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Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With Chronic Kidney Disease (CKD), Not on Dialysis

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: NCT02174627
Recruitment Status : Completed
First Posted : June 25, 2014
Results First Posted : December 16, 2019
Last Update Posted : December 16, 2019
Sponsor:
Collaborator:
FibroGen
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Anemia
Interventions Drug: Roxadustat
Drug: Placebo
Enrollment 2781
Recruitment Details This study was conducted at 385 centers in 25 countries worldwide across the United States, Canada, Latin America, Asia and Europe between 26 June 2014 and 04 October 2018. Participants with chronic kidney disease who were not on dialysis were recruited in this study.
Pre-assignment Details Study had a screening period (up to 6 weeks), treatment period (up to 4 years) and follow-up period (4 weeks after treatment period for those who completed treatment). 2781 participants were randomized, of which 2761 were included in the analysis and 20 were excluded. Only participants included in the analysis are presented in the participant flow.
Arm/Group Title Roxadustat Placebo
Hide Arm/Group Description Participants received roxadustat tablets orally three times a week (TIW). The initial dose was 70 milligram (mg) TIW and was titrated to achieve and maintain haemoglobin (Hb) 11±1 grams per deciliter (g/dL). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values. Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Period Title: Overall Study
Started [1] 1384 1377
Received Treatment 1384 1376
Discontinued Treatment 499 801
Completed [2] 1300 1247
Not Completed 84 130
Reason Not Completed
Missing             0             1
Incorrect enrolment before randomization             0             1
Participant decision             84             128
[1]
Randomized and included in the analysis
[2]
Completed the study
Arm/Group Title Roxadustat Placebo Total
Hide Arm/Group Description Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values. Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values. Total of all reporting groups
Overall Number of Baseline Participants 1384 1377 2761
Hide Baseline Analysis Population Description
The Intention-To-Treat (ITT) analysis set included all participants who were randomized to investigational product (IP) irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 1384 participants 1377 participants 2761 participants
60.9  (14.67) 62.4  (14.14) 61.7  (14.43)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1384 participants 1377 participants 2761 participants
Female
820
  59.2%
774
  56.2%
1594
  57.7%
Male
564
  40.8%
603
  43.8%
1167
  42.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1384 participants 1377 participants 2761 participants
Hispanic or Latino
344
  24.9%
357
  25.9%
701
  25.4%
Not Hispanic or Latino
1040
  75.1%
1020
  74.1%
2060
  74.6%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 1384 participants 1377 participants 2761 participants
White
623
  45.0%
611
  44.4%
1234
  44.7%
Black or African American
112
   8.1%
115
   8.4%
227
   8.2%
Asian
544
  39.3%
538
  39.1%
1082
  39.2%
Native Hawaiian or other Pacific Islander
0
   0.0%
2
   0.1%
2
   0.1%
American Indian or Alaska Native
24
   1.7%
29
   2.1%
53
   1.9%
Other
81
   5.9%
82
   6.0%
163
   5.9%
1.Primary Outcome
Title Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52
Hide Description Baseline Hb was defined as the mean of the last 3 central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to mean value from Week 28 to Week 52 was analyzed using a missing at random (MAR) based multiple imputation analysis of covariance (ANCOVA) model with baseline Hb, baseline estimated glomerular filtration rate (eGFR), cardiovascular (CV) history, geographic region and treatment group as fixed effect covariates. The adjusted least squares (LS) mean estimates of change from baseline to mean during Week 28 to Week 52 are presented.
Time Frame Baseline (Day 1, Week 0) and Week 28 to Week 52.
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
Arm/Group Title Roxadustat Placebo
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Overall Number of Participants Analyzed 1334 1330
Least Squares Mean (Standard Error)
Unit of Measure: g/dL
1.75  (0.033) 0.40  (0.034)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Placebo
Comments Difference between groups (roxadustat minus placebo) in LS mean changes; MAR-based multiple imputation ANCOVA model.
Type of Statistical Test Superiority
Comments Superiority of roxadustat compared with placebo would be declared if the lower bound of the 2-sided 95% confidence interval (CI) of the difference between roxadustat and placebo exceeded 0 g/dL.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 1.35
Confidence Interval (2-Sided) 95%
1.27 to 1.43
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.041
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Participants With Hb Response During the First 24 Weeks of Treatment
Hide Description

Hb response was defined as:

  • Hb ≥ 11.0 g/dL and Hb increase from baseline by ≥ 1.0 g/dL for participants with baseline Hb > 8.0 g/dL; or
  • Hb increase from baseline by ≥ 2.0 g/dL, for participants with baseline Hb ≤ 8.0 g/dL at 2 consecutive visits (with available data) separated at least 5 days during the first 24 weeks of treatment without having received rescue therapy (red blood cell [RBC] transfusion, erythropoietin analogue, or intravenous [IV] iron) prior to Hb response. The percentage of participants with an Hb response during the first 24 weeks of treatment is presented.
Time Frame Baseline (Day 1, Week 0) up to Week 24.
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) included all participants in the ITT analysis set who received at least 1 dose of IP and had baseline Hb and at least 1 post-dose Hb assessment. Participants from the FAS, with data available for analysis are presented.
Arm/Group Title Roxadustat Placebo
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Overall Number of Participants Analyzed 1371 1357
Measure Type: Number
Unit of Measure: Percentage of participants
77.0 8.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Placebo
Comments Comparison of the percentage of responders for roxadustat versus placebo was analysed using a Cochran-Mantel-Haenszel test adjusting for baseline Hb, baseline eGFR, geographic region and CV history.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Relative Risk
Estimated Value 9.12
Confidence Interval (2-Sided) 95%
7.63 to 10.89
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Mean Change From Baseline in Hb Averaged Over Week 28 to Week 52 in Participants With Baseline High Sensitivity C-Reactive Protein (hsCRP) Greater Than the Upper Limit of Normal (ULN)
Hide Description Baseline hsCRP was quantified from stored biomarker samples obtained at randomization. Baseline Hb was defined as the mean of the last 3 central laboratory Hb values from the screening and randomization visits. Mean change in Hb from baseline to mean value during Week 28 to Week 52 was analyzed using a MAR based multiple imputation ANCOVA model with baseline Hb, baseline eGFR, CV history, geographic region and treatment group as fixed effect covariates. The adjusted LS mean estimates of change from baseline in participants with baseline hsCRP >ULN to mean during Week 28 to Week 52 are presented.
Time Frame Baseline (Day 1, Week 0) and Week 28 to Week 52.
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. Only participants who consented to the use of donated biomarker samples and had baseline hsCRP >ULN were included in the analysis.
Arm/Group Title Roxadustat Placebo
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Overall Number of Participants Analyzed 213 198
Least Squares Mean (Standard Error)
Unit of Measure: g/dL
1.75  (0.087) 0.62  (0.091)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Placebo
Comments Difference between groups (roxadustat minus placebo) in LS mean changes; MAR-based multiple imputation ANCOVA model.
