Renal cell carcinoma † 1  2/2019 (0.10%)  6/2004 (0.30%) 
Small cell lung cancer stage unspecified † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Squamous cell carcinoma † 1  3/2019 (0.15%)  2/2004 (0.10%) 
Thyroid cancer † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Thyroid neoplasm † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Uterine cancer † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Uterine leiomyoma † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Vaginal cancer † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Vulval cancer † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Nervous system disorders     
Altered state of consciousness † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Anoxic encephalopathy † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Aphasia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Brain mass † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Brain stem infarction † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Carotid artery disease † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Carotid artery occlusion † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Carotid artery stenosis † 1  11/2019 (0.54%)  8/2004 (0.40%) 
Cerebellar infarction † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cerebellar ischaemia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cerebral artery occlusion † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cerebral haemorrhage † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Cerebral infarction † 1  1/2019 (0.05%)  3/2004 (0.15%) 
Cerebral ischaemia † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Cerebrovascular accident † 1  37/2019 (1.83%)  72/2004 (3.59%) 
Cerebrovascular disorder † 1  0/2019 (0.00%)  3/2004 (0.15%) 
Cerebrovascular insufficiency † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Cervical myelopathy † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cervicobrachial syndrome † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Coma † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Convulsion † 1  3/2019 (0.15%)  4/2004 (0.20%) 
Dementia † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Dementia Alzheimer's type † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Diabetic coma † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Diabetic neuropathy † 1  5/2019 (0.25%)  5/2004 (0.25%) 
Dizziness † 1  3/2019 (0.15%)  5/2004 (0.25%) 
Dysarthria † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Encephalopathy † 1  0/2019 (0.00%)  3/2004 (0.15%) 
Epilepsy † 1  0/2019 (0.00%)  3/2004 (0.15%) 
Extrapyramidal disorder † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Global amnesia † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Guillain-Barre syndrome † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Haemorrhage intracranial † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Haemorrhagic cerebral infarction † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Haemorrhagic stroke † 1  1/2019 (0.05%)  4/2004 (0.20%) 
Headache † 1  3/2019 (0.15%)  5/2004 (0.25%) 
Hemiparesis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Hepatic encephalopathy † 1  3/2019 (0.15%)  5/2004 (0.25%) 
Hydrocephalus † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Hypertensive encephalopathy † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Hypoaesthesia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Hypoglycaemic coma † 1  1/2019 (0.05%)  4/2004 (0.20%) 
Hypoglycaemic encephalopathy † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Intracranial haematoma † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Ischaemic cerebral infarction † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Ischaemic stroke † 1  4/2019 (0.20%)  6/2004 (0.30%) 
Lacunar infarction † 1  1/2019 (0.05%)  5/2004 (0.25%) 
Leukoaraiosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Loss of consciousness † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Lumbar radiculopathy † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Metabolic encephalopathy † 1  3/2019 (0.15%)  0/2004 (0.00%) 
Migraine † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Neuropathy peripheral † 1  3/2019 (0.15%)  1/2004 (0.05%) 
Normal pressure hydrocephalus † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Paraplegia † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Presyncope † 1  3/2019 (0.15%)  7/2004 (0.35%) 
Ruptured cerebral aneurysm † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Sciatica † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Sedation † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Senile dementia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Somnolence † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Status epilepticus † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Stroke in evolution † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Subarachnoid haemorrhage † 1  2/2019 (0.10%)  4/2004 (0.20%) 
Syncope † 1  26/2019 (1.29%)  16/2004 (0.80%) 
Syncope vasovagal † 1  3/2019 (0.15%)  3/2004 (0.15%) 
Thalamic infarction † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Transient ischaemic attack † 1  18/2019 (0.89%)  28/2004 (1.40%) 
Uraemic encephalopathy † 1  1/2019 (0.05%)  3/2004 (0.15%) 
Vascular encephalopathy † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Vertebrobasilar insufficiency † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Pregnancy, puerperium and perinatal conditions     
Abortion spontaneous † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cephalhaematoma † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Psychiatric disorders     
