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Anemia Treatment for Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Receiving Chemotherapy

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: NCT00858364
Recruitment Status : Terminated (Primary objective reached)
First Posted : March 9, 2009
Results First Posted : July 6, 2018
Last Update Posted : July 6, 2018
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: Supportive Care
Conditions Non-Small Cell Lung Cancer
Anemia
Cancer
Lung Cancer
Interventions Drug: Darbepoetin alfa
Drug: Placebo
Enrollment 2549
Recruitment Details This study was conducted at 371 centers in Europe, Latin America, Asia, India, North America, Israel, and South Africa.
Pre-assignment Details Eligible participants were randomized to darbepoetin alfa or placebo in a 2:1 ratio. Randomization was stratified by histology (squamous vs other), screening hemoglobin (< 10.0 g/dL vs ≥ 10.0 g/dL), and geographic region.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description Participants received placebo once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first. Participants received darbepoetin alfa 500 µg once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Period Title: Overall Study
Started 846 1703
Received Study Drug 837 1681
Completed [1] 642 1246
Not Completed 204 457
Reason Not Completed
Administrative Decision             3             2
Adverse Event             5             2
Withdrawal by Subject             44             118
Ineligibility Determined             1             10
Lost to Follow-up             24             54
Noncompliance             3             4
Protocol Deviation             0             2
Other             9             17
Missing             1             1
Still on-study             114             247
[1]
Participants who died
Arm/Group Title Placebo Darbepoetin Alfa Total
Hide Arm/Group Description Participants received placebo once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first. Participants received darbepoetin alfa 500 µg once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first. Total of all reporting groups
Overall Number of Baseline Participants 846 1703 2549
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 846 participants 1703 participants 2549 participants
62.2  (9.9) 61.6  (9.8) 61.8  (9.8)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 846 participants 1703 participants 2549 participants
18 - 64 years
482
  57.0%
1014
  59.5%
1496
  58.7%
65 - 74 years
287
  33.9%
547
  32.1%
834
  32.7%
75 - 84 years
71
   8.4%
134
   7.9%
205
   8.0%
≥ 85 years
6
   0.7%
8
   0.5%
14
   0.5%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 846 participants 1703 participants 2549 participants
Female
281
  33.2%
585
  34.4%
866
  34.0%
Male
565
  66.8%
1118
  65.6%
1683
  66.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 846 participants 1703 participants 2549 participants
White or Caucasian
404
  47.8%
808
  47.4%
1212
  47.5%
Black or African American
27
   3.2%
46
   2.7%
73
   2.9%
Asian
357
  42.2%
741
  43.5%
1098
  43.1%
Japanese
7
   0.8%
12
   0.7%
19
   0.7%
Native Hawaiian or Other Pacific Islander
1
   0.1%
0
   0.0%
1
   0.0%
Aborigine
0
   0.0%
1
   0.1%
1
   0.0%
Other
5
   0.6%
14
   0.8%
19
   0.7%
Hispanic
45
   5.3%
81
   4.8%
126
   4.9%
Geographic Region   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 836 participants 1680 participants 2516 participants
Western Europe, Israel and South Africa
54
   6.5%
108
   6.4%
162
   6.4%
Central and Eastern Europe
220
  26.3%
451
  26.8%
671
  26.7%
Latin America and Asia
166
  19.9%
337
  20.1%
503
  20.0%
India
168
  20.1%
339
  20.2%
507
  20.2%
North America
99
  11.8%
192
  11.4%
291
  11.6%
China
123
  14.7%
243
  14.5%
366
  14.5%
Japan
6
   0.7%
10
   0.6%
16
   0.6%
[1]
Measure Description: Stratification factor at the time of randomization.
[2]
Measure Analysis Population Description: The primary analysis set includes all randomized and consented participants with non-small cell lung cancer who received at least one dose of study drug.
Histology   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 836 participants 1680 participants 2516 participants
Squamous
289
  34.6%
589
  35.1%
878
  34.9%
Non-squamous
547
  65.4%
1091
  64.9%
1638
  65.1%
[1]
Measure Description: Stratification factor at the time of randomization
[2]
Measure Analysis Population Description: Primary analysis set
Screening Hemoglobin   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 836 participants 1680 participants 2516 participants
< 10 g/dL
433
  51.8%
870
  51.8%
1303
  51.8%
≥ 10 g/dL
403
  48.2%
810
  48.2%
1213
  48.2%
[1]
Measure Description: Stratification factor at the time of randomization.
[2]
Measure Analysis Population Description: Primary analysis set
1.Primary Outcome
Title Overall Survival (OS)
Hide Description Overall survival (OS) was defined as the time from randomization to the date of death due to any cause. Participants were censored on the date of last contact (ie, the date the participant was last known to be alive) if they were not known to have died.
Time Frame From randomization until death or end of study; maximum time on follow-up was 93.6 months.
Hide Outcome Measure Data
Hide Analysis Population Description
Primary analysis set (all randomized and consented participants with non-small cell lung cancer who received at least one dose of study drug)
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Participants received placebo once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Participants received darbepoetin alfa 500 µg once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Overall Number of Participants Analyzed 836 1680
Median (95% Confidence Interval)
Unit of Measure: months
9.260
(8.250 to 10.020)
9.460
(8.900 to 10.120)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments The primary analysis used the Cox Proportional Hazard Model stratified by the randomization stratification factors (geographic region, histology, and screening hemoglobin), with treatment group as the only covariate.
Type of Statistical Test Non-Inferiority
Comments Non-inferiority was declared if the upper confidence limit for the hazard ratio (darbepoetin alfa to placebo) was less than 1.15 using a 1-sided significance level of 0.025.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.92
Confidence Interval (2-Sided) 95%
0.83 to 1.01
Estimation Comments A hazard ratio < 1.0 indicates a lower risk of death for darbepoetin alfa relative to placebo.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments As a sensitivity analysis, an unstratified Cox Proportional Hazard Model with treatment group as the only covariate was conducted.
Type of Statistical Test Non-Inferiority
Comments Non-inferiority was declared if the upper confidence limit for the hazard ratio (darbepoetin alfa to placebo) was less than 1.15 using a 1-sided significance level of 0.025.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.91
Confidence Interval (2-Sided) 95%
0.83 to 1.00
Estimation Comments A hazard ratio < 1.0 indicates a lower risk of death for darbepoetin alfa relative to placebo.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority
Comments If non-inferiority was demonstrated for both OS and PFS and superiority was demonstrated for the transfusion endpoint, superiority was then tested for both OS and PFS using the Hochberg procedure to adjust for multiplicity.
Statistical Test of Hypothesis P-Value 0.070
Comments [Not Specified]
Method Stratified log-rank test
Comments Stratified by the randomization stratification factors (geographic region, histology, screening hemoglobin)
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.047
Comments [Not Specified]
Method Log Rank
Comments Unstratified log rank test
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments To evaluate the potential effect of cross-in (participants in the placebo group who began treatment with an erythropoiesis-stimulating agent (ESA) at any point after randomization), a sensitivity analysis was conducted that included ESA use as a time-dependent covariate in a Cox regression model stratified by the randomization stratification factors (geographic region, histology, and screening hemoglobin).
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.93
Confidence Interval (2-Sided) 95%
0.84 to 1.02
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Progression-free Survival (PFS)
Hide Description Progression-free survival was defined as the time from randomization to the date of radiographic disease progression or death from any cause, whichever event occurred first. Participants without either event were censored on the date of their last disease assessment. Disease progression was based on the investigator’s assessment of scans using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 or 1.1 depending on the timing of enrollment.
Time Frame From randomization until disease progression or death; maximum time on follow-up was 87.23 months.
Hide Outcome Measure Data
Hide Analysis Population Description
The radiographic endpoint primary analysis set includes all participants in the primary analysis set who did not have disease progression prior to randomization.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Participants received placebo once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Participants received darbepoetin alfa 500 µg once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Overall Number of Participants Analyzed 819 1638
Median (95% Confidence Interval)
Unit of Measure: months
4.340
(4.170 to 4.700)
4.800
(4.370 to 5.320)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments The primary analysis of PFS used a Cox Proportional Hazard Model stratified by the randomization stratification factors (geographic region, histology, and screening hemoglobin), with treatment group as the only covariate.
Type of Statistical Test Non-Inferiority
Comments If non-inferiority was declared for OS, non-inferiority would be declared for PFS if the upper confidence limit for the hazard ratio was less than 1.15 using a 1-sided significance level of 0.025.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.95
Confidence Interval (2-Sided) 95%
0.87 to 1.04
Estimation Comments A hazard ratio < 1.0 indicates a lower risk of death or progression for darbepoetin alfa relative to placebo.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments As a sensitivity analysis, an unstratified Cox Proportional Hazard Model with treatment group as the only covariate was conducted.
Type of Statistical Test Non-Inferiority
Comments If non-inferiority was declared for OS, non-inferiority would be declared for PFS if the upper confidence limit for the hazard ratio was less than 1.15 using a 1-sided significance level of 0.025.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.95
Confidence Interval (2-Sided) 95%
0.87 to 1.04
Estimation Comments A hazard ratio < 1.0 indicates a lower risk of death or progression for darbepoetin alfa relative to placebo.
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority
Comments If non-inferiority was demonstrated for both OS and PFS and superiority was demonstrated for the transfusion endpoint, superiority was then tested for both OS and PFS using the Hochberg procedure to adjust for multiplicity.
Statistical Test of Hypothesis P-Value 0.31
Comments [Not Specified]
Method Stratified log-rank test
Comments Stratified by the randomization stratification factors (geographic region, histology, screening hemoglobin).
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.27
Comments [Not Specified]
Method Log Rank
Comments Unstratified log rank test
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments To evaluate the potential effect of cross-in (participants in the placebo group who began treatment with an erythropoiesis-stimulating agent (ESA) at any point after randomization), a sensitivity analysis was conducted that included ESA use as a time-dependent covariate in a Cox regression model stratified by the randomization stratification factors (geographic region, histology, and screening hemoglobin).
Type of Statistical Test Other
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.96
Confidence Interval (2-Sided) 95%
0.88 to 1.05
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Participants With a Red Blood Cell Transfusion or Hemoglobin ≤ 8.0 g/dL From Week 5 to End of the Efficacy Treatment Period
Hide Description Any red blood cell (RBC) transfusion (packed RBCs or whole blood) given or a hemoglobin ≤ 8.0 g/dL on or after study day 29 until the EOETP, inclusive.
Time Frame Week 5 (day 29) to end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later); median (range) duration of dosing was 10 (1 to 106) weeks in both groups.
Hide Outcome Measure Data
Hide Analysis Population Description
Primary analysis set participants who were on study as of day 29
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Participants received placebo once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Participants received darbepoetin alfa 500 µg once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Overall Number of Participants Analyzed 764 1517
Measure Type: Number
Unit of Measure: percentage of participants
29.2 22.5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments The primary analysis of the incidence of a transfusion or hemoglobin ≤ 8.0 g/dL from day 29 to EOETP was based on the Cochran-Mantel-Haenszel method to test for treatment group differences while adjusting for the randomization stratification factors (geographic region, histology, and screening hemoglobin).
Type of Statistical Test Superiority
Comments If non-inferiority was declared for OS and PFS, superiority would be declared for the transfusion endpoint if the p-value from a two-sided test of significance using the Cochran-Mantel-Haenszel method was less than 0.05 in favor of the darbepoetin alfa group.