Type of Statistical Test Superiority
Comments Superiority of roxadustat compared with placebo would be declared if the lower bound of the 2-sided 95% CI of the difference between roxadustat and placebo exceeded 0 g/dL.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 1.13
Confidence Interval (2-Sided) 95%
0.91 to 1.35
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.112
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Proportion of Total Time of Interpolated Hb Values Greater Than or Equal To 10 g/dL From Week 28 to Week 52
Hide Description Proportion of total time of interpolated Hb values ≥10 g/dL was calculated as the time the linearly interpolated curve between measurements ≥10 g/dL divided by the time between measurements from Week 28 to Week 52. Proportion of total time was analyzed using an ANCOVA model with baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from Week 28 to Week 52 are presented.
Time Frame Week 28 up to Week 52.
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. Participants without any Hb measurements from Week 28 were not included in the analysis.
Arm/Group Title Roxadustat Placebo
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Overall Number of Participants Analyzed 1220 1145
Least Squares Mean (Standard Error)
Unit of Measure: proportion of total time
0.82  (0.011) 0.33  (0.011)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Placebo
Comments Difference between groups (roxadustat minus placebo) in LS mean changes; ANCOVA model.
Type of Statistical Test Superiority
Comments Superiority of roxadustat compared with placebo would be declared if the lower bound of the 2-sided 95% CI of the difference between roxadustat and placebo exceeded 0.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.50
Confidence Interval (2-Sided) 95%
0.47 to 0.52
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.013
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Proportion of Total Time of Interpolated Hb Values Within the Interval of 10 to 12 g/dL From Week 28 to Week 52
Hide Description Proportion of total time of interpolated Hb values within the interval of 10 to 12 g/dL was calculated as the time the linearly interpolated curve between measurements were within 10 to 12 g/dL divided by the time between measurements from Week 28 to Week 52. Proportion of total time was analyzed using an ANCOVA model with baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from Week 28 to Week 52 are presented.
Time Frame Week 28 up to Week 52.
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. Participants without any Hb measurements from Week 28 were not included in the analysis.
Arm/Group Title Roxadustat Placebo
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Overall Number of Participants Analyzed 1220 1145
Least Squares Mean (Standard Error)
Unit of Measure: proportion of total time
0.70  (0.010) 0.28  (0.010)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Placebo
Comments Difference between groups (roxadustat minus placebo) in LS mean changes; ANCOVA model.
Type of Statistical Test Superiority
Comments Superiority of roxadustat compared with placebo would be declared if the lower bound of the 2-sided 95% CI of the difference between roxadustat and placebo exceeded 0.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.42
Confidence Interval (2-Sided) 95%
0.40 to 0.45
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.013
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Mean Change in Low-Density Lipoprotein (LDL) Cholesterol From Baseline to Week 24
Hide Description Baseline LDL was defined as the last result obtained prior to randomization. Mean changes in LDL cholesterol from baseline to Week 24 was analyzed using an ANCOVA model with baseline LDL, baseline Hb and baseline eGFR as covariates, and CV history, geographic region and treatment group as fixed effects. The adjusted LS mean estimates of change from baseline to Week 24 are presented.
Time Frame Baseline (Day 1, Week 0) and Week 24
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
Arm/Group Title Roxadustat Placebo
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Overall Number of Participants Analyzed 1147 1133
Least Squares Mean (Standard Error)
Unit of Measure: millimole per liter
-0.38  (0.028) -0.02  (0.027)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Placebo
Comments Difference between groups (roxadustat minus placebo) in LS mean changes; ANCOVA model.
Type of Statistical Test Superiority
Comments Superiority of roxadustat compared with placebo would be declared if the lower bound of the 2-sided 95% CI of the difference between roxadustat and placebo exceeded 0.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.36
Confidence Interval (2-Sided) 95%
-0.42 to -0.29
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.033
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Time-To-First Instance of Receiving IV Iron, RBC Transfusion or Erythropoietin Analogue as Rescue Therapy
Hide Description Time-to-first rescue therapy (IV iron, RBC transfusion or erythropoietin analogue) was calculated as (date of first rescue therapy, or date of censoring if no rescue therapy was taken) minus (date of first dose of IP) +1. Event rate was calculated as (number of participants with event) divided by (the total number of days at risk for event across all participants in given group divided by 365.25) multiplied by 100. The event rate is presented for participants with events.
Time Frame Baseline (Day1, Week 0) up to End of Study (EOS) visit (4 weeks after the treatment period) (or up to date of first rescue therapy), with treatment duration up to 4 years.
Hide Outcome Measure Data
Hide Analysis Population Description
The on-treatment plus 28 days (OT+28) analysis set included all participants who received at least 1 dose of randomized IP, except for those excluded from analysis. Participants were censored 28 days after last intake of IP.
Arm/Group Title Roxadustat Placebo
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Overall Number of Participants Analyzed 1384 1376
Measure Type: Number
Unit of Measure: Events per 100 participant years
11.90 39.76
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Placebo
Comments Treatments were compared using a Cox proportional hazards model, with baseline Hb and baseline eGFR as continuous variables used as covariates, and treatment group, CV history and geographic region as fixed effects. The Efron method was used for ties and p-values were calculated using the Wald test.
Type of Statistical Test Superiority
Comments Superiority of roxadustat compared with placebo would be declared if the upper limit of the 2-sided 95% CI for the HR was ≤1.0.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.26
Confidence Interval (2-Sided) 95%
0.23 to 0.31
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Time-To-First Instance of Receiving a RBC Transfusion As Rescue Therapy
Hide Description Time-to-first RBC rescue therapy was calculated as (date of first RBC rescue therapy, or date of censoring if no rescue therapy was taken) minus (date of first dose of IP) +1. Event rate was calculated as (number of participants with event) divided by (the total number of days at risk for event across all participants in given group divided by 365.25) multiplied by 100. The event rate is presented for participants with events.
Time Frame Baseline (Day1, Week 0) up to EOS visit (4 weeks after the treatment period) (or up to date of first RBC rescue therapy), with treatment duration up to 4 years.
Hide Outcome Measure Data
Hide Analysis Population Description
The OT+28 analysis set included all participants who received at least 1 dose of randomized IP, except for those excluded from analysis. Participants were censored 28 days after last intake of IP.
Arm/Group Title Roxadustat Placebo
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Overall Number of Participants Analyzed 1384 1376
Measure Type: Number
Unit of Measure: Events per 100 participant years
7.98 19.61
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Placebo
Comments Treatments were compared using a Cox proportional hazards model, with baseline Hb and baseline eGFR as continuous variables used as covariates, and treatment group, CV history and geographic region as fixed effects. The Efron method was used for ties and p-values were calculated using the Wald test.