Alcohol withdrawal syndrome † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Alcoholism † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Anxiety † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Bipolar disorder † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Confusional state † 1  3/2019 (0.15%)  3/2004 (0.15%) 
Conversion disorder † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Delirium † 1  0/2019 (0.00%)  3/2004 (0.15%) 
Depression † 1  5/2019 (0.25%)  7/2004 (0.35%) 
Disorientation † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Impaired self-care † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Mental status changes † 1  4/2019 (0.20%)  3/2004 (0.15%) 
Schizophrenia † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Stress † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Suicidal ideation † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Withdrawal syndrome † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Renal and urinary disorders     
Acute prerenal failure † 1  3/2019 (0.15%)  1/2004 (0.05%) 
Atonic urinary bladder † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Azotaemia † 1  3/2019 (0.15%)  10/2004 (0.50%) 
Bladder diverticulum † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Bladder neck obstruction † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Bladder perforation † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Bladder stenosis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Calculus ureteric † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Calculus urinary † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Cystitis haemorrhagic † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cystitis noninfective † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Diabetic nephropathy † 1  4/2019 (0.20%)  8/2004 (0.40%) 
Glomerulonephritis membranoproliferative † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Haematuria † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Haemorrhage urinary tract † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Hydronephrosis † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Kidney enlargement † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Mesangioproliferative glomerulonephritis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Nephrolithiasis † 1  3/2019 (0.15%)  6/2004 (0.30%) 
Nephropathy † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Nephrotic syndrome † 1  6/2019 (0.30%)  10/2004 (0.50%) 
Neurogenic bladder † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Obstructive uropathy † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Renal artery occlusion † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Renal artery stenosis † 1  4/2019 (0.20%)  3/2004 (0.15%) 
Renal colic † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Renal cyst † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Renal disorder † 1  0/2019 (0.00%)  3/2004 (0.15%) 
Renal failure † 1  82/2019 (4.06%)  72/2004 (3.59%) 
Renal failure acute † 1  69/2019 (3.42%)  70/2004 (3.49%) 
Renal failure chronic † 1  180/2019 (8.92%)  223/2004 (11.13%) 
Renal haemorrhage † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Renal impairment † 1  6/2019 (0.30%)  11/2004 (0.55%) 
Renal mass † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Renal papillary necrosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Renal tubular acidosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Renal tubular necrosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Stag horn calculus † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Ureteric obstruction † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Urinary retention † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Urinary tract inflammation † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Reproductive system and breast disorders     
Benign prostatic hyperplasia † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Breast calcifications † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Breast haematoma † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Breast hyperplasia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cystocele † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Epididymitis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Metrorrhagia † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Ovarian cyst † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pelvic haematoma † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Pelvic pain † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Postmenopausal haemorrhage † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Prostatitis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Prostatomegaly † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Scrotal oedema † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Urogenital prolapse † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Vaginal haemorrhage † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Vaginal prolapse † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema † 1  5/2019 (0.25%)  6/2004 (0.30%) 
Acute respiratory distress syndrome † 1  1/2019 (0.05%)  3/2004 (0.15%) 
Acute respiratory failure † 1  7/2019 (0.35%)  7/2004 (0.35%) 
Alveolitis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Asphyxia † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Aspiration † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Asthma † 1  9/2019 (0.45%)  12/2004 (0.60%) 
Atelectasis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Bronchial hyperreactivity † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Bronchitis chronic † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Bronchospasm † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Chronic obstructive pulmonary disease † 1  20/2019 (0.99%)  25/2004 (1.25%) 