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.704
Confidence Interval (2-Sided) 95%
0.573 to 0.864
Estimation Comments An odds ratio < 1.0 indicates a lower event rate for darbepoetin alfa relative to placebo.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo
Comments As a sensitivity analysis a logistic regression analysis was conducted, stratified by the randomization stratification factors (geographic region, histology, screening hemoglobin).
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.001
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.705
Confidence Interval (2-Sided) 95%
0.574 to 0.866
Estimation Comments An odds ratio < 1.0 indicates a lower event rate for darbepoetin alfa relative to placebo.
4.Secondary Outcome
Title Number of Participants With Adverse Events of Special Interest
Hide Description Adverse events of interest for darbepoetin alfa, based on clinical data in anemic patients with cancer to date, included the following categories: antibody-mediated pure red cell aplasia (PRCA), cardiac failure, central nervous system vascular disorders, convulsions, embolic and thrombotic events, hypersensitivity, hypertension, ischemic heart disease, malignancies, and severe cutaneous adverse reactions. Lack of efficacy and medication errors were also evaluated.
Time Frame From first dose of study drug until 30 days after last dose; the median (range) duration of treatment was 10 (1 to 106) weeks in both groups.
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized and consented participants who received at least 1 dose of study drug. Four participants in the placebo group received at least 1 dose of darbepoetin alfa during the study and were included in the darbepoetin alfa group for safety analyses.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Participants received placebo once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Participants received darbepoetin alfa 500 µg once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Overall Number of Participants Analyzed 833 1685
Measure Type: Count of Participants
Unit of Measure: Participants
Any adverse events of interest
157
  18.8%
369
  21.9%
Antibody-mediated pure red cell aplasia
20
   2.4%
51
   3.0%
Cardiac failure
7
   0.8%
12
   0.7%
Central nervous system vascular disorders
8
   1.0%
25
   1.5%
Convulsions
8
   1.0%
9
   0.5%
Embolic and thrombotic events
34
   4.1%
89
   5.3%
Embolic and thrombotic events, arterial
6
   0.7%
19
   1.1%
Embolic and thrombotic events, venous
23
   2.8%
51
   3.0%
Embolic and thrombotic events, unspecified/mixed
10
   1.2%
26
   1.5%
Hypersensitivity
75
   9.0%
178
  10.6%
Hypertension
26
   3.1%
41
   2.4%
Ischaemic heart disease
9
   1.1%
23
   1.4%
Lack of efficacy/effect
0
   0.0%
0
   0.0%
Malignancies
16
   1.9%
38
   2.3%
Medication errors
0
   0.0%
1
   0.1%
Severe cutaneous adverse reactions
11
   1.3%
35
   2.1%
5.Secondary Outcome
Title Percentage of Participants With an Objective Tumor Response
Hide Description Objective response was defined as the incidence of a complete or partial response at any time during the study. Response was determined by the investigator’s assessment of the scans using RECIST version 1.0 or 1.1 depending on the timing of enrollment.
Time Frame Day 1 to end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later); median (range) duration of dosing was 10 (1 to 106) weeks in both groups.
Hide Outcome Measure Data
Hide Analysis Population Description
The radiographic endpoint primary analysis set includes all participants in the primary analysis set who did not have disease progression prior to randomization.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Participants received placebo once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Participants received darbepoetin alfa 500 µg once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Overall Number of Participants Analyzed 819 1638
Measure Type: Number
Unit of Measure: percentage of participants
32.6 36.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.076
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel method adjusted for the randomization stratification factors (geographic region, histology, screening hemoglobin).
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.173
Confidence Interval (2-Sided) 95%
0.983 to 1.401
Estimation Comments An odds ratio < 1.0 indicates a lower event rate for darbepoetin alfa relative to placebo.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.078
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Unstratified analysis
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.173
Confidence Interval (2-Sided) 95%
0.982 to 1.401
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Number of Participants Who Developed Neutralizing Antibodies to Darbepoetin Alfa
Hide Description Developing antibody incidence was defined as neutralizing antibody positive postbaseline with a negative or no result at baseline.
Time Frame Baseline and end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later. the median (range) duration of treatment was 10 (1 to 106) weeks in both groups.
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized and consented participants who received at least one dose of study drug and with a postbaseline result.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Participants received placebo once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Participants received darbepoetin alfa 500 µg once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Overall Number of Participants Analyzed 803 1606
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
7.Secondary Outcome
Title Percentage of Participants With a Red Blood Cell Transfusion or Hemoglobin ≤ 8.0 g/dL From Week 1 to End of the Efficacy Treatment Period
Hide Description Any red blood cell (RBC) transfusion (packed RBCs or whole blood) given or a hemoglobin ≤ 8.0 g/dL on or after study day 1 until the EOETP, inclusive.
Time Frame Week 1 to end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later); the median (range) duration of treatment was 10 (1 to 106) weeks in both groups.
Hide Outcome Measure Data
Hide Analysis Population Description
Primary analysis set
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Participants received placebo once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Participants received darbepoetin alfa 500 µg once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Overall Number of Participants Analyzed 836 1680
Measure Type: Number
Unit of Measure: percentage of participants
29.7 24.2
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Cochran-Mantel-Haenszel method adjusted for the randomization stratification factors (geographic region, histology, screening hemoglobin).
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.741
Confidence Interval (2-Sided) 95%
0.610 to 0.901
Estimation Comments An odds ratio < 1.0 indicates a lower event rate for darbepoetin alfa relative to placebo.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Darbepoetin Alfa
Comments [Not Specified]
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Unstratified analysis
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.758
Confidence Interval (2-Sided) 95%
0.630 to 0.913
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Change From Baseline in Hemoglobin to End of Efficacy Treatment Period
Hide Description Post-baseline hemoglobin values within 28 days after a RBC transfusion were not be used in the calculation of change.
Time Frame Baseline and end of the efficacy treatment period (EOETP; defined as 21 days after either the last dose of study drug or the last dose of chemotherapy, whichever was later); the median (range) duration of treatment was 10 (1 to 106) weeks in both groups.
Hide Outcome Measure Data
Hide Analysis Population Description
Primary analysis set with available baseline and at least 1 postbaseline value; if the EOETP value was missing, the last available postbaseline value was used.
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description:
Participants received placebo once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Participants received darbepoetin alfa 500 µg once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
Overall Number of Participants Analyzed 633 1344
Mean (Standard Deviation)
Unit of Measure: g/dL
-0.11  (1.71) 0.50  (1.81)