Type of Statistical Test Superiority
Comments Superiority of roxadustat compared with placebo would be declared if the upper limit of the 2-sided 95% CI for the HR was ≤1.0.
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Regression, Cox
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.37
Confidence Interval (2-Sided) 95%
0.30 to 0.44
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Mean Change From Baseline in Short Form 36 (SF-36) Vitality Sub-Score From Week 12 to Week 28
Hide Description SF-36 is a Quality of Life (QoL) scale comprising 8 domains of health status: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional and Mental Health. Each domain score is on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Mean change in SF-36 Vitality sub-score from baseline to mean from Week 12 to Week 28 was analyzed using a mixed model for repeated measures (MMRM) with terms for baseline score, treatment group, baseline Hb, baseline eGFR, CV history, geographic region, visit and treatment-by-visit interaction as fixed effects and participant as random effect. The adjusted LS mean estimates of change from baseline to mean score from Week 12 to Week 28 are presented.
Time Frame Baseline (Day 1, Week 0) and Week 12 to Week 28.
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
Arm/Group Title Roxadustat Placebo
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Overall Number of Participants Analyzed 1279 1235
Least Squares Mean (Standard Error)
Unit of Measure: scores on a scale
1.59  (0.231) 1.15  (0.233)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Placebo
Comments Difference between groups (roxadustat minus placebo) in LS mean changes; MMRM analysis.
Type of Statistical Test Superiority
Comments Superiority of roxadustat compared with placebo would be declared if the lower bound of the 2-sided 95% CI of the difference between roxadustat and placebo exceeded 0.
Statistical Test of Hypothesis P-Value 0.120
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.44
Confidence Interval (2-Sided) 95%
-0.11 to 0.99
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.283
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Annual Rate of eGFR Change From Baseline Prior to the Initiation of Dialysis or Kidney Transplant
Hide Description Baseline eGFR was defined as the mean of all available central laboratory values prior to or at randomization. Rate of change in eGFR from baseline during the entire treatment period (in millilitres/minute/1.73 meters squared/years [mL/min/1.73m^2/years]) was estimated using a random effects model using all post-baseline eGFR values prior to initiation of dialysis/transplant. Baseline eGFR, baseline Hb, geographic region, CV history, treatment group and post-baseline eGFR measurement time were used as fixed effects and participant and time (years) as random effects, ie, random intercept and slope.
Time Frame Baseline (Day1, Week 0) up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years.
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
Arm/Group Title Roxadustat Placebo
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Overall Number of Participants Analyzed 1326 1314
Measure Type: Number
Unit of Measure: eGFR rate (mL/min/1.73m^2/years)
-3.70 -3.19
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Placebo
Comments Difference between groups (roxadustat minus placebo) in rate of change in eGFR; random effects analysis.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.046
Comments Nominal p-value (as prior sequential outcome measure p-value did not meet < 0.05.
Method Random Effects Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Rate of Change Difference
Estimated Value -0.51
Confidence Interval (2-Sided) 95%
-1.00 to -0.01
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.254
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Mean Change From Baseline in SF-36 Physical Functioning Sub-Score From Week 12 to Week 28
Hide Description SF-36 is a QoL scale comprising 8 domains of health status: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role Emotional and Mental Health. Each domain score is on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Mean change in SF-36 Physical Functioning sub-score from baseline to mean from Week 12 to Week 28 was analyzed using a MMRM with terms for baseline score, treatment group, baseline Hb, baseline eGFR, CV history, geographic region, visit and treatment-by-visit interaction as fixed effects and participant as random effect. The adjusted LS mean estimates of change from baseline to mean score from Week 12 to Week 28 are presented.
Time Frame Baseline (Day 1, Week 0) and Week 12 to Week 28.
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis.
Arm/Group Title Roxadustat Placebo
Hide Arm/Group Description:
Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
Overall Number of Participants Analyzed 1279 1234
Least Squares Mean (Standard Error)
Unit of Measure: scores on a scale
0.14  (0.222) -0.39  (0.224)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Roxadustat, Placebo
Comments Difference between groups (roxadustat minus placebo) in LS mean changes; MMRM analysis.
Type of Statistical Test Superiority
Comments Superiority of roxadustat compared with placebo would be declared if the lower bound of the 2-sided 95% CI of the difference between roxadustat and placebo exceeded 0.
Statistical Test of Hypothesis P-Value 0.051
Comments Nominal p-value (as prior sequential outcome measure p-value did not meet < 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 0.52
Confidence Interval (2-Sided) 95%
0.00 to 1.05
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.269
Estimation Comments [Not Specified]
Time Frame From date of randomization up to EOS visit (4 weeks after the treatment period), with treatment duration up to 4 years.
Adverse Event Reporting Description The ITT analysis set included all participants who were randomized to IP irrespective of their protocol adherence and continued participation in the study, except for those excluded from analysis. All-Cause Mortality represents all deaths due to any cause.
 
Arm/Group Title Roxadustat Placebo
Hide Arm/Group Description Participants received roxadustat tablets orally TIW. The initial dose was 70 mg TIW and was titrated to achieve and maintain Hb 11±1 g/dL. Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values. Participants received placebo tablets orally TIW. Dosing instructions were matched to instructions provided for roxadustat (ie, initial dose matched to 70 mg TIW). Treatment started on Day 1 and treatment duration was variable for individual participants (estimated up to 4 years). Dose adjustments were permitted starting at Week 4 and at intervals of every 4 weeks until Week 52, every 8 weeks thereafter using a dose adjustment algorithm; all dose adjustments were based on Hb values.