Chronic respiratory failure † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Cough † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Dyspnoea † 1  10/2019 (0.50%)  10/2004 (0.50%) 
Dyspnoea exertional † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Emphysema † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Epistaxis † 1  2/2019 (0.10%)  5/2004 (0.25%) 
Haemoptysis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Haemothorax † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Hydrothorax † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Hyperventilation † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hypoxia † 1  3/2019 (0.15%)  5/2004 (0.25%) 
Laryngeal polyp † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Lung disorder † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Lung infiltration † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Non-cardiogenic pulmonary oedema † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pleural effusion † 1  12/2019 (0.59%)  6/2004 (0.30%) 
Pleurisy † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Pneumonia aspiration † 1  4/2019 (0.20%)  7/2004 (0.35%) 
Pneumonitis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Pneumothorax † 1  2/2019 (0.10%)  2/2004 (0.10%) 
Pulmonary alveolar haemorrhage † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Pulmonary congestion † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Pulmonary embolism † 1  12/2019 (0.59%)  14/2004 (0.70%) 
Pulmonary fibrosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Pulmonary haemorrhage † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pulmonary hypertension † 1  2/2019 (0.10%)  1/2004 (0.05%) 
Pulmonary mass † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Pulmonary oedema † 1  11/2019 (0.54%)  15/2004 (0.75%) 
Respiratory arrest † 1  3/2019 (0.15%)  1/2004 (0.05%) 
Respiratory depression † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Respiratory distress † 1  5/2019 (0.25%)  0/2004 (0.00%) 
Respiratory failure † 1  26/2019 (1.29%)  23/2004 (1.15%) 
Rhinitis allergic † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Sleep apnoea syndrome † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Tracheal stenosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Wegener's granulomatosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Skin and subcutaneous tissue disorders     
Angioedema † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Blister † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Decubitus ulcer † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Dermatitis † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Dermatitis allergic † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Dermatitis exfoliative † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Diabetic neuropathic ulcer † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Diabetic ulcer † 1  3/2019 (0.15%)  0/2004 (0.00%) 
Ecchymosis † 1  0/2019 (0.00%)  2/2004 (0.10%) 
Hidradenitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Neuropathic ulcer † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Night sweats † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Panniculitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Pruritus † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Pyoderma gangrenosum † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Rash † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Skin graft failure † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Skin lesion † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Skin necrosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Skin ulcer † 1  12/2019 (0.59%)  20/2004 (1.00%) 
Stasis dermatitis † 1  2/2019 (0.10%)  0/2004 (0.00%) 
Stevens-Johnson syndrome † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Urticaria † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Social circumstances     
Social stay hospitalisation † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Surgical and medical procedures     
Abdominal cavity drainage † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Arteriovenous graft † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cardiac pacemaker battery replacement † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Cardiac pacemaker replacement † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Catheterisation cardiac † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Coronary angioplasty † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Coronary revascularisation † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Foot amputation † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Hip arthroplasty † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Leg amputation † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Limb operation † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Removal of inert matter from skin or subcutaneous tissue † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Skin graft † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Vascular disorders     
Accelerated hypertension † 1  7/2019 (0.35%)  3/2004 (0.15%) 
Aortic aneurysm † 1  2/2019 (0.10%)  3/2004 (0.15%) 
Aortic stenosis † 1  7/2019 (0.35%)  1/2004 (0.05%) 
Aorto-duodenal fistula † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Arterial disorder † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Arterial stenosis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Arterial stenosis limb † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Arterial thrombosis limb † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Arteriosclerosis † 1  5/2019 (0.25%)  5/2004 (0.25%) 