Time Frame From first dose of study drug until 30 days after last dose; the median (range) duration of treatment was 10 (1 to 106) weeks in both groups.
Adverse Event Reporting Description

The safety population included all randomized and consented participants who received at least 1 dose of study drug. Four participants in the placebo group received at least 1 dose of darbepoetin alfa during the study and were included in the darbepoetin alfa group for safety analyses.

Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.

 
Arm/Group Title Placebo Darbepoetin Alfa
Hide Arm/Group Description Participants received placebo once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first. Participants received darbepoetin alfa 500 µg once every 3 weeks (Q3W) administered subcutaneously until 3 weeks after the completion of chemotherapy or upon determination of disease progression, whichever occurred first.
All-Cause Mortality
Placebo Darbepoetin Alfa
Affected / at Risk (%) Affected / at Risk (%)
Total   657/833 (78.87%)   1273/1685 (75.55%) 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Darbepoetin Alfa
Affected / at Risk (%) Affected / at Risk (%)
Total   259/833 (31.09%)   524/1685 (31.10%) 
Blood and lymphatic system disorders     
Anaemia  1  46/833 (5.52%)  57/1685 (3.38%) 
Bicytopenia  1  0/833 (0.00%)  1/1685 (0.06%) 
Bone marrow failure  1  8/833 (0.96%)  20/1685 (1.19%) 
Disseminated intravascular coagulation  1  1/833 (0.12%)  0/1685 (0.00%) 
Febrile neutropenia  1  7/833 (0.84%)  14/1685 (0.83%) 
Haemolytic anaemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Haemorrhagic anaemia  1  1/833 (0.12%)  0/1685 (0.00%) 
Leukocytosis  1  0/833 (0.00%)  1/1685 (0.06%) 
Leukopenia  1  2/833 (0.24%)  7/1685 (0.42%) 
Neutropenia  1  6/833 (0.72%)  17/1685 (1.01%) 
Pancytopenia  1  4/833 (0.48%)  9/1685 (0.53%) 
Sideroblastic anaemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Thrombocytopenia  1  16/833 (1.92%)  28/1685 (1.66%) 
Thrombocytosis  1  0/833 (0.00%)  1/1685 (0.06%) 
Cardiac disorders     
Acute coronary syndrome  1  1/833 (0.12%)  3/1685 (0.18%) 
Acute myocardial infarction  1  3/833 (0.36%)  5/1685 (0.30%) 
Angina pectoris  1  1/833 (0.12%)  1/1685 (0.06%) 
Arrhythmia  1  0/833 (0.00%)  2/1685 (0.12%) 
Atrial fibrillation  1  3/833 (0.36%)  8/1685 (0.47%) 
Atrioventricular block complete  1  1/833 (0.12%)  0/1685 (0.00%) 
Cardiac arrest  1  2/833 (0.24%)  7/1685 (0.42%) 
Cardiac failure  1  0/833 (0.00%)  1/1685 (0.06%) 
Cardiac failure acute  1  0/833 (0.00%)  1/1685 (0.06%) 
Cardiac failure congestive  1  2/833 (0.24%)  1/1685 (0.06%) 
Cardiac tamponade  1  1/833 (0.12%)  1/1685 (0.06%) 
Cardio-respiratory arrest  1  7/833 (0.84%)  9/1685 (0.53%) 
Cardio-respiratory distress  1  1/833 (0.12%)  1/1685 (0.06%) 
Cardiogenic shock  1  1/833 (0.12%)  1/1685 (0.06%) 
Cardiopulmonary failure  1  2/833 (0.24%)  2/1685 (0.12%) 
Cardiovascular insufficiency  1  1/833 (0.12%)  0/1685 (0.00%) 
Left ventricular dysfunction  1  0/833 (0.00%)  1/1685 (0.06%) 
Myocardial infarction  1  1/833 (0.12%)  5/1685 (0.30%) 
Myocardial ischaemia  1  0/833 (0.00%)  2/1685 (0.12%) 
Nodal arrhythmia  1  0/833 (0.00%)  1/1685 (0.06%) 
Pericardial effusion  1  1/833 (0.12%)  2/1685 (0.12%) 
Sinus node dysfunction  1  0/833 (0.00%)  1/1685 (0.06%) 
Sinus tachycardia  1  0/833 (0.00%)  1/1685 (0.06%) 
Ventricular fibrillation  1  0/833 (0.00%)  1/1685 (0.06%) 
Ear and labyrinth disorders     
Vertigo  1  1/833 (0.12%)  1/1685 (0.06%) 
Endocrine disorders     
Adrenal insufficiency  1  0/833 (0.00%)  1/1685 (0.06%) 
Toxic nodular goitre  1  0/833 (0.00%)  1/1685 (0.06%) 
Eye disorders     
Angle closure glaucoma  1  0/833 (0.00%)  1/1685 (0.06%) 
Retinal detachment  1  0/833 (0.00%)  1/1685 (0.06%) 
Gastrointestinal disorders     
Abdominal distension  1  0/833 (0.00%)  2/1685 (0.12%) 
Abdominal pain  1  0/833 (0.00%)  12/1685 (0.71%) 
Abdominal pain upper  1  0/833 (0.00%)  2/1685 (0.12%) 
Constipation  1  0/833 (0.00%)  4/1685 (0.24%) 
Diarrhoea  1  8/833 (0.96%)  12/1685 (0.71%) 
Duodenal ulcer haemorrhage  1  0/833 (0.00%)  1/1685 (0.06%) 
Dysphagia  1  1/833 (0.12%)  1/1685 (0.06%) 
Enterocolitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Faecaloma  1  0/833 (0.00%)  1/1685 (0.06%) 
Faeces discoloured  1  0/833 (0.00%)  1/1685 (0.06%) 
Gastric ulcer haemorrhage  1  1/833 (0.12%)  0/1685 (0.00%) 
Gastrointestinal haemorrhage  1  0/833 (0.00%)  2/1685 (0.12%) 
Gastrointestinal motility disorder  1  0/833 (0.00%)  1/1685 (0.06%) 
Haematemesis  1  1/833 (0.12%)  1/1685 (0.06%) 
Ileus  1  1/833 (0.12%)  0/1685 (0.00%) 
Incarcerated inguinal hernia  1  1/833 (0.12%)  0/1685 (0.00%) 
Intestinal haemorrhage  1  1/833 (0.12%)  0/1685 (0.00%) 
Intestinal obstruction  1  1/833 (0.12%)  0/1685 (0.00%) 
Large intestine perforation  1  0/833 (0.00%)  2/1685 (0.12%) 
Melaena  1  1/833 (0.12%)  1/1685 (0.06%) 
Nausea  1  2/833 (0.24%)  3/1685 (0.18%) 
Necrotising colitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Neutropenic colitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Oesophageal ulcer  1  0/833 (0.00%)  1/1685 (0.06%) 
Peritoneal haemorrhage  1  1/833 (0.12%)  0/1685 (0.00%) 
Small intestinal perforation  1  0/833 (0.00%)  1/1685 (0.06%) 
Upper gastrointestinal haemorrhage  1  1/833 (0.12%)  2/1685 (0.12%) 
Vomiting  1  2/833 (0.24%)  9/1685 (0.53%) 
General disorders     
Asthenia  1  7/833 (0.84%)  11/1685 (0.65%) 
Chest pain  1  2/833 (0.24%)  5/1685 (0.30%) 
Chills  1  0/833 (0.00%)  1/1685 (0.06%) 
Death  1  9/833 (1.08%)  12/1685 (0.71%) 
Disease progression  1  1/833 (0.12%)  1/1685 (0.06%) 
Fatigue  1  2/833 (0.24%)  2/1685 (0.12%) 
General physical health deterioration  1  2/833 (0.24%)  3/1685 (0.18%) 
Inflammation  1  0/833 (0.00%)  1/1685 (0.06%) 
Malaise  1  1/833 (0.12%)  2/1685 (0.12%) 
Multiple organ dysfunction syndrome  1  4/833 (0.48%)  7/1685 (0.42%) 
Non-cardiac chest pain  1  0/833 (0.00%)  5/1685 (0.30%) 
Organ failure  1  0/833 (0.00%)  1/1685 (0.06%) 
Pain  1  1/833 (0.12%)  4/1685 (0.24%) 
Performance status decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Pyrexia  1  3/833 (0.36%)  15/1685 (0.89%) 
Sudden cardiac death  1  1/833 (0.12%)  2/1685 (0.12%) 
Sudden death  1  8/833 (0.96%)  12/1685 (0.71%) 
Swelling  1  0/833 (0.00%)  1/1685 (0.06%) 
Systemic inflammatory response syndrome  1  0/833 (0.00%)  1/1685 (0.06%) 
Hepatobiliary disorders     
Cholangitis  1  1/833 (0.12%)  0/1685 (0.00%) 
Cholecystitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Hepatic failure  1  1/833 (0.12%)  0/1685 (0.00%) 
Hyperbilirubinaemia  1  1/833 (0.12%)  0/1685 (0.00%) 
Immune system disorders     
Anaphylactic reaction  1  1/833 (0.12%)  0/1685 (0.00%) 
Hypersensitivity  1  0/833 (0.00%)  1/1685 (0.06%) 
Transfusion associated graft versus host disease  1  0/833 (0.00%)  1/1685 (0.06%) 
Infections and infestations     
Abdominal abscess  1  1/833 (0.12%)  0/1685 (0.00%) 
Abscess  1  1/833 (0.12%)  0/1685 (0.00%) 
Appendicitis  1  1/833 (0.12%)  0/1685 (0.00%) 
Bacteraemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Bacterial sepsis  1  0/833 (0.00%)  1/1685 (0.06%) 
Bronchitis  1  3/833 (0.36%)  2/1685 (0.12%) 
Cellulitis  1  1/833 (0.12%)  3/1685 (0.18%) 
Clostridium difficile colitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Cystitis  1  1/833 (0.12%)  0/1685 (0.00%) 
Dengue fever  1  0/833 (0.00%)  1/1685 (0.06%) 
Device related infection  1  1/833 (0.12%)  1/1685 (0.06%) 
Empyema  1  1/833 (0.12%)  2/1685 (0.12%) 
Endometritis  1  0/833 (0.00%)  1/1685 (0.06%) 
Erysipelas  1  1/833 (0.12%)  0/1685 (0.00%) 
Furuncle  1  0/833 (0.00%)  1/1685 (0.06%) 
Gangrene  1  2/833 (0.24%)  2/1685 (0.12%) 
Gastroenteritis  1  2/833 (0.24%)  7/1685 (0.42%) 
Gastroenteritis viral  1  0/833 (0.00%)  1/1685 (0.06%) 
Hepatitis B  1  0/833 (0.00%)  1/1685 (0.06%) 
Infection  1  1/833 (0.12%)  0/1685 (0.00%) 
Localised infection  1  0/833 (0.00%)  2/1685 (0.12%) 
Lower respiratory tract infection  1  0/833 (0.00%)  4/1685 (0.24%) 
Lung abscess  1  0/833 (0.00%)  1/1685 (0.06%) 
Lung infection  1  7/833 (0.84%)  13/1685 (0.77%) 
Neutropenic sepsis  1  1/833 (0.12%)  1/1685 (0.06%) 
Osteomyelitis  1  1/833 (0.12%)  0/1685 (0.00%) 
Pneumonia  1  20/833 (2.40%)  44/1685 (2.61%) 
Pneumonia bacterial  1  1/833 (0.12%)  6/1685 (0.36%) 
Respiratory tract infection  1  4/833 (0.48%)  6/1685 (0.36%) 