All-Cause Mortality
Roxadustat Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   284/1384 (20.52%)      245/1377 (17.79%)    
Hide Serious Adverse Events
Roxadustat Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   795/1384 (57.44%)      749/1377 (54.39%)    
Blood and lymphatic system disorders     
Anaemia  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Coagulopathy  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Evans syndrome  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Febrile neutropenia  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Haemolytic uraemic syndrome  1  0/1384 (0.00%)  0 1/1377 (0.07%)  2
Haemorrhagic anaemia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Histiocytosis haematophagic  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Hypocoagulable state  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Iron deficiency anaemia  1  2/1384 (0.14%)  2 1/1377 (0.07%)  1
Leukocytosis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Lymphadenitis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Neutropenia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Pancytopenia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Thrombocytopenia  1  3/1384 (0.22%)  3 1/1377 (0.07%)  1
Cardiac disorders     
Acute coronary syndrome  1  8/1384 (0.58%)  8 5/1377 (0.36%)  5
Acute left ventricular failure  1  5/1384 (0.36%)  6 4/1377 (0.29%)  4
Acute myocardial infarction  1  26/1384 (1.88%)  28 27/1377 (1.96%)  31
Angina pectoris  1  10/1384 (0.72%)  10 9/1377 (0.65%)  9
Angina unstable  1  10/1384 (0.72%)  10 10/1377 (0.73%)  11
Aortic valve stenosis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Arrhythmia  1  6/1384 (0.43%)  6 3/1377 (0.22%)  3
Arteriosclerosis coronary artery  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Atrial fibrillation  1  10/1384 (0.72%)  10 12/1377 (0.87%)  15
Atrial flutter  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Atrioventricular block  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Atrioventricular block complete  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Bradyarrhythmia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Bradycardia  1  2/1384 (0.14%)  2 3/1377 (0.22%)  4
Bundle branch block left  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Cardiac arrest  1  9/1384 (0.65%)  9 4/1377 (0.29%)  4
Cardiac asthma  1  3/1384 (0.22%)  3 0/1377 (0.00%)  0
Cardiac failure  1  25/1384 (1.81%)  31 32/1377 (2.32%)  35
Cardiac failure acute  1  8/1384 (0.58%)  8 14/1377 (1.02%)  16
Cardiac failure chronic  1  4/1384 (0.29%)  4 5/1377 (0.36%)  6
Cardiac failure congestive  1  33/1384 (2.38%)  41 31/1377 (2.25%)  42
Cardiac tamponade  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Cardio-respiratory arrest  1  6/1384 (0.43%)  6 4/1377 (0.29%)  4
Cardiogenic shock  1  3/1384 (0.22%)  3 1/1377 (0.07%)  1
Cardiomegaly  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Cardiomyopathy  1  2/1384 (0.14%)  2 1/1377 (0.07%)  1
Cardiopulmonary failure  1  3/1384 (0.22%)  3 1/1377 (0.07%)  1
Chronic left ventricular failure  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Congestive cardiomyopathy  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Coronary artery disease  1  12/1384 (0.87%)  12 7/1377 (0.51%)  7
Coronary artery insufficiency  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Coronary artery stenosis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Heart valve incompetence  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Heart valve stenosis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Hypertensive cardiomyopathy  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Ischaemic cardiomyopathy  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Left ventricular dysfunction  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Left ventricular failure  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Left ventricular hypertrophy  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Metabolic cardiomyopathy  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Mitral valve disease  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Mitral valve incompetence  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Myocardial infarction  1  14/1384 (1.01%)  14 13/1377 (0.94%)  13
Myocardial ischaemia  1  4/1384 (0.29%)  4 8/1377 (0.58%)  8
Pericardial effusion  1  3/1384 (0.22%)  3 0/1377 (0.00%)  0
Pulseless electrical activity  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Right ventricular failure  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Sinoatrial block  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Sinus arrest  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Sinus bradycardia  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Sinus node dysfunction  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Supraventricular tachycardia  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Tachycardia  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Ventricular arrhythmia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Ventricular extrasystoles  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Ventricular fibrillation  1  1/1384 (0.07%)  1 3/1377 (0.22%)  3
Ventricular tachycardia  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Congenital, familial and genetic disorders     
Congenital cystic kidney disease  1  0/1384 (0.00%)  0 2/1377 (0.15%)  3
Hydrocele  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Ear and labyrinth disorders     
Vertigo  1  3/1384 (0.22%)  3 3/1377 (0.22%)  3
Vertigo positional  1  2/1384 (0.14%)  2 1/1377 (0.07%)  1
Vestibular ataxia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Vestibular disorder  1  5/1384 (0.36%)  5 1/1377 (0.07%)  1
Endocrine disorders     
Adrenal insufficiency  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Goitre  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Hyperparathyroidism  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Hyperparathyroidism secondary  1  3/1384 (0.22%)  3 0/1377 (0.00%)  0
Eye disorders     
Blindness unilateral  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Cataract  1  1/1384 (0.07%)  2 2/1377 (0.15%)  2
Diabetic retinopathy  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Ulcerative keratitis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Visual acuity reduced  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Visual impairment  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Vitreous haemorrhage  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Gastrointestinal disorders     
Abdominal adhesions  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Abdominal discomfort  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Abdominal pain  1  3/1384 (0.22%)  3 4/1377 (0.29%)  4
Abdominal pain lower  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Abdominal pain upper  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Abdominal wall haematoma  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Anal fistula  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Anal incontinence  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Ascites  1  2/1384 (0.14%)  2 1/1377 (0.07%)  1
Chronic gastritis  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Colitis  1  3/1384 (0.22%)  3 1/1377 (0.07%)  1
Colitis ischaemic  1  2/1384 (0.14%)  2 1/1377 (0.07%)  1
Constipation  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Crohn's disease  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Diabetic gastroparesis  1  1/1384 (0.07%)  2 0/1377 (0.00%)  0
Diabetic gastropathy  1  0/1384 (0.00%)  0 1/1377 (0.07%)  2
Diarrhoea  1  9/1384 (0.65%)  9 5/1377 (0.36%)  5
Dieulafoy's vascular malformation  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Diverticulum  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Diverticulum intestinal  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Diverticulum intestinal haemorrhagic  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Duodenal ulcer  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Duodenal ulcer haemorrhage  1  4/1384 (0.29%)  5 1/1377 (0.07%)  1
Duodenitis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Duodenitis haemorrhagic  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Dyspepsia  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Dysphagia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Enteritis  1  3/1384 (0.22%)  3 2/1377 (0.15%)  2
Enterocolitis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Enterocolitis haemorrhagic  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Erosive duodenitis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Femoral hernia incarcerated  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Functional gastrointestinal disorder  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Gastric haemorrhage  1  3/1384 (0.22%)  3 0/1377 (0.00%)  0
Gastric polyps  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Gastric ulcer  1  4/1384 (0.29%)  4 2/1377 (0.15%)  2
Gastric ulcer haemorrhage  1  2/1384 (0.14%)  2 3/1377 (0.22%)  3
Gastritis  1  18/1384 (1.30%)  24 15/1377 (1.09%)  18
Gastritis erosive  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Gastritis haemorrhagic  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Gastroduodenitis haemorrhagic  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Gastrointestinal disorder  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Gastrointestinal haemorrhage  1  20/1384 (1.45%)  20 15/1377 (1.09%)  16