Blood pressure fluctuation † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Cardiovascular insufficiency † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Deep vein thrombosis † 1  6/2019 (0.30%)  14/2004 (0.70%) 
Diabetic microangiopathy † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Extremity necrosis † 1  1/2019 (0.05%)  3/2004 (0.15%) 
Femoral arterial stenosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Haematoma † 1  4/2019 (0.20%)  7/2004 (0.35%) 
Hypertension † 1  40/2019 (1.98%)  48/2004 (2.40%) 
Hypertensive crisis † 1  8/2019 (0.40%)  13/2004 (0.65%) 
Hypertensive emergency † 1  0/2019 (0.00%)  4/2004 (0.20%) 
Hypotension † 1  13/2019 (0.64%)  16/2004 (0.80%) 
Hypovolaemic shock † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Infarction † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Intermittent claudication † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Ischaemia † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Lymphocele † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Lymphoedema † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Malignant hypertension † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Microangiopathy † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Orthostatic hypotension † 1  5/2019 (0.25%)  6/2004 (0.30%) 
Peripheral arterial occlusive disease † 1  1/2019 (0.05%)  5/2004 (0.25%) 
Peripheral ischaemia † 1  3/2019 (0.15%)  4/2004 (0.20%) 
Peripheral vascular disorder † 1  9/2019 (0.45%)  13/2004 (0.65%) 
Phlebitis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Shock † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Shock haemorrhagic † 1  1/2019 (0.05%)  2/2004 (0.10%) 
Subclavian artery stenosis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Temporal arteritis † 1  1/2019 (0.05%)  0/2004 (0.00%) 
Thrombophlebitis † 1  1/2019 (0.05%)  3/2004 (0.15%) 
Thrombophlebitis superficial † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Thrombosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Varicophlebitis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Vascular insufficiency † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Vascular stenosis † 1  0/2019 (0.00%)  1/2004 (0.05%) 
Venous insufficiency † 1  1/2019 (0.05%)  1/2004 (0.05%) 
Venous thrombosis † 1  1/2019 (0.05%)  1/2004 (0.05%) 
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.1
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Darbepoetin Alfa
Affected / at Risk (%) Affected / at Risk (%)
Total   1547/2019 (76.62%)   1571/2004 (78.39%) 
Blood and lymphatic system disorders     
Anaemia † 1  102/2019 (5.05%)  57/2004 (2.84%) 
Gastrointestinal disorders     
Constipation † 1  154/2019 (7.63%)  130/2004 (6.49%) 
Diarrhoea † 1  283/2019 (14.02%)  279/2004 (13.92%) 
Nausea † 1  227/2019 (11.24%)  231/2004 (11.53%) 
Vomiting † 1  190/2019 (9.41%)  200/2004 (9.98%) 
General disorders     
Asthenia † 1  166/2019 (8.22%)  140/2004 (6.99%) 
Fatigue † 1  351/2019 (17.38%)  322/2004 (16.07%) 
Oedema † 1  126/2019 (6.24%)  124/2004 (6.19%) 
Oedema peripheral † 1  417/2019 (20.65%)  414/2004 (20.66%) 
Infections and infestations     
Bronchitis † 1  169/2019 (8.37%)  163/2004 (8.13%) 
Influenza † 1  115/2019 (5.70%)  108/2004 (5.39%) 
Nasopharyngitis † 1  179/2019 (8.87%)  210/2004 (10.48%) 
Sinusitis † 1  91/2019 (4.51%)  112/2004 (5.59%) 
Upper respiratory tract infection † 1  182/2019 (9.01%)  185/2004 (9.23%) 
Urinary tract infection † 1  247/2019 (12.23%)  262/2004 (13.07%) 
Injury, poisoning and procedural complications     
Contusion † 1  93/2019 (4.61%)  111/2004 (5.54%) 
Fall † 1  135/2019 (6.69%)  165/2004 (8.23%) 
Investigations     
Blood pressure increased † 1  102/2019 (5.05%)  109/2004 (5.44%) 
Metabolism and nutrition disorders     
Gout † 1  94/2019 (4.66%)  106/2004 (5.29%) 
Hyperglycaemia † 1  95/2019 (4.71%)  101/2004 (5.04%) 
Hyperkalaemia † 1  106/2019 (5.25%)  110/2004 (5.49%) 
Hypoglycaemia † 1  215/2019 (10.65%)  225/2004 (11.23%) 
Musculoskeletal and connective tissue disorders     
Arthralgia † 1  249/2019 (12.33%)  257/2004 (12.82%) 
Back pain † 1  266/2019 (13.17%)  223/2004 (11.13%) 
Muscle spasms † 1  134/2019 (6.64%)  129/2004 (6.44%) 
Musculoskeletal pain † 1  117/2019 (5.79%)  119/2004 (5.94%) 
Pain in extremity † 1  289/2019 (14.31%)  293/2004 (14.62%) 
Nervous system disorders     
Dizziness † 1  206/2019 (10.20%)  226/2004 (11.28%) 
Headache † 1  161/2019 (7.97%)  192/2004 (9.58%) 
Respiratory, thoracic and mediastinal disorders     
Cough † 1  236/2019 (11.69%)  214/2004 (10.68%) 
Dyspnoea † 1  307/2019 (15.21%)  259/2004 (12.92%) 
Skin and subcutaneous tissue disorders     
Rash † 1  80/2019 (3.96%)  111/2004 (5.54%) 
Vascular disorders     
Hypertension † 1  301/2019 (14.91%)  332/2004 (16.57%) 
Hypotension † 1  88/2019 (4.36%)  110/2004 (5.49%) 
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.1
4047 subjects were enrolled, but before unblinding, all information from 9 subjects was excluded from two sites (3 and 6 subjects, respectively) that did not adhere to Good Clinical Practice guidelines. 4038 subjects were analyzed and reported.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multi-center studies, the investigator agrees not to publish any results before the first multi-center publication.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Study Director
Organization: Amgen Inc.
Phone: 866-572-6436
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Amgen
ClinicalTrials.gov Identifier: NCT00093015    
Other Study ID Numbers: 20010184
TREAT
First Submitted: September 28, 2004
First Posted: September 29, 2004
Results First Submitted: August 6, 2010
Results First Posted: September 2, 2010
Last Update Posted: November 8, 2022