Sepsis  1  9/833 (1.08%)  15/1685 (0.89%) 
Septic encephalopathy  1  0/833 (0.00%)  1/1685 (0.06%) 
Septic shock  1  1/833 (0.12%)  3/1685 (0.18%) 
Staphylococcal infection  1  1/833 (0.12%)  0/1685 (0.00%) 
Superinfection viral  1  1/833 (0.12%)  0/1685 (0.00%) 
Tracheitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Upper respiratory tract infection  1  2/833 (0.24%)  1/1685 (0.06%) 
Urinary tract infection  1  4/833 (0.48%)  6/1685 (0.36%) 
Urinary tract infection bacterial  1  2/833 (0.24%)  1/1685 (0.06%) 
Injury, poisoning and procedural complications     
Fall  1  2/833 (0.24%)  0/1685 (0.00%) 
Femoral neck fracture  1  0/833 (0.00%)  1/1685 (0.06%) 
Femur fracture  1  1/833 (0.12%)  1/1685 (0.06%) 
Fracture  1  0/833 (0.00%)  1/1685 (0.06%) 
Infusion related reaction  1  1/833 (0.12%)  0/1685 (0.00%) 
Injury  1  1/833 (0.12%)  1/1685 (0.06%) 
Laceration  1  1/833 (0.12%)  0/1685 (0.00%) 
Lower limb fracture  1  0/833 (0.00%)  1/1685 (0.06%) 
Lumbar vertebral fracture  1  0/833 (0.00%)  1/1685 (0.06%) 
Nerve root injury lumbar  1  0/833 (0.00%)  1/1685 (0.06%) 
Poisoning  1  2/833 (0.24%)  0/1685 (0.00%) 
Procedural pneumothorax  1  0/833 (0.00%)  1/1685 (0.06%) 
Radiation dysphagia  1  1/833 (0.12%)  0/1685 (0.00%) 
Radiation pneumonitis  1  0/833 (0.00%)  2/1685 (0.12%) 
Spinal compression fracture  1  0/833 (0.00%)  1/1685 (0.06%) 
Subdural haematoma  1  1/833 (0.12%)  0/1685 (0.00%) 
Toxicity to various agents  1  0/833 (0.00%)  1/1685 (0.06%) 
Investigations     
Alanine aminotransferase increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Aspartate aminotransferase increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Blood albumin abnormal  1  0/833 (0.00%)  1/1685 (0.06%) 
Blood bilirubin increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Blood lactate dehydrogenase increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Blood pressure increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Eastern Cooperative Oncology Group performance status worsened  1  0/833 (0.00%)  1/1685 (0.06%) 
Ejection fraction decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Haemoglobin abnormal  1  0/833 (0.00%)  1/1685 (0.06%) 
Haemoglobin decreased  1  1/833 (0.12%)  2/1685 (0.12%) 
Liver function test abnormal  1  0/833 (0.00%)  2/1685 (0.12%) 
Neutrophil count decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Oxygen saturation decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Platelet count decreased  1  6/833 (0.72%)  6/1685 (0.36%) 
Salmonella test positive  1  0/833 (0.00%)  1/1685 (0.06%) 
Transaminases increased  1  0/833 (0.00%)  1/1685 (0.06%) 
White blood cell count decreased  1  1/833 (0.12%)  2/1685 (0.12%) 
White blood cell count increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Metabolism and nutrition disorders     
Acidosis  1  1/833 (0.12%)  0/1685 (0.00%) 
Cachexia  1  1/833 (0.12%)  0/1685 (0.00%) 
Decreased appetite  1  1/833 (0.12%)  7/1685 (0.42%) 
Dehydration  1  5/833 (0.60%)  6/1685 (0.36%) 
Diabetes mellitus inadequate control  1  1/833 (0.12%)  0/1685 (0.00%) 
Electrolyte imbalance  1  2/833 (0.24%)  2/1685 (0.12%) 
Failure to thrive  1  1/833 (0.12%)  0/1685 (0.00%) 
Hypercalcaemia  1  4/833 (0.48%)  1/1685 (0.06%) 
Hyperkalaemia  1  1/833 (0.12%)  1/1685 (0.06%) 
Hyperuricaemia  1  1/833 (0.12%)  0/1685 (0.00%) 
Hypocalcaemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Hypoglycaemia  1  0/833 (0.00%)  5/1685 (0.30%) 
Hypokalaemia  1  0/833 (0.00%)  2/1685 (0.12%) 
Hypomagnesaemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Hyponatraemia  1  3/833 (0.36%)  2/1685 (0.12%) 
Hypophagia  1  0/833 (0.00%)  1/1685 (0.06%) 
Hypoproteinaemia  1  1/833 (0.12%)  1/1685 (0.06%) 
Hypovolaemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  0/833 (0.00%)  1/1685 (0.06%) 
Back pain  1  3/833 (0.36%)  3/1685 (0.18%) 
Bone pain  1  1/833 (0.12%)  1/1685 (0.06%) 
Groin pain  1  0/833 (0.00%)  1/1685 (0.06%) 
Intervertebral disc protrusion  1  0/833 (0.00%)  1/1685 (0.06%) 
Muscular weakness  1  1/833 (0.12%)  0/1685 (0.00%) 
Musculoskeletal chest pain  1  1/833 (0.12%)  0/1685 (0.00%) 
Musculoskeletal pain  1  1/833 (0.12%)  0/1685 (0.00%) 
Myalgia  1  1/833 (0.12%)  0/1685 (0.00%) 
Neck pain  1  0/833 (0.00%)  1/1685 (0.06%) 
Osteonecrosis of jaw  1  0/833 (0.00%)  1/1685 (0.06%) 
Pain in extremity  1  4/833 (0.48%)  2/1685 (0.12%) 
Pathological fracture  1  1/833 (0.12%)  1/1685 (0.06%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Cancer pain  1  0/833 (0.00%)  2/1685 (0.12%) 
Lung adenocarcinoma stage IV  1  1/833 (0.12%)  0/1685 (0.00%) 
Lung cancer metastatic  1  0/833 (0.00%)  1/1685 (0.06%) 
Lung neoplasm malignant  1  1/833 (0.12%)  1/1685 (0.06%) 
Malignant pleural effusion  1  1/833 (0.12%)  2/1685 (0.12%) 
Metastases to adrenals  1  0/833 (0.00%)  1/1685 (0.06%) 
Metastases to bone  1  1/833 (0.12%)  0/1685 (0.00%) 
Metastases to central nervous system  1  1/833 (0.12%)  1/1685 (0.06%) 
Non-small cell lung cancer  1  0/833 (0.00%)  3/1685 (0.18%) 
Tumour associated fever  1  1/833 (0.12%)  0/1685 (0.00%) 
Tumour haemorrhage  1  0/833 (0.00%)  1/1685 (0.06%) 
Tumour pain  1  0/833 (0.00%)  1/1685 (0.06%) 
Nervous system disorders     
Cerebellar infarction  1  1/833 (0.12%)  0/1685 (0.00%) 
Cerebral haemorrhage  1  0/833 (0.00%)  1/1685 (0.06%) 
Cerebral infarction  1  0/833 (0.00%)  4/1685 (0.24%) 
Cerebral ischaemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Cerebrovascular accident  1  1/833 (0.12%)  4/1685 (0.24%) 
Cognitive disorder  1  0/833 (0.00%)  1/1685 (0.06%) 
Coma  1  1/833 (0.12%)  0/1685 (0.00%) 
Dementia  1  1/833 (0.12%)  0/1685 (0.00%) 
Depressed level of consciousness  1  0/833 (0.00%)  1/1685 (0.06%) 
Diabetic neuropathy  1  1/833 (0.12%)  0/1685 (0.00%) 
Dizziness  1  1/833 (0.12%)  0/1685 (0.00%) 
Encephalopathy  1  2/833 (0.24%)  1/1685 (0.06%) 
Epilepsy  1  2/833 (0.24%)  1/1685 (0.06%) 
Facial nerve disorder  1  0/833 (0.00%)  1/1685 (0.06%) 
Haemorrhage intracranial  1  0/833 (0.00%)  1/1685 (0.06%) 
Headache  1  1/833 (0.12%)  2/1685 (0.12%) 
Hemiparesis  1  0/833 (0.00%)  1/1685 (0.06%) 
Hemiplegia  1  0/833 (0.00%)  2/1685 (0.12%) 
Hydrocephalus  1  1/833 (0.12%)  1/1685 (0.06%) 
Hypoaesthesia  1  0/833 (0.00%)  1/1685 (0.06%) 
Ischaemic stroke  1  0/833 (0.00%)  1/1685 (0.06%) 
Lethargy  1  0/833 (0.00%)  2/1685 (0.12%) 
Loss of consciousness  1  0/833 (0.00%)  1/1685 (0.06%) 
Paraesthesia  1  0/833 (0.00%)  1/1685 (0.06%) 
Paraplegia  1  1/833 (0.12%)  1/1685 (0.06%) 
Partial seizures  1  0/833 (0.00%)  1/1685 (0.06%) 
Peripheral sensory neuropathy  1  1/833 (0.12%)  0/1685 (0.00%) 
Presyncope  1  1/833 (0.12%)  0/1685 (0.00%) 
Seizure  1  2/833 (0.24%)  4/1685 (0.24%) 
Somnolence  1  1/833 (0.12%)  0/1685 (0.00%) 
Stroke in evolution  1  0/833 (0.00%)  1/1685 (0.06%) 
Syncope  1  1/833 (0.12%)  1/1685 (0.06%) 
Thrombotic cerebral infarction  1  1/833 (0.12%)  1/1685 (0.06%) 
Thrombotic stroke  1  1/833 (0.12%)  0/1685 (0.00%) 
Transient ischaemic attack  1  0/833 (0.00%)  4/1685 (0.24%) 
Unresponsive to stimuli  1  0/833 (0.00%)  1/1685 (0.06%) 
Psychiatric disorders     
Anxiety  1  1/833 (0.12%)  0/1685 (0.00%) 
Completed suicide  1  1/833 (0.12%)  0/1685 (0.00%) 
Confusional state  1  0/833 (0.00%)  1/1685 (0.06%) 
Delirium  1  0/833 (0.00%)  1/1685 (0.06%) 
Depression  1  1/833 (0.12%)  0/1685 (0.00%) 
Disorientation  1  0/833 (0.00%)  2/1685 (0.12%) 
Mental status changes  1  1/833 (0.12%)  1/1685 (0.06%) 
Psychotic disorder  1  0/833 (0.00%)  2/1685 (0.12%) 
Renal and urinary disorders     
Acute kidney injury  1  4/833 (0.48%)  12/1685 (0.71%) 
Azotaemia  1  1/833 (0.12%)  0/1685 (0.00%) 
Chronic kidney disease  1  0/833 (0.00%)  1/1685 (0.06%) 
Haematuria  1  0/833 (0.00%)  2/1685 (0.12%) 
Obstructive uropathy  1  1/833 (0.12%)  0/1685 (0.00%) 
Renal failure  1  2/833 (0.24%)  5/1685 (0.30%) 
Urinary retention  1  0/833 (0.00%)  2/1685 (0.12%) 
Vesical fistula  1  0/833 (0.00%)  1/1685 (0.06%) 
Reproductive system and breast disorders     
Pelvic pain  1  0/833 (0.00%)  1/1685 (0.06%) 
Respiratory, thoracic and mediastinal disorders     
Acute pulmonary oedema  1  0/833 (0.00%)  2/1685 (0.12%) 
Acute respiratory distress syndrome  1  1/833 (0.12%)  1/1685 (0.06%) 
Acute respiratory failure  1  2/833 (0.24%)  9/1685 (0.53%) 
Aspiration  1  0/833 (0.00%)  2/1685 (0.12%) 
Asthma  1  0/833 (0.00%)  1/1685 (0.06%) 