Gastrointestinal inflammation  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Gastrooesophageal reflux disease  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Haematemesis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Haematochezia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Haemorrhagic ascites  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Haemorrhagic erosive gastritis  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Haemorrhoidal haemorrhage  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Hiatus hernia  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Ileal perforation  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Ileus  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Impaired gastric emptying  1  1/1384 (0.07%)  2 1/1377 (0.07%)  1
Incarcerated umbilical hernia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Inguinal hernia  1  4/1384 (0.29%)  5 3/1377 (0.22%)  4
Inguinal hernia strangulated  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Intestinal haemorrhage  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Intestinal obstruction  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Large intestine perforation  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Lower gastrointestinal haemorrhage  1  1/1384 (0.07%)  1 5/1377 (0.36%)  5
Mallory-Weiss syndrome  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Melaena  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Mesenteric artery thrombosis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Nausea  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Oesophageal ulcer  1  1/1384 (0.07%)  2 1/1377 (0.07%)  1
Oesophageal varices haemorrhage  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Oesophagitis  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Oesophagitis ulcerative  1  1/1384 (0.07%)  2 0/1377 (0.00%)  0
Pancreatic cyst  1  1/1384 (0.07%)  2 0/1377 (0.00%)  0
Pancreatitis  1  5/1384 (0.36%)  5 0/1377 (0.00%)  0
Pancreatitis acute  1  4/1384 (0.29%)  4 4/1377 (0.29%)  4
Peptic ulcer  1  0/1384 (0.00%)  0 3/1377 (0.22%)  3
Peptic ulcer haemorrhage  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Peptic ulcer perforation  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Peritoneal adhesions  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Peritoneal cloudy effluent  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Peritoneal haemorrhage  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Pneumatosis intestinalis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Rectal haemorrhage  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Small intestinal haemorrhage  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Small intestinal obstruction  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Umbilical hernia  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Upper gastrointestinal haemorrhage  1  11/1384 (0.79%)  11 4/1377 (0.29%)  4
Uraemic gastropathy  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Vomiting  1  4/1384 (0.29%)  4 2/1377 (0.15%)  2
General disorders     
Asthenia  1  13/1384 (0.94%)  14 9/1377 (0.65%)  9
Catheter site haemorrhage  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Catheter site pain  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Chest pain  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Death  1  43/1384 (3.11%)  43 28/1377 (2.03%)  28
Device related thrombosis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Fatigue  1  1/1384 (0.07%)  1 1/1377 (0.07%)  2
Generalised oedema  1  17/1384 (1.23%)  25 7/1377 (0.51%)  11
Hernia pain  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Implant site extravasation  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Implant site necrosis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Inflammation  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Multiple organ dysfunction syndrome  1  2/1384 (0.14%)  2 1/1377 (0.07%)  1
Non-cardiac chest pain  1  2/1384 (0.14%)  2 2/1377 (0.15%)  2
Oedema  1  7/1384 (0.51%)  9 7/1377 (0.51%)  7
Oedema due to renal disease  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Oedema peripheral  1  7/1384 (0.51%)  10 5/1377 (0.36%)  10
Pacemaker generated arrhythmia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Peripheral swelling  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Pyrexia  1  6/1384 (0.43%)  7 5/1377 (0.36%)  5
Stenosis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  2
Sudden cardiac death  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Sudden death  1  5/1384 (0.36%)  5 11/1377 (0.80%)  11
Hepatobiliary disorders     
Bile duct stenosis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Bile duct stone  1  4/1384 (0.29%)  6 1/1377 (0.07%)  1
Cholangitis  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Cholangitis acute  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Cholecystitis  1  2/1384 (0.14%)  2 1/1377 (0.07%)  1
Cholecystitis acute  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Cholecystitis chronic  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Cholelithiasis  1  4/1384 (0.29%)  4 1/1377 (0.07%)  1
Cholestasis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Chronic hepatic failure  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Cirrhosis alcoholic  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Haemorrhagic hepatic cyst  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Hepatic cirrhosis  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Hepatitis acute  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Hepatitis alcoholic  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Hyperbilirubinaemia  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Jaundice  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Liver disorder  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Liver injury  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Immune system disorders     
Anaphylactic shock  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Device allergy  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Hypersensitivity  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Kidney transplant rejection  1  2/1384 (0.14%)  3 1/1377 (0.07%)  1
Renal transplant failure  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Transplant rejection  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Infections and infestations     
Abdominal abscess  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Abdominal infection  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Abscess  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Abscess limb  1  3/1384 (0.22%)  3 3/1377 (0.22%)  3
Acute hepatitis B  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Appendicitis  1  3/1384 (0.22%)  3 5/1377 (0.36%)  5
Appendicitis perforated  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Arteriovenous fistula site infection  1  3/1384 (0.22%)  3 3/1377 (0.22%)  3
Arteriovenous graft site infection  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Arthritis bacterial  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Bacteraemia  1  4/1384 (0.29%)  4 1/1377 (0.07%)  1
Bacterial infection  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Bone tuberculosis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Bronchitis  1  7/1384 (0.51%)  7 9/1377 (0.65%)  9
Carbuncle  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Cardiac valve abscess  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Catheter site cellulitis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Catheter site infection  1  3/1384 (0.22%)  3 8/1377 (0.58%)  9
Cellulitis  1  24/1384 (1.73%)  27 13/1377 (0.94%)  13
Cellulitis gangrenous  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Clostridial infection  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Clostridium difficile colitis  1  4/1384 (0.29%)  4 2/1377 (0.15%)  2
Clostridium difficile infection  1  2/1384 (0.14%)  2 2/1377 (0.15%)  2
Cystitis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Cystitis bacterial  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Cytomegalovirus infection  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Cytomegalovirus nephritis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Dengue fever  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Device related infection  1  14/1384 (1.01%)  14 5/1377 (0.36%)  6
Device related sepsis  1  3/1384 (0.22%)  4 5/1377 (0.36%)  5
Diabetic foot infection  1  1/1384 (0.07%)  1 4/1377 (0.29%)  4
Diabetic gangrene  1  1/1384 (0.07%)  1 1/1377 (0.07%)  3
Diarrhoea infectious  1  4/1384 (0.29%)  4 4/1377 (0.29%)  5
Diverticulitis  1  4/1384 (0.29%)  7 3/1377 (0.22%)  3
Emphysematous cystitis  1  1/1384 (0.07%)  1 1/1377 (0.07%)  2
Emphysematous pyelonephritis  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Empyema  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Endocarditis  1  2/1384 (0.14%)  2 1/1377 (0.07%)  1
Endocarditis bacterial  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Endotoxic shock  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Enteritis infectious  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Enterobacter sepsis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Enterococcal sepsis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Epiglottitis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Erysipelas  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Escherichia sepsis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Escherichia urinary tract infection  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Fungaemia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Fungal oesophagitis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Fungal peritonitis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Furuncle  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Gangrene  1  10/1384 (0.72%)  10 7/1377 (0.51%)  9