Bronchial haemorrhage  1  0/833 (0.00%)  2/1685 (0.12%) 
Bronchitis chronic  1  0/833 (0.00%)  1/1685 (0.06%) 
Chronic obstructive pulmonary disease  1  1/833 (0.12%)  3/1685 (0.18%) 
Cough  1  1/833 (0.12%)  4/1685 (0.24%) 
Dyspnoea  1  26/833 (3.12%)  31/1685 (1.84%) 
Dyspnoea exertional  1  0/833 (0.00%)  1/1685 (0.06%) 
Emphysema  1  0/833 (0.00%)  1/1685 (0.06%) 
Epistaxis  1  1/833 (0.12%)  1/1685 (0.06%) 
Haemoptysis  1  3/833 (0.36%)  14/1685 (0.83%) 
Hypoxia  1  2/833 (0.24%)  2/1685 (0.12%) 
Lung disorder  1  0/833 (0.00%)  1/1685 (0.06%) 
Oesophagobronchial fistula  1  0/833 (0.00%)  1/1685 (0.06%) 
Painful respiration  1  1/833 (0.12%)  0/1685 (0.00%) 
Pleural effusion  1  12/833 (1.44%)  6/1685 (0.36%) 
Pneumonia aspiration  1  0/833 (0.00%)  4/1685 (0.24%) 
Pneumonitis  1  1/833 (0.12%)  1/1685 (0.06%) 
Pneumothorax  1  2/833 (0.24%)  2/1685 (0.12%) 
Pulmonary artery thrombosis  1  0/833 (0.00%)  1/1685 (0.06%) 
Pulmonary embolism  1  6/833 (0.72%)  20/1685 (1.19%) 
Pulmonary haemorrhage  1  2/833 (0.24%)  5/1685 (0.30%) 
Pulmonary hypertension  1  1/833 (0.12%)  0/1685 (0.00%) 
Respiratory acidosis  1  1/833 (0.12%)  0/1685 (0.00%) 
Respiratory arrest  1  0/833 (0.00%)  1/1685 (0.06%) 
Respiratory depression  1  0/833 (0.00%)  1/1685 (0.06%) 
Respiratory distress  1  1/833 (0.12%)  2/1685 (0.12%) 
Respiratory failure  1  13/833 (1.56%)  24/1685 (1.42%) 
Skin and subcutaneous tissue disorders     
Peau d'orange  1  0/833 (0.00%)  1/1685 (0.06%) 
Surgical and medical procedures     
Lymphadenectomy  1  0/833 (0.00%)  1/1685 (0.06%) 
Thyroidectomy  1  0/833 (0.00%)  1/1685 (0.06%) 
Vascular disorders     
Accelerated hypertension  1  0/833 (0.00%)  1/1685 (0.06%) 
Deep vein thrombosis  1  3/833 (0.36%)  11/1685 (0.65%) 
Extremity necrosis  1  0/833 (0.00%)  1/1685 (0.06%) 
Hypertension  1  0/833 (0.00%)  3/1685 (0.18%) 
Hypotension  1  6/833 (0.72%)  3/1685 (0.18%) 
Hypovolaemic shock  1  1/833 (0.12%)  1/1685 (0.06%) 
Peripheral artery stenosis  1  0/833 (0.00%)  1/1685 (0.06%) 
Peripheral artery thrombosis  1  1/833 (0.12%)  1/1685 (0.06%) 
Peripheral embolism  1  1/833 (0.12%)  0/1685 (0.00%) 
Peripheral ischaemia  1  0/833 (0.00%)  2/1685 (0.12%) 
Superior vena cava occlusion  1  1/833 (0.12%)  0/1685 (0.00%) 
Superior vena cava syndrome  1  0/833 (0.00%)  1/1685 (0.06%) 
Thrombosis  1  0/833 (0.00%)  1/1685 (0.06%) 
Varicose ulceration  1  0/833 (0.00%)  1/1685 (0.06%) 
Vascular occlusion  1  0/833 (0.00%)  1/1685 (0.06%) 
Venous thrombosis limb  1  0/833 (0.00%)  1/1685 (0.06%) 
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Placebo Darbepoetin Alfa
Affected / at Risk (%) Affected / at Risk (%)
Total   674/833 (80.91%)   1319/1685 (78.28%) 
Blood and lymphatic system disorders     
Agranulocytosis  1  1/833 (0.12%)  0/1685 (0.00%) 
Anaemia  1  244/833 (29.29%)  451/1685 (26.77%) 
Anaemia megaloblastic  1  0/833 (0.00%)  1/1685 (0.06%) 
Autoimmune haemolytic anaemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Bandaemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Bicytopenia  1  0/833 (0.00%)  1/1685 (0.06%) 
Bone marrow failure  1  16/833 (1.92%)  39/1685 (2.31%) 
Disseminated intravascular coagulation  1  1/833 (0.12%)  0/1685 (0.00%) 
Erythropenia  1  2/833 (0.24%)  0/1685 (0.00%) 
Febrile neutropenia  1  1/833 (0.12%)  4/1685 (0.24%) 
Granulocytopenia  1  3/833 (0.36%)  11/1685 (0.65%) 
Haematotoxicity  1  0/833 (0.00%)  1/1685 (0.06%) 
Haemolytic anaemia  1  1/833 (0.12%)  0/1685 (0.00%) 
Hypercoagulation  1  0/833 (0.00%)  1/1685 (0.06%) 
Increased tendency to bruise  1  0/833 (0.00%)  1/1685 (0.06%) 
Iron deficiency anaemia  1  0/833 (0.00%)  4/1685 (0.24%) 
Leukocytosis  1  5/833 (0.60%)  11/1685 (0.65%) 
Leukopenia  1  40/833 (4.80%)  101/1685 (5.99%) 
Lymph node pain  1  0/833 (0.00%)  1/1685 (0.06%) 
Lymphadenitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Lymphadenopathy  1  1/833 (0.12%)  2/1685 (0.12%) 
Lymphopenia  1  1/833 (0.12%)  1/1685 (0.06%) 
Neutropenia  1  79/833 (9.48%)  202/1685 (11.99%) 
Neutrophilia  1  1/833 (0.12%)  1/1685 (0.06%) 
Pancytopenia  1  2/833 (0.24%)  4/1685 (0.24%) 
Platelet disorder  1  2/833 (0.24%)  4/1685 (0.24%) 
Platelet production decreased  1  1/833 (0.12%)  0/1685 (0.00%) 
Thrombocytopenia  1  66/833 (7.92%)  156/1685 (9.26%) 
Thrombocytopenia neonatal  1  0/833 (0.00%)  1/1685 (0.06%) 
Thrombocytosis  1  1/833 (0.12%)  7/1685 (0.42%) 
Cardiac disorders     
Acute coronary syndrome  1  1/833 (0.12%)  1/1685 (0.06%) 
Angina pectoris  1  1/833 (0.12%)  3/1685 (0.18%) 
Angina unstable  1  1/833 (0.12%)  0/1685 (0.00%) 
Arrhythmia  1  2/833 (0.24%)  2/1685 (0.12%) 
Arrhythmia supraventricular  1  0/833 (0.00%)  1/1685 (0.06%) 
Arteriosclerosis coronary artery  1  0/833 (0.00%)  1/1685 (0.06%) 
Atrial fibrillation  1  2/833 (0.24%)  2/1685 (0.12%) 
Atrial tachycardia  1  0/833 (0.00%)  3/1685 (0.18%) 
Cardiac discomfort  1  0/833 (0.00%)  1/1685 (0.06%) 
Cardiac disorder  1  0/833 (0.00%)  1/1685 (0.06%) 
Cardiac failure  1  2/833 (0.24%)  1/1685 (0.06%) 
Cardiac failure congestive  1  0/833 (0.00%)  1/1685 (0.06%) 
Cardiomyopathy  1  0/833 (0.00%)  1/1685 (0.06%) 
Congestive cardiomyopathy  1  0/833 (0.00%)  1/1685 (0.06%) 
Cyanosis  1  0/833 (0.00%)  2/1685 (0.12%) 
Metabolic cardiomyopathy  1  0/833 (0.00%)  2/1685 (0.12%) 
Myocardial infarction  1  0/833 (0.00%)  1/1685 (0.06%) 
Myocardial ischaemia  1  1/833 (0.12%)  1/1685 (0.06%) 
Palpitations  1  2/833 (0.24%)  4/1685 (0.24%) 
Pericardial effusion  1  1/833 (0.12%)  0/1685 (0.00%) 
Pericarditis  1  0/833 (0.00%)  1/1685 (0.06%) 
Sinus arrhythmia  1  1/833 (0.12%)  0/1685 (0.00%) 
Sinus tachycardia  1  1/833 (0.12%)  5/1685 (0.30%) 
Supraventricular extrasystoles  1  2/833 (0.24%)  3/1685 (0.18%) 
Supraventricular tachycardia  1  1/833 (0.12%)  0/1685 (0.00%) 
Tachycardia  1  7/833 (0.84%)  10/1685 (0.59%) 
Congenital, familial and genetic disorders     
Aplasia  1  1/833 (0.12%)  0/1685 (0.00%) 
Ear and labyrinth disorders     
Deafness  1  1/833 (0.12%)  0/1685 (0.00%) 
Ear pain  1  0/833 (0.00%)  1/1685 (0.06%) 
Hypoacusis  1  0/833 (0.00%)  4/1685 (0.24%) 
Otorrhoea  1  1/833 (0.12%)  0/1685 (0.00%) 
Tinnitus  1  4/833 (0.48%)  3/1685 (0.18%) 
Vertigo  1  4/833 (0.48%)  5/1685 (0.30%) 
Endocrine disorders     
Goitre  1  1/833 (0.12%)  0/1685 (0.00%) 
Hypercalcaemia of malignancy  1  0/833 (0.00%)  1/1685 (0.06%) 
Hyperthyroidism  1  1/833 (0.12%)  1/1685 (0.06%) 
Thyroid dysfunction in pregnancy  1  0/833 (0.00%)  1/1685 (0.06%) 
Eye disorders     
Asthenopia  1  1/833 (0.12%)  0/1685 (0.00%) 
Blindness  1  0/833 (0.00%)  1/1685 (0.06%) 
Blindness unilateral  1  0/833 (0.00%)  1/1685 (0.06%) 
Cataract  1  1/833 (0.12%)  1/1685 (0.06%) 
Conjunctival haemorrhage  1  1/833 (0.12%)  1/1685 (0.06%) 
Conjunctival pallor  1  0/833 (0.00%)  1/1685 (0.06%) 
Diplopia  1  1/833 (0.12%)  1/1685 (0.06%) 
Dry eye  1  1/833 (0.12%)  3/1685 (0.18%) 
Eye disorder  1  2/833 (0.24%)  0/1685 (0.00%) 
Eye irritation  1  0/833 (0.00%)  2/1685 (0.12%) 
Eye pain  1  0/833 (0.00%)  3/1685 (0.18%) 
Eyelid margin crusting  1  1/833 (0.12%)  0/1685 (0.00%) 
Eyelid oedema  1  0/833 (0.00%)  3/1685 (0.18%) 
Glaucoma  1  0/833 (0.00%)  1/1685 (0.06%) 
Keratitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Lacrimation increased  1  5/833 (0.60%)  7/1685 (0.42%) 
Ocular hyperaemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Photophobia  1  0/833 (0.00%)  2/1685 (0.12%) 
Pupils unequal  1  1/833 (0.12%)  0/1685 (0.00%) 
Ulcerative keratitis  1  1/833 (0.12%)  0/1685 (0.00%) 
Vision blurred  1  3/833 (0.36%)  3/1685 (0.18%) 
Visual impairment  1  0/833 (0.00%)  1/1685 (0.06%) 
Gastrointestinal disorders     
Abdominal discomfort  1  3/833 (0.36%)  6/1685 (0.36%) 
Abdominal distension  1  8/833 (0.96%)  9/1685 (0.53%) 
Abdominal pain  1  18/833 (2.16%)  50/1685 (2.97%) 
Abdominal pain lower  1  2/833 (0.24%)  5/1685 (0.30%) 
Abdominal pain upper  1  15/833 (1.80%)  17/1685 (1.01%) 
Abdominal tenderness  1  2/833 (0.24%)  0/1685 (0.00%) 
Acute abdomen  1  1/833 (0.12%)  0/1685 (0.00%) 
Anal inflammation  1  1/833 (0.12%)  0/1685 (0.00%) 
Ascites  1  2/833 (0.24%)  2/1685 (0.12%) 
Chronic gastritis  1  0/833 (0.00%)  1/1685 (0.06%) 
Constipation  1  56/833 (6.72%)  106/1685 (6.29%) 
Dental caries  1  0/833 (0.00%)  2/1685 (0.12%) 
Diarrhoea  1  46/833 (5.52%)  106/1685 (6.29%) 
Diverticulum intestinal  1  0/833 (0.00%)  1/1685 (0.06%) 
Dry mouth  1  1/833 (0.12%)  1/1685 (0.06%) 
Duodenitis  1  1/833 (0.12%)  0/1685 (0.00%) 
Dyspepsia  1  5/833 (0.60%)  12/1685 (0.71%) 
Dysphagia  1  5/833 (0.60%)  16/1685 (0.95%) 
Enteritis  1  1/833 (0.12%)  0/1685 (0.00%) 
Epigastric discomfort  1  0/833 (0.00%)  2/1685 (0.12%) 
Faeces hard  1  0/833 (0.00%)  1/1685 (0.06%) 
Flatulence  1  1/833 (0.12%)  3/1685 (0.18%) 
Gastric polyps  1  0/833 (0.00%)  1/1685 (0.06%) 
Gastric ulcer  1  1/833 (0.12%)  2/1685 (0.12%) 
Gastritis  1  5/833 (0.60%)  11/1685 (0.65%) 
Gastrointestinal disorder  1  2/833 (0.24%)  1/1685 (0.06%) 
Gastrointestinal haemorrhage  1  1/833 (0.12%)  0/1685 (0.00%) 
Gastrooesophageal reflux disease  1  2/833 (0.24%)  6/1685 (0.36%) 
Gingival swelling  1  0/833 (0.00%)  3/1685 (0.18%) 
Glossitis  1  1/833 (0.12%)  0/1685 (0.00%) 
Glossodynia  1  1/833 (0.12%)  0/1685 (0.00%) 
Haematemesis  1  0/833 (0.00%)  1/1685 (0.06%) 
Haematochezia  1  2/833 (0.24%)  2/1685 (0.12%) 
Haemorrhoidal haemorrhage  1  2/833 (0.24%)  1/1685 (0.06%) 
Haemorrhoids  1  3/833 (0.36%)  1/1685 (0.06%) 
Hyperchlorhydria  1  0/833 (0.00%)  3/1685 (0.18%) 
Ileus  1  1/833 (0.12%)  0/1685 (0.00%) 
Inguinal hernia  1  0/833 (0.00%)  1/1685 (0.06%) 
Intestinal haemorrhage  1  1/833 (0.12%)  0/1685 (0.00%) 
Irritable bowel syndrome  1  0/833 (0.00%)  1/1685 (0.06%) 
Lip dry  1  0/833 (0.00%)  1/1685 (0.06%) 
Lip swelling  1  0/833 (0.00%)  1/1685 (0.06%) 
Melaena  1  1/833 (0.12%)  0/1685 (0.00%) 
Mouth ulceration  1  3/833 (0.36%)  7/1685 (0.42%) 
Nausea  1  101/833 (12.12%)  187/1685 (11.10%) 
Odynophagia  1  1/833 (0.12%)  5/1685 (0.30%) 
Oesophageal stenosis  1  1/833 (0.12%)  0/1685 (0.00%) 
Oesophagitis  1  2/833 (0.24%)  2/1685 (0.12%) 
Oral disorder  1  0/833 (0.00%)  1/1685 (0.06%) 
Oral pain  1  0/833 (0.00%)  2/1685 (0.12%) 
Rectal haemorrhage  1  1/833 (0.12%)  2/1685 (0.12%) 
Rectal ulcer  1  0/833 (0.00%)  1/1685 (0.06%) 
Regurgitation  1  0/833 (0.00%)  1/1685 (0.06%) 
Retching  1  1/833 (0.12%)  2/1685 (0.12%) 
Small intestinal obstruction  1  0/833 (0.00%)  1/1685 (0.06%) 
Stomatitis  1  6/833 (0.72%)  20/1685 (1.19%) 
Tooth loss  1  0/833 (0.00%)  1/1685 (0.06%) 
Toothache  1  0/833 (0.00%)  3/1685 (0.18%) 
Vomiting  1  57/833 (6.84%)  118/1685 (7.00%) 
General disorders     
Adverse drug reaction  1  0/833 (0.00%)  3/1685 (0.18%) 
Asthenia  1  92/833 (11.04%)  158/1685 (9.38%) 
Axillary pain  1  0/833 (0.00%)  2/1685 (0.12%) 
Catheter site haemorrhage  1  1/833 (0.12%)  0/1685 (0.00%) 
Catheter site pain  1  1/833 (0.12%)  3/1685 (0.18%) 
Chest discomfort  1  2/833 (0.24%)  5/1685 (0.30%) 
Chest pain  1  30/833 (3.60%)  52/1685 (3.09%) 
Chills  1  5/833 (0.60%)  9/1685 (0.53%) 
Complication associated with device  1  1/833 (0.12%)  1/1685 (0.06%) 
Extravasation  1  0/833 (0.00%)  1/1685 (0.06%) 
Face oedema  1  2/833 (0.24%)  5/1685 (0.30%) 
Facial pain  1  1/833 (0.12%)  1/1685 (0.06%) 
Fatigue  1  69/833 (8.28%)  117/1685 (6.94%) 
Feeling abnormal  1  0/833 (0.00%)  1/1685 (0.06%) 
Feeling cold  1  0/833 (0.00%)  1/1685 (0.06%) 
Gait disturbance  1  1/833 (0.12%)  4/1685 (0.24%) 
General physical health deterioration  1  0/833 (0.00%)  2/1685 (0.12%) 
Generalised oedema  1  0/833 (0.00%)  2/1685 (0.12%) 
Gravitational oedema  1  0/833 (0.00%)  1/1685 (0.06%) 
Hyperthermia  1  1/833 (0.12%)  2/1685 (0.12%) 
Implant site pain  1  0/833 (0.00%)  1/1685 (0.06%) 
Inflammation  1  1/833 (0.12%)  3/1685 (0.18%) 
Influenza like illness  1  2/833 (0.24%)  3/1685 (0.18%) 
Infusion site extravasation  1  0/833 (0.00%)  1/1685 (0.06%) 
Injection site haematoma  1  0/833 (0.00%)  1/1685 (0.06%) 
Injection site phlebitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Injection site reaction  1  0/833 (0.00%)  1/1685 (0.06%) 
Local swelling  1  0/833 (0.00%)  3/1685 (0.18%) 
Localised oedema  1  1/833 (0.12%)  2/1685 (0.12%) 
Malaise  1  6/833 (0.72%)  14/1685 (0.83%) 
Mass  1  0/833 (0.00%)  1/1685 (0.06%) 
Mucosal inflammation  1  8/833 (0.96%)  7/1685 (0.42%) 
Mucous membrane disorder  1  0/833 (0.00%)  1/1685 (0.06%) 
Non-cardiac chest pain  1  7/833 (0.84%)  23/1685 (1.36%) 
Oedema  1  7/833 (0.84%)  10/1685 (0.59%) 
Oedema peripheral  1  30/833 (3.60%)  50/1685 (2.97%) 
Pain  1  18/833 (2.16%)  41/1685 (2.43%) 
Performance status decreased  1  1/833 (0.12%)  1/1685 (0.06%) 
Peripheral swelling  1  5/833 (0.60%)  5/1685 (0.30%) 
Pyrexia  1  57/833 (6.84%)  110/1685 (6.53%) 
Temperature intolerance  1  0/833 (0.00%)  3/1685 (0.18%) 
Vessel puncture site pain  1  1/833 (0.12%)  0/1685 (0.00%) 
Vessel puncture site swelling  1  1/833 (0.12%)  0/1685 (0.00%) 
Hepatobiliary disorders     
Cholecystitis  1  1/833 (0.12%)  1/1685 (0.06%) 
Chronic hepatic failure  1  0/833 (0.00%)  3/1685 (0.18%) 
Drug-induced liver injury  1  0/833 (0.00%)  1/1685 (0.06%) 
Gallbladder polyp  1  1/833 (0.12%)  0/1685 (0.00%) 
Hepatic cyst  1  0/833 (0.00%)  2/1685 (0.12%) 
Hepatic failure  1  0/833 (0.00%)  1/1685 (0.06%) 
Hepatic function abnormal  1  4/833 (0.48%)  9/1685 (0.53%) 
Hepatic lesion  1  1/833 (0.12%)  0/1685 (0.00%) 
Hepatic pain  1  1/833 (0.12%)  1/1685 (0.06%) 
Hepatic steatosis  1  1/833 (0.12%)  1/1685 (0.06%) 
Hepatotoxicity  1  0/833 (0.00%)  2/1685 (0.12%) 
Hyperbilirubinaemia  1  2/833 (0.24%)  2/1685 (0.12%) 
Hyperplastic cholecystopathy  1  0/833 (0.00%)  1/1685 (0.06%) 
Liver disorder  1  0/833 (0.00%)  1/1685 (0.06%) 
Liver injury  1  3/833 (0.36%)  4/1685 (0.24%) 
Ocular icterus  1  0/833 (0.00%)  1/1685 (0.06%) 
Immune system disorders     
Anaphylactic reaction  1  0/833 (0.00%)  1/1685 (0.06%) 
Contrast media allergy  1  0/833 (0.00%)  1/1685 (0.06%) 
Drug hypersensitivity  1  5/833 (0.60%)  2/1685 (0.12%) 
Hypersensitivity  1  1/833 (0.12%)  8/1685 (0.47%) 
Immune system disorder  1  1/833 (0.12%)  0/1685 (0.00%) 
Immunodeficiency  1  0/833 (0.00%)  1/1685 (0.06%) 
Iodine allergy  1  0/833 (0.00%)  1/1685 (0.06%) 
Seasonal allergy  1  1/833 (0.12%)  3/1685 (0.18%) 
Infections and infestations     
Abdominal wall infection  1  0/833 (0.00%)  1/1685 (0.06%) 
Alveolar osteitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Amoebiasis  1  1/833 (0.12%)  0/1685 (0.00%) 
Anorectal cellulitis  1  1/833 (0.12%)  0/1685 (0.00%) 
Bacterial infection  1  1/833 (0.12%)  0/1685 (0.00%) 
Balanoposthitis infective  1  1/833 (0.12%)  0/1685 (0.00%) 
Bronchiolitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Bronchitis  1  7/833 (0.84%)  18/1685 (1.07%) 
Bronchitis bacterial  1  1/833 (0.12%)  0/1685 (0.00%) 
Candida infection  1  1/833 (0.12%)  2/1685 (0.12%) 
Catheter site cellulitis  1  1/833 (0.12%)  2/1685 (0.12%) 
Cellulitis  1  2/833 (0.24%)  5/1685 (0.30%) 
Chikungunya virus infection  1  1/833 (0.12%)  0/1685 (0.00%) 
Clostridium difficile colitis  1  1/833 (0.12%)  0/1685 (0.00%) 
Conjunctivitis  1  3/833 (0.36%)  4/1685 (0.24%) 
Cystitis  1  1/833 (0.12%)  2/1685 (0.12%) 
Device related infection  1  0/833 (0.00%)  4/1685 (0.24%) 
Erysipelas  1  0/833 (0.00%)  2/1685 (0.12%) 
Eye infection  1  0/833 (0.00%)  1/1685 (0.06%) 
Febrile infection  1  1/833 (0.12%)  1/1685 (0.06%) 
Folliculitis  1  1/833 (0.12%)  0/1685 (0.00%) 
Fungal infection  1  2/833 (0.24%)  2/1685 (0.12%) 
Fungal skin infection  1  0/833 (0.00%)  1/1685 (0.06%) 
Furuncle  1  1/833 (0.12%)  2/1685 (0.12%) 
Gastroenteritis  1  1/833 (0.12%)  3/1685 (0.18%) 
Gastroenteritis viral  1  0/833 (0.00%)  1/1685 (0.06%) 
Gastrointestinal infection  1  0/833 (0.00%)  1/1685 (0.06%) 
Hepatitis B  1  2/833 (0.24%)  2/1685 (0.12%) 
Herpes dermatitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Herpes simplex  1  0/833 (0.00%)  1/1685 (0.06%) 
Herpes virus infection  1  0/833 (0.00%)  1/1685 (0.06%) 
Herpes zoster  1  3/833 (0.36%)  7/1685 (0.42%) 
Infected bite  1  0/833 (0.00%)  1/1685 (0.06%) 
Infection  1  3/833 (0.36%)  4/1685 (0.24%) 
Influenza  1  5/833 (0.60%)  8/1685 (0.47%) 
Kidney infection  1  1/833 (0.12%)  0/1685 (0.00%) 
Localised infection  1  1/833 (0.12%)  0/1685 (0.00%) 
Lower respiratory tract infection  1  1/833 (0.12%)  6/1685 (0.36%) 
Lung infection  1  6/833 (0.72%)  12/1685 (0.71%) 
Mastoiditis  1  0/833 (0.00%)  2/1685 (0.12%) 
Meningoencephalitis bacterial  1  0/833 (0.00%)  1/1685 (0.06%) 
Mucosal infection  1  0/833 (0.00%)  1/1685 (0.06%) 
Nasopharyngitis  1  1/833 (0.12%)  1/1685 (0.06%) 
Oesophageal candidiasis  1  0/833 (0.00%)  1/1685 (0.06%) 
Onychomycosis  1  0/833 (0.00%)  1/1685 (0.06%) 