Gastroenteritis  1  13/1384 (0.94%)  16 8/1377 (0.58%)  8
Gastroenteritis bacterial  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Gastroenteritis viral  1  2/1384 (0.14%)  2 1/1377 (0.07%)  1
Gastrointestinal infection  1  2/1384 (0.14%)  2 2/1377 (0.15%)  2
H1N1 influenza  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Helicobacter gastritis  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Hepatitis B  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Hepatitis B reactivation  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Hepatitis C  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Herpes virus infection  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Herpes zoster  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Infected lymphocele  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Infected skin ulcer  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Infection  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Infective aneurysm  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Influenza  1  4/1384 (0.29%)  4 5/1377 (0.36%)  5
Intestinal tuberculosis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Kidney infection  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Klebsiella sepsis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Localised infection  1  2/1384 (0.14%)  4 5/1377 (0.36%)  5
Lower respiratory tract infection  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Lung abscess  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Lung infection  1  1/1384 (0.07%)  1 3/1377 (0.22%)  3
Lymph node tuberculosis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Nasopharyngitis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Oesophageal candidiasis  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Orchitis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Osteomyelitis  1  3/1384 (0.22%)  3 2/1377 (0.15%)  3
Osteomyelitis acute  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Osteomyelitis chronic  1  1/1384 (0.07%)  2 0/1377 (0.00%)  0
Otitis media chronic  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Parvovirus infection  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Perineal abscess  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Perinephric abscess  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Peritonitis  1  15/1384 (1.08%)  17 14/1377 (1.02%)  19
Peritonitis bacterial  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Peritonsillar abscess  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Pharyngitis  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Pleural infection  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Pneumonia  1  113/1384 (8.16%)  149 88/1377 (6.39%)  107
Pneumonia bacterial  1  2/1384 (0.14%)  2 3/1377 (0.22%)  3
Pneumonia influenzal  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Pneumonia klebsiella  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Pneumonia mycoplasmal  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Pneumonia viral  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Post procedural cellulitis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Post procedural infection  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Post procedural pneumonia  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Postoperative wound infection  1  2/1384 (0.14%)  2 2/1377 (0.15%)  2
Pseudomembranous colitis  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Pseudomonas infection  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Pulmonary tuberculosis  1  3/1384 (0.22%)  3 2/1377 (0.15%)  2
Purulence  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Pyelonephritis  1  8/1384 (0.58%)  9 5/1377 (0.36%)  5
Pyelonephritis acute  1  6/1384 (0.43%)  6 4/1377 (0.29%)  4
Pyelonephritis chronic  1  11/1384 (0.79%)  14 11/1377 (0.80%)  14
Pyoderma  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Pyonephrosis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Renal cyst infection  1  3/1384 (0.22%)  5 1/1377 (0.07%)  1
Respiratory tract infection  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Sepsis  1  49/1384 (3.54%)  51 23/1377 (1.67%)  24
Septic shock  1  18/1384 (1.30%)  19 15/1377 (1.09%)  15
Sinusitis  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Staphylococcal bacteraemia  1  3/1384 (0.22%)  3 0/1377 (0.00%)  0
Staphylococcal infection  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Staphylococcal sepsis  1  1/1384 (0.07%)  1 3/1377 (0.22%)  3
Stenotrophomonas sepsis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Streptococcal bacteraemia  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Streptococcal endocarditis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Subcutaneous abscess  1  3/1384 (0.22%)  3 4/1377 (0.29%)  4
Taeniasis  1  1/1384 (0.07%)  4 0/1377 (0.00%)  0
Tracheobronchitis  1  1/1384 (0.07%)  2 0/1377 (0.00%)  0
Tuberculosis  1  5/1384 (0.36%)  5 3/1377 (0.22%)  4
Typhoid fever  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Upper respiratory tract infection  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Urinary tract infection  1  36/1384 (2.60%)  38 26/1377 (1.89%)  32
Urinary tract infection bacterial  1  3/1384 (0.22%)  3 0/1377 (0.00%)  0
Urosepsis  1  8/1384 (0.58%)  11 6/1377 (0.44%)  6
Vascular access site infection  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Vestibular neuronitis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Viral infection  1  0/1384 (0.00%)  0 3/1377 (0.22%)  3
Injury, poisoning and procedural complications     
Anastomotic stenosis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Ankle fracture  1  3/1384 (0.22%)  3 1/1377 (0.07%)  1
Arteriovenous fistula occlusion  1  7/1384 (0.51%)  7 4/1377 (0.29%)  4
Arteriovenous fistula site complication  1  3/1384 (0.22%)  3 4/1377 (0.29%)  4
Arteriovenous fistula site haemorrhage  1  1/1384 (0.07%)  2 1/1377 (0.07%)  1
Arteriovenous fistula thrombosis  1  18/1384 (1.30%)  19 9/1377 (0.65%)  9
Cervical vertebral fracture  1  3/1384 (0.22%)  3 0/1377 (0.00%)  0
Chemical peritonitis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Chemical poisoning  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Chest injury  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Comminuted fracture  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Complications of transplanted kidney  1  2/1384 (0.14%)  3 0/1377 (0.00%)  0
Compression fracture  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Concussion  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Dialysis disequilibrium syndrome  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Dialysis related complication  1  3/1384 (0.22%)  3 0/1377 (0.00%)  0
Facial bones fracture  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Femoral neck fracture  1  2/1384 (0.14%)  2 3/1377 (0.22%)  3
Femur fracture  1  3/1384 (0.22%)  3 2/1377 (0.15%)  3
Foot fracture  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Forearm fracture  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Fractured sacrum  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Head injury  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Heat stroke  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Hip fracture  1  5/1384 (0.36%)  5 6/1377 (0.44%)  6
Humerus fracture  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Injury  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Joint dislocation  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Joint injury  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Laceration  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Limb injury  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Lip injury  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Lower limb fracture  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Muscle injury  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Pelvic fracture  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Periorbital haemorrhage  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Peritoneal dialysis complication  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Post procedural complication  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Post procedural haemorrhage  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Procedural complication  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Procedural haemorrhage  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Procedural hypotension  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Procedural pain  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Rib fracture  1  3/1384 (0.22%)  3 1/1377 (0.07%)  1
Seroma  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Shunt malfunction  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Shunt occlusion  1  2/1384 (0.14%)  2 2/1377 (0.15%)  2
Skin injury  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Spinal compression fracture  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Spinal cord injury cervical  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Spinal fracture  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Spleen contusion  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Stoma obstruction  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Stoma site haemorrhage  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Subarachnoid haemorrhage  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Subdural haematoma  1  2/1384 (0.14%)  2 2/1377 (0.15%)  2