Oral candidiasis  1  2/833 (0.24%)  7/1685 (0.42%) 
Oral fungal infection  1  1/833 (0.12%)  1/1685 (0.06%) 
Oral herpes  1  1/833 (0.12%)  3/1685 (0.18%) 
Oral infection  1  0/833 (0.00%)  1/1685 (0.06%) 
Orchitis  1  1/833 (0.12%)  0/1685 (0.00%) 
Oropharyngeal candidiasis  1  0/833 (0.00%)  2/1685 (0.12%) 
Paronychia  1  0/833 (0.00%)  2/1685 (0.12%) 
Penile infection  1  1/833 (0.12%)  0/1685 (0.00%) 
Pharyngitis  1  3/833 (0.36%)  3/1685 (0.18%) 
Pneumonia  1  13/833 (1.56%)  26/1685 (1.54%) 
Pneumonia bacterial  1  1/833 (0.12%)  1/1685 (0.06%) 
Post procedural infection  1  1/833 (0.12%)  0/1685 (0.00%) 
Rash pustular  1  0/833 (0.00%)  1/1685 (0.06%) 
Respiratory tract infection  1  3/833 (0.36%)  9/1685 (0.53%) 
Respiratory tract infection viral  1  5/833 (0.60%)  5/1685 (0.30%) 
Rhinitis  1  2/833 (0.24%)  3/1685 (0.18%) 
Sepsis  1  0/833 (0.00%)  2/1685 (0.12%) 
Sinusitis  1  1/833 (0.12%)  4/1685 (0.24%) 
Skin infection  1  1/833 (0.12%)  0/1685 (0.00%) 
Sputum purulent  1  1/833 (0.12%)  0/1685 (0.00%) 
Staphylococcal infection  1  0/833 (0.00%)  1/1685 (0.06%) 
Strongyloidiasis  1  0/833 (0.00%)  1/1685 (0.06%) 
Tinea cruris  1  0/833 (0.00%)  1/1685 (0.06%) 
Tonsillitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Tooth infection  1  0/833 (0.00%)  2/1685 (0.12%) 
Tracheitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Tracheobronchitis  1  3/833 (0.36%)  2/1685 (0.12%) 
Upper respiratory tract infection  1  14/833 (1.68%)  33/1685 (1.96%) 
Urinary tract infection  1  14/833 (1.68%)  27/1685 (1.60%) 
Urinary tract infection fungal  1  0/833 (0.00%)  1/1685 (0.06%) 
Viral infection  1  2/833 (0.24%)  1/1685 (0.06%) 
Viral upper respiratory tract infection  1  6/833 (0.72%)  8/1685 (0.47%) 
Vulvovaginal mycotic infection  1  1/833 (0.12%)  0/1685 (0.00%) 
Wound infection  1  0/833 (0.00%)  1/1685 (0.06%) 
Injury, poisoning and procedural complications     
Airway complication of anaesthesia  1  0/833 (0.00%)  1/1685 (0.06%) 
Animal scratch  1  0/833 (0.00%)  1/1685 (0.06%) 
Ankle fracture  1  0/833 (0.00%)  1/1685 (0.06%) 
Arthropod bite  1  0/833 (0.00%)  1/1685 (0.06%) 
Chemical poisoning  1  0/833 (0.00%)  1/1685 (0.06%) 
Clavicle fracture  1  0/833 (0.00%)  1/1685 (0.06%) 
Concussion  1  0/833 (0.00%)  1/1685 (0.06%) 
Contusion  1  5/833 (0.60%)  6/1685 (0.36%) 
Fall  1  3/833 (0.36%)  7/1685 (0.42%) 
Fracture  1  0/833 (0.00%)  2/1685 (0.12%) 
Humerus fracture  1  0/833 (0.00%)  1/1685 (0.06%) 
Infusion related reaction  1  0/833 (0.00%)  3/1685 (0.18%) 
Laceration  1  2/833 (0.24%)  3/1685 (0.18%) 
Limb injury  1  0/833 (0.00%)  1/1685 (0.06%) 
Lumbar vertebral fracture  1  0/833 (0.00%)  1/1685 (0.06%) 
Overdose  1  0/833 (0.00%)  1/1685 (0.06%) 
Poisoning  1  4/833 (0.48%)  4/1685 (0.24%) 
Post procedural fistula  1  0/833 (0.00%)  1/1685 (0.06%) 
Procedural pain  1  0/833 (0.00%)  1/1685 (0.06%) 
Radiation oesophagitis  1  0/833 (0.00%)  2/1685 (0.12%) 
Radiation pneumonitis  1  1/833 (0.12%)  0/1685 (0.00%) 
Radiation skin injury  1  0/833 (0.00%)  1/1685 (0.06%) 
Rib fracture  1  1/833 (0.12%)  0/1685 (0.00%) 
Skin abrasion  1  1/833 (0.12%)  1/1685 (0.06%) 
Spinal compression fracture  1  0/833 (0.00%)  1/1685 (0.06%) 
Tooth fracture  1  0/833 (0.00%)  1/1685 (0.06%) 
Toxicity to various agents  1  0/833 (0.00%)  1/1685 (0.06%) 
Upper limb fracture  1  1/833 (0.12%)  0/1685 (0.00%) 
Wound  1  0/833 (0.00%)  1/1685 (0.06%) 
Wound complication  1  1/833 (0.12%)  1/1685 (0.06%) 
Investigations     
Alanine aminotransferase  1  0/833 (0.00%)  2/1685 (0.12%) 
Alanine aminotransferase decreased  1  0/833 (0.00%)  2/1685 (0.12%) 
Alanine aminotransferase increased  1  26/833 (3.12%)  43/1685 (2.55%) 
Albumin CSF decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Alpha hydroxybutyrate dehydrogenase increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Antineutrophil cytoplasmic antibody decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Aspartate aminotransferase decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Aspartate aminotransferase increased  1  21/833 (2.52%)  38/1685 (2.26%) 
Aspiration pleural cavity  1  0/833 (0.00%)  1/1685 (0.06%) 
Biopsy pleura  1  1/833 (0.12%)  0/1685 (0.00%) 
Blood albumin decreased  1  5/833 (0.60%)  7/1685 (0.42%) 
Blood alkaline phosphatase increased  1  7/833 (0.84%)  20/1685 (1.19%) 
Blood bicarbonate decreased  1  1/833 (0.12%)  1/1685 (0.06%) 
Blood bicarbonate increased  1  1/833 (0.12%)  0/1685 (0.00%) 
Blood bilirubin increased  1  0/833 (0.00%)  2/1685 (0.12%) 
Blood bilirubin unconjugated increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Blood calcitonin increased  1  1/833 (0.12%)  1/1685 (0.06%) 
Blood calcium decreased  1  1/833 (0.12%)  1/1685 (0.06%) 
Blood chloride decreased  1  1/833 (0.12%)  2/1685 (0.12%) 
Blood chloride increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Blood cholesterol increased  1  0/833 (0.00%)  2/1685 (0.12%) 
Blood creatine  1  0/833 (0.00%)  1/1685 (0.06%) 
Blood creatine abnormal  1  1/833 (0.12%)  2/1685 (0.12%) 
Blood creatine increased  1  0/833 (0.00%)  6/1685 (0.36%) 
Blood creatine phosphokinase MB increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Blood creatinine  1  0/833 (0.00%)  1/1685 (0.06%) 
Blood creatinine increased  1  16/833 (1.92%)  27/1685 (1.60%) 
Blood glucose increased  1  5/833 (0.60%)  6/1685 (0.36%) 
Blood iron abnormal  1  0/833 (0.00%)  1/1685 (0.06%) 
Blood iron decreased  1  0/833 (0.00%)  3/1685 (0.18%) 
Blood lactate dehydrogenase increased  1  8/833 (0.96%)  13/1685 (0.77%) 
Blood potassium decreased  1  2/833 (0.24%)  6/1685 (0.36%) 
Blood pressure increased  1  2/833 (0.24%)  2/1685 (0.12%) 
Blood pressure systolic increased  1  1/833 (0.12%)  0/1685 (0.00%) 
Blood testosterone decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Blood thyroid stimulating hormone decreased  1  1/833 (0.12%)  0/1685 (0.00%) 
Blood triglycerides increased  1  1/833 (0.12%)  0/1685 (0.00%) 
Blood urea decreased  1  1/833 (0.12%)  1/1685 (0.06%) 
Blood urea increased  1  6/833 (0.72%)  10/1685 (0.59%) 
Blood uric acid increased  1  2/833 (0.24%)  4/1685 (0.24%) 
Body temperature increased  1  3/833 (0.36%)  1/1685 (0.06%) 
Brain natriuretic peptide increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Breath sounds abnormal  1  2/833 (0.24%)  1/1685 (0.06%) 
C-reactive protein increased  1  0/833 (0.00%)  2/1685 (0.12%) 
Creatinine renal clearance decreased  1  2/833 (0.24%)  3/1685 (0.18%) 
Creatinine renal clearance increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Eastern Cooperative Oncology Group performance status worsened  1  1/833 (0.12%)  4/1685 (0.24%) 
Electrocardiogram QT prolonged  1  0/833 (0.00%)  2/1685 (0.12%) 
Fibrin D dimer increased  1  0/833 (0.00%)  2/1685 (0.12%) 
Fibrin degradation products increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Gamma-glutamyltransferase  1  0/833 (0.00%)  1/1685 (0.06%) 
Gamma-glutamyltransferase decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Gamma-glutamyltransferase increased  1  10/833 (1.20%)  22/1685 (1.31%) 
Gastric pH decreased  1  1/833 (0.12%)  0/1685 (0.00%) 
General physical condition abnormal  1  0/833 (0.00%)  1/1685 (0.06%) 
Globulins decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Glomerular filtration rate decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Glucose tolerance decreased  1  1/833 (0.12%)  0/1685 (0.00%) 
Glucose urine present  1  0/833 (0.00%)  1/1685 (0.06%) 
Glycosylated haemoglobin increased  1  1/833 (0.12%)  0/1685 (0.00%) 
Granulocyte count decreased  1  2/833 (0.24%)  9/1685 (0.53%) 
Haematocrit decreased  1  1/833 (0.12%)  0/1685 (0.00%) 
Haemoglobin decreased  1  10/833 (1.20%)  8/1685 (0.47%) 
Heart rate increased  1  2/833 (0.24%)  1/1685 (0.06%) 
Hepatic enzyme increased  1  1/833 (0.12%)  2/1685 (0.12%) 
Human epidermal growth factor receptor decreased  1  1/833 (0.12%)  0/1685 (0.00%) 
International normalised ratio increased  1  1/833 (0.12%)  1/1685 (0.06%) 
Iron binding capacity total decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Iron binding capacity unsaturated decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Laboratory test abnormal  1  1/833 (0.12%)  0/1685 (0.00%) 
Liver function test abnormal  1  1/833 (0.12%)  10/1685 (0.59%) 
Liver function test increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Lymphocyte count abnormal  1  0/833 (0.00%)  1/1685 (0.06%) 