Subdural haemorrhage  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Thermal burn  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Toxicity to various agents  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Transplant dysfunction  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Traumatic liver injury  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Upper limb fracture  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Vascular access malfunction  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Vascular access site thrombosis  1  6/1384 (0.43%)  7 2/1377 (0.15%)  2
Vascular graft complication  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Vascular graft occlusion  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Vascular pseudoaneurysm  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Wound dehiscence  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Wound haematoma  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Investigations     
Anticoagulation drug level increased  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Blood bicarbonate decreased  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Blood bilirubin increased  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Blood creatine increased  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Blood creatinine increased  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Blood glucose abnormal  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Blood glucose increased  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Blood pressure decreased  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Blood pressure increased  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Blood urine present  1  1/1384 (0.07%)  2 0/1377 (0.00%)  0
Coagulation factor decreased  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Hepatic enzyme increased  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Troponin increased  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Metabolism and nutrition disorders     
Acidosis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Adult failure to thrive  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Calciphylaxis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Decreased appetite  1  2/1384 (0.14%)  2 2/1377 (0.15%)  2
Dehydration  1  8/1384 (0.58%)  8 4/1377 (0.29%)  4
Diabetes mellitus  1  1/1384 (0.07%)  1 3/1377 (0.22%)  3
Diabetes mellitus inadequate control  1  4/1384 (0.29%)  5 3/1377 (0.22%)  3
Diabetic ketoacidosis  1  6/1384 (0.43%)  10 10/1377 (0.73%)  12
Diabetic metabolic decompensation  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Electrolyte imbalance  1  1/1384 (0.07%)  1 3/1377 (0.22%)  3
Failure to thrive  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Fluid overload  1  20/1384 (1.45%)  28 22/1377 (1.60%)  27
Fluid retention  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Food aversion  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Gout  1  4/1384 (0.29%)  4 1/1377 (0.07%)  1
Hypercalcaemia  1  0/1384 (0.00%)  0 3/1377 (0.22%)  4
Hyperglycaemia  1  16/1384 (1.16%)  17 9/1377 (0.65%)  10
Hyperglycaemic hyperosmolar nonketotic syndrome  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Hyperinsulinaemic hypoglycaemia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Hyperkalaemia  1  41/1384 (2.96%)  53 25/1377 (1.82%)  35
Hypernatraemia  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Hyperuricaemia  1  2/1384 (0.14%)  2 2/1377 (0.15%)  2
Hypervolaemia  1  4/1384 (0.29%)  5 0/1377 (0.00%)  0
Hypocalcaemia  1  2/1384 (0.14%)  2 2/1377 (0.15%)  2
Hypoglycaemia  1  32/1384 (2.31%)  38 26/1377 (1.89%)  27
Hypokalaemia  1  3/1384 (0.22%)  3 1/1377 (0.07%)  1
Hyponatraemia  1  7/1384 (0.51%)  8 6/1377 (0.44%)  9
Hypovolaemia  1  3/1384 (0.22%)  3 4/1377 (0.29%)  4
Iron deficiency  1  0/1384 (0.00%)  0 1/1377 (0.07%)  2
Ketoacidosis  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Ketosis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Malnutrition  1  4/1384 (0.29%)  4 4/1377 (0.29%)  4
Metabolic acidosis  1  7/1384 (0.51%)  7 3/1377 (0.22%)  3
Type 1 diabetes mellitus  1  1/1384 (0.07%)  2 2/1377 (0.15%)  2
Type 2 diabetes mellitus  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Musculoskeletal and connective tissue disorders     
Arthralgia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Arthritis  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Back pain  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Cervical spinal stenosis  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Flank pain  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Gouty arthritis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Haemarthrosis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Intervertebral disc protrusion  1  3/1384 (0.22%)  4 1/1377 (0.07%)  1
Lumbar spinal stenosis  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Muscular weakness  1  2/1384 (0.14%)  2 2/1377 (0.15%)  2
Musculoskeletal chest pain  1  5/1384 (0.36%)  7 1/1377 (0.07%)  2
Myalgia  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Myositis  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Osteoarthritis  1  2/1384 (0.14%)  4 2/1377 (0.15%)  2
Pain in extremity  1  3/1384 (0.22%)  3 0/1377 (0.00%)  0
Rhabdomyolysis  1  3/1384 (0.22%)  3 1/1377 (0.07%)  1
Spinal osteoarthritis  1  3/1384 (0.22%)  3 3/1377 (0.22%)  3
Spondylitis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Systemic lupus erythematosus  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Acute myeloid leukaemia  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Adenocarcinoma of colon  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Bladder cancer  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Breast cancer female  1  2/1384 (0.14%)  2 2/1377 (0.15%)  2
Breast cancer metastatic  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Breast neoplasm  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Cervix carcinoma  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Colon adenoma  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Colon cancer  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Colon neoplasm  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Colorectal cancer metastatic  1  1/1384 (0.07%)  2 0/1377 (0.00%)  0
Endometrial cancer  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Epiglottic carcinoma  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Gastric adenoma  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Gastric cancer  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Gastric neoplasm  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Gastrointestinal tract adenoma  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Hepatic cancer  1  1/1384 (0.07%)  2 0/1377 (0.00%)  0
Hepatocellular carcinoma  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Invasive ductal breast carcinoma  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Laryngeal cancer  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Leiomyoma  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Lip squamous cell carcinoma  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Lung carcinoma cell type unspecified stage IV  1  0/1384 (0.00%)  0 1/1377 (0.07%)  2
Lung neoplasm  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Lung neoplasm malignant  1  5/1384 (0.36%)  5 1/1377 (0.07%)  1
Malignant melanoma  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Metastatic neoplasm  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Myelodysplastic syndrome  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Myelofibrosis  1  0/1384 (0.00%)  0 2/1377 (0.15%)  4
Neoplasm of appendix  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Neuroendocrine tumour of the lung  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Oesophageal carcinoma  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Ovarian cancer  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Papillary thyroid cancer  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Plasma cell myeloma  1  1/1384 (0.07%)  1 4/1377 (0.29%)  4
Prostate cancer  1  5/1384 (0.36%)  5 0/1377 (0.00%)  0
Renal cancer  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Small cell lung cancer  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Squamous cell carcinoma  1  1/1384 (0.07%)  2 0/1377 (0.00%)  0
Squamous cell carcinoma of skin  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Squamous cell carcinoma of the vagina  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Uterine leiomyoma  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Nervous system disorders     
Aphasia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Autonomic nervous system imbalance  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Brain injury  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Carotid artery stenosis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Cerebellar infarction  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Cerebellar stroke  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Cerebral haematoma  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Cerebral haemorrhage  1  9/1384 (0.65%)  9 3/1377 (0.22%)  3
Cerebral infarction  1  13/1384 (0.94%)  14 8/1377 (0.58%)  9
Cerebrovascular accident  1  15/1384 (1.08%)  15 11/1377 (0.80%)  11
Cerebrovascular disorder  1  3/1384 (0.22%)  3 0/1377 (0.00%)  0
Cerebrovascular insufficiency  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Cervical cord compression  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Coma  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Coma uraemic  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Dementia  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Dementia Alzheimer's type  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Demyelination  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Depressed level of consciousness  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Diabetic hyperglycaemic coma  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Diabetic hyperosmolar coma  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Diabetic ketoacidotic hyperglycaemic coma  1  0/1384 (0.00%)  0 1/1377 (0.07%)  2
Diabetic neuropathy  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Dizziness  1  4/1384 (0.29%)  5 2/1377 (0.15%)  2
Encephalopathy  1  5/1384 (0.36%)  5 0/1377 (0.00%)  0
Epilepsy  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Facial paralysis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Facial spasm  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Generalised tonic-clonic seizure  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Haemorrhage intracranial  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Haemorrhagic stroke  1  3/1384 (0.22%)  3 6/1377 (0.44%)  6
Headache  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Hepatic encephalopathy  1  2/1384 (0.14%)  2 1/1377 (0.07%)  1
Hypertensive encephalopathy  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Intercostal neuralgia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Ischaemic cerebral infarction  1  0/1384 (0.00%)  0 3/1377 (0.22%)  3
Ischaemic stroke  1  9/1384 (0.65%)  9 7/1377 (0.51%)  7
Lacunar infarction  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Lacunar stroke  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Metabolic encephalopathy  1  1/1384 (0.07%)  1 3/1377 (0.22%)  3
Migraine  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Myoclonus  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Neurodegenerative disorder  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Neuroleptic malignant syndrome  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Neuropathy peripheral  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Occipital neuralgia  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Paraparesis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Partial seizures  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Polyneuropathy  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Post stroke seizure  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Presyncope  1  2/1384 (0.14%)  2 0/1377 (0.00%)  0
Sciatica  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Seizure  1  6/1384 (0.43%)  6 2/1377 (0.15%)  3
Senile dementia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Somnolence  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Syncope  1  4/1384 (0.29%)  4 3/1377 (0.22%)  3
Thalamic infarction  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Thalamus haemorrhage  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Transient ischaemic attack  1  2/1384 (0.14%)  2 5/1377 (0.36%)  5
Uraemic encephalopathy  1  2/1384 (0.14%)  2 2/1377 (0.15%)  2
VIth nerve paralysis  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Vascular encephalopathy  1  2/1384 (0.14%)  2 1/1377 (0.07%)  1
Vertebrobasilar insufficiency  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Vertigo CNS origin  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Vestibular migraine  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Pregnancy, puerperium and perinatal conditions     
Abortion spontaneous  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Product Issues     
Device dislocation  1  0/1384 (0.00%)  0 1/1377 (0.07%)  2
Device failure  1  2/1384 (0.14%)  3 0/1377 (0.00%)  0
Device malfunction  1  3/1384 (0.22%)  4 2/1377 (0.15%)  2
Psychiatric disorders     
Alcohol withdrawal syndrome  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Anxiety  1  0/1384 (0.00%)  0 1/1377 (0.07%)  2
Bipolar disorder  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Completed suicide  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Confusional state  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Delirium  1  3/1384 (0.22%)  4 1/1377 (0.07%)  1
Depression  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Insomnia  1  1/1384 (0.07%)  2 0/1377 (0.00%)  0
Mental disorder  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Mental status changes  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Paranoia  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Vascular cognitive impairment  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Renal and urinary disorders     
Acute kidney injury  1  41/1384 (2.96%)  48 32/1377 (2.32%)  33
Anuria  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Azotaemia  1  61/1384 (4.41%)  73 60/1377 (4.36%)  79
Chronic kidney disease  1  8/1384 (0.58%)  8 7/1377 (0.51%)  7
Cystitis haemorrhagic  1  1/1384 (0.07%)  2 0/1377 (0.00%)  0
Diabetic nephropathy  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
End stage renal disease  1  199/1384 (14.38%)  211 201/1377 (14.60%)  211
Glomerulonephritis  1  1/1384 (0.07%)  2 1/1377 (0.07%)  1
Glomerulonephritis chronic  1  2/1384 (0.14%)  2 1/1377 (0.07%)  1
Haematuria  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Nephritic syndrome  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Nephrolithiasis  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Nephropathy toxic  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Nephrotic syndrome  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Obstructive uropathy  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Oedematous kidney  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Oliguria  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Polyuria  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Pyelocaliectasis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Renal atrophy  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Renal colic  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Renal cyst  1  0/1384 (0.00%)  0 2/1377 (0.15%)  2
Renal cyst haemorrhage  1  1/1384 (0.07%)  1 3/1377 (0.22%)  4
Renal failure  1  3/1384 (0.22%)  3 1/1377 (0.07%)  1
Renal impairment  1  4/1384 (0.29%)  5 1/1377 (0.07%)  1
Renal pain  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Renal papillary necrosis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Renal pelvis fistula  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Renal tubular necrosis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Tubulointerstitial nephritis  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Ureteric obstruction  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Ureteric stenosis  1  1/1384 (0.07%)  1 1/1377 (0.07%)  1
Ureterolithiasis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  3
Urinary fistula  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Urinary retention  1  5/1384 (0.36%)  5 1/1377 (0.07%)  1
Urinary tract inflammation  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Urinary tract obstruction  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Reproductive system and breast disorders     
Benign prostatic hyperplasia  1  2/1384 (0.14%)  2 1/1377 (0.07%)  1
Dysfunctional uterine bleeding  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Menorrhagia  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Ovarian cyst  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Ovarian cyst ruptured  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Ovarian cyst torsion  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Ovarian mass  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Pelvic prolapse  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Prostatic fibrosis  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Prostatic mass  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Prostatitis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Prostatomegaly  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema  1  13/1384 (0.94%)  13 22/1377 (1.60%)  25
Acute respiratory distress syndrome  1  1/1384 (0.07%)  1 2/1377 (0.15%)  2
Acute respiratory failure  1  12/1384 (0.87%)  13 20/1377 (1.45%)  20
Aspiration  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Asthma  1  2/1384 (0.14%)  6 3/1377 (0.22%)  3
Bronchial fistula  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Bronchitis chronic  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Bronchospasm  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Chronic obstructive pulmonary disease  1  2/1384 (0.14%)  2 8/1377 (0.58%)  8
Dyspnoea  1  11/1384 (0.79%)  11 12/1377 (0.87%)  14
Dyspnoea exertional  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Epistaxis  1  3/1384 (0.22%)  3 1/1377 (0.07%)  2
Haemoptysis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Haemothorax  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Laryngeal stenosis  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Obstructive airways disorder  1  1/1384 (0.07%)  2 0/1377 (0.00%)  0
Oropharyngeal pain  1  1/1384 (0.07%)  1 0/1377 (0.00%)  0
Pleural effusion  1  15/1384 (1.08%)  17 16/1377 (1.16%)  20
Pleural thickening  1  0/1384 (0.00%)  0 1/1377 (0.07%)  1
Pleurisy  1  3/1384 (0.22%)  3 1/1377 (0.07%)  1
Pneumonia aspiration  1  2/1384 (0.14%)  2 2/1377 (0.15%)  2
Pneumonitis  1  2/1384 (0.14%)