Lymphocyte count decreased  1  5/833 (0.60%)  15/1685 (0.89%) 
Lymphocyte count increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Mean cell volume increased  1  1/833 (0.12%)  0/1685 (0.00%) 
Monocyte percentage increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Myoglobin blood increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Neutrophil count  1  1/833 (0.12%)  1/1685 (0.06%) 
Neutrophil count abnormal  1  1/833 (0.12%)  1/1685 (0.06%) 
Neutrophil count decreased  1  47/833 (5.64%)  95/1685 (5.64%) 
Neutrophil count increased  1  0/833 (0.00%)  5/1685 (0.30%) 
Neutrophil percentage increased  1  0/833 (0.00%)  2/1685 (0.12%) 
PCO2 decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Platelet adhesiveness decreased  1  1/833 (0.12%)  0/1685 (0.00%) 
Platelet adhesiveness increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Platelet count abnormal  1  0/833 (0.00%)  1/1685 (0.06%) 
Platelet count decreased  1  66/833 (7.92%)  130/1685 (7.72%) 
Platelet count increased  1  2/833 (0.24%)  3/1685 (0.18%) 
Protein total decreased  1  1/833 (0.12%)  2/1685 (0.12%) 
Protein total increased  1  1/833 (0.12%)  0/1685 (0.00%) 
Protein urine present  1  1/833 (0.12%)  0/1685 (0.00%) 
Respiratory rate decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Serum ferritin decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Serum ferritin increased  1  1/833 (0.12%)  1/1685 (0.06%) 
Transaminases increased  1  1/833 (0.12%)  0/1685 (0.00%) 
Troponin I increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Troponin increased  1  0/833 (0.00%)  1/1685 (0.06%) 
Urine output decreased  1  1/833 (0.12%)  1/1685 (0.06%) 
Vitamin D decreased  1  0/833 (0.00%)  1/1685 (0.06%) 
Weight decreased  1  24/833 (2.88%)  53/1685 (3.15%) 
Weight increased  1  4/833 (0.48%)  4/1685 (0.24%) 
White blood cell count  1  1/833 (0.12%)  1/1685 (0.06%) 
White blood cell count decreased  1  64/833 (7.68%)  138/1685 (8.19%) 
White blood cell count increased  1  3/833 (0.36%)  7/1685 (0.42%) 
White blood cells urine positive  1  0/833 (0.00%)  1/1685 (0.06%) 
Metabolism and nutrition disorders     
Acidosis  1  0/833 (0.00%)  1/1685 (0.06%) 
Cachexia  1  1/833 (0.12%)  0/1685 (0.00%) 
Decreased appetite  1  63/833 (7.56%)  134/1685 (7.95%) 
Dehydration  1  14/833 (1.68%)  37/1685 (2.20%) 
Diabetes mellitus  1  4/833 (0.48%)  1/1685 (0.06%) 
Diabetes mellitus inadequate control  1  2/833 (0.24%)  0/1685 (0.00%) 
Dyslipidaemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Electrolyte imbalance  1  1/833 (0.12%)  1/1685 (0.06%) 
Fluid retention  1  1/833 (0.12%)  0/1685 (0.00%) 
Glucose tolerance impaired  1  1/833 (0.12%)  0/1685 (0.00%) 
Gout  1  2/833 (0.24%)  0/1685 (0.00%) 
Hypercalcaemia  1  5/833 (0.60%)  4/1685 (0.24%) 
Hyperchloraemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Hypercholesterolaemia  1  3/833 (0.36%)  1/1685 (0.06%) 
Hypercreatininaemia  1  2/833 (0.24%)  4/1685 (0.24%) 
Hyperglycaemia  1  14/833 (1.68%)  32/1685 (1.90%) 
Hyperkalaemia  1  1/833 (0.12%)  7/1685 (0.42%) 
Hyperlipidaemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Hypernatraemia  1  1/833 (0.12%)  2/1685 (0.12%) 
Hyperphosphataemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Hypertriglyceridaemia  1  1/833 (0.12%)  3/1685 (0.18%) 
Hyperuricaemia  1  2/833 (0.24%)  8/1685 (0.47%) 
Hypoalbuminaemia  1  16/833 (1.92%)  47/1685 (2.79%) 
Hypocalcaemia  1  11/833 (1.32%)  25/1685 (1.48%) 
Hypochloraemia  1  2/833 (0.24%)  1/1685 (0.06%) 
Hypoglycaemia  1  4/833 (0.48%)  1/1685 (0.06%) 
Hypokalaemia  1  36/833 (4.32%)  53/1685 (3.15%) 
Hypomagnesaemia  1  10/833 (1.20%)  9/1685 (0.53%) 
Hyponatraemia  1  12/833 (1.44%)  25/1685 (1.48%) 
Hypophagia  1  1/833 (0.12%)  2/1685 (0.12%) 
Hypophosphataemia  1  3/833 (0.36%)  0/1685 (0.00%) 
Hypoproteinaemia  1  11/833 (1.32%)  9/1685 (0.53%) 
Hypovolaemia  1  0/833 (0.00%)  1/1685 (0.06%) 
Iron deficiency  1  0/833 (0.00%)  2/1685 (0.12%) 
Iron overload  1  0/833 (0.00%)  1/1685 (0.06%) 
Malnutrition  1  1/833 (0.12%)  4/1685 (0.24%) 
Marasmus  1  1/833 (0.12%)  0/1685 (0.00%) 
Metabolic disorder  1  1/833 (0.12%)  0/1685 (0.00%) 
Protein deficiency  1  0/833 (0.00%)  2/1685 (0.12%) 
Tetany  1  0/833 (0.00%)  1/1685 (0.06%) 
Type 2 diabetes mellitus  1  1/833 (0.12%)  1/1685 (0.06%) 
Vitamin D deficiency  1  1/833 (0.12%)  1/1685 (0.06%) 
Weight loss poor  1  1/833 (0.12%)  1/1685 (0.06%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  21/833 (2.52%)  32/1685 (1.90%) 
Arthritis  1  0/833 (0.00%)  1/1685 (0.06%) 
Back pain  1  35/833 (4.20%)  65/1685 (3.86%) 
Bone formation increased  1  1/833 (0.12%)  0/1685 (0.00%) 
Bone pain  1  10/833 (1.20%)  30/1685 (1.78%) 
Bursitis  1  1/833 (0.12%)  1/1685 (0.06%) 
Coccydynia  1  0/833 (0.00%)  1/1685 (0.06%) 
Connective tissue disorder  1  0/833 (0.00%)  1/1685 (0.06%) 
Exostosis  1  1/833 (0.12%)  0/1685 (0.00%) 
Fistula  1  0/833 (0.00%)  1/1685 (0.06%) 
Flank pain  1  1/833 (0.12%)  5/1685 (0.30%) 
Gouty arthritis  1  0/833 (0.00%)  1/1685 (0.06%) 
Hypercreatinaemia  1  1/833 (0.12%)  3/1685 (0.18%) 
Joint range of motion decreased  1  1/833 (0.12%)  1/1685 (0.06%) 
Joint swelling  1  2/833 (0.24%)  1/1685 (0.06%) 
Limb discomfort  1  1/833 (0.12%)  0/1685 (0.00%) 
Muscle fatigue  1  1/833 (0.12%)  0/1685 (0.00%) 
Muscle spasms  1  5/833 (0.60%)  6/1685 (0.36%) 
Muscle twitching  1  0/833 (0.00%)  1/1685 (0.06%) 
Muscular weakness  1  9/833 (1.08%)  12/1685 (0.71%) 
Musculoskeletal chest pain  1  8/833 (0.96%)  17/1685 (1.01%) 
Musculoskeletal discomfort  1  0/833 (0.00%)  1/1685 (0.06%) 
Musculoskeletal pain  1  12/833 (1.44%)  25/1685 (1.48%) 
Musculoskeletal stiffness  1  0/833 (0.00%)  1/1685 (0.06%) 
Myalgia  1  12/833 (1.44%)  26/1685 (1.54%) 
Neck pain  1  4/833 (0.48%)  7/1685 (0.42%) 
Osteolysis  1  1/833 (0.12%)  0/1685 (0.00%) 
Osteoporosis  1  0/833 (0.00%)  1/1685 (0.06%) 
Pain in extremity  1  22/833 (2.64%)  57/1685 (3.38%) 
Pain in jaw  1  0/833 (0.00%)  2/1685 (0.12%) 
Patellofemoral pain syndrome  1  1/833 (0.12%)  1/1685 (0.06%) 
Pathological fracture  1  1/833 (0.12%)  1/1685 (0.06%) 
Rhabdomyolysis  1  0/833 (0.00%)  1/1685 (0.06%) 
Spinal pain  1  1/833 (0.12%)  5/1685 (0.30%) 
Synovial cyst  1  1/833 (0.12%)  1/1685 (0.06%) 
Trismus  1  1/833 (0.12%)  0/1685 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Cancer pain  1  1/833 (0.12%)  8/1685 (0.47%) 
Malignant pleural effusion  1  0/833 (0.00%)  1/1685 (0.06%) 
Metastases to central nervous system  1  0/833 (0.00%)  1/1685 (0.06%) 
Paraneoplastic syndrome  1  2/833 (0.24%)  0/1685 (0.00%) 
Tumour haemorrhage  1  1/833 (0.12%)  0/1685 (0.00%) 
Tumour pain  1  2/833 (0.24%)  6/1685 (0.36%) 
Uterine leiomyoma  1  0/833 (0.00%)  1/1685 (0.06%) 
Nervous system disorders     
Amnesia  1  0/833 (0.00%)  2/1685 (0.12%) 
Anaesthesia  1  0/833 (0.00%)  1/1685 (0.06%) 
Aphasia  1  0/833 (0.00%)  1/1685 (0.06%) 
Aphonia  1  0/833 (0.00%)  1/1685 (0.06%) 
Ataxia  1  2/833 (0.24%)  5/1685 (0.30%) 
Burning sensation  1  1/833 (0.12%)  2/1685 (0.12%) 
Central nervous system lesion  1  1/833 (0.12%)  0/1685 (0.00%) 
Central pain syndrome  1  0/833 (0.00%)  1/1685 (0.06%) 
Cerebral atrophy  1  0/833 (0.00%)  2/1685 (0.12%) 
Cerebral infarction  1  0/833 (0.00%)  1/1685 (0.06%) 
Cerebral ischaemia  1  1/833 (0.12%)  0/1685 (0.00%) 
Cerebrovascular disorder  1  1/833 (0.12%)  0/1685 (0.00%) 
Cervical radiculopathy  1  0/833 (0.00%)  1/1685 (0.06%) 
Cognitive disorder  1  1/833 (0.12%)  2/1685 (0.12%) 
Diabetic neuropathy  1  1/833 (0.12%)  0/1685 (0.00%) 
Dizziness  1  24/833 (2.88%)  58/1685 (3.44%) 
Dizziness postural  1  0/833 (0.00%)  2/1685 (0.12%) 
Dysarthria  1  1/833 (0.12%)  1/1685 (0.06%) 
Dysgeusia  1  2/833 (0.24%)  7/1685 (0.42%) 
Dyskinesia  1  0/833 (0.00%)  2/1685 (0.12%) 
Encephalopathy  1  1/833 (0.12%)  0/1685 (0.00%) 
Epilepsy  1  1/833 (0.12%)  0/1685 (0.00%) 
Facial paralysis  1  0/833 (0.00%)  1/1685 (0.06%) 
Head discomfort  1  0/833 (0.00%)  2/1685 (0.12%) 
Headache  1  18/833 (2.16%)  55/1685 (3.26%) 
Hemiparesis  1  2/833 (0.24%)  4/1685 (0.24%) 
Hemiplegia  1  0/833 (0.00%)  2/1685 (0.12%) 
Hypoaesthesia  1  13/833 (1.56%)  21/1685 (1.25%) 
Hypogeusia  1  2/833 (0.24%)  2/1685 (0.12%) 
Intellectual disability  1  0/833 (0.00%)  1/1685 (0.06%) 
Intercostal neuralgia  1  1/833 (0.12%)  0/1685 (0.00%) 
Lethargy  1  0/833 (0.00%)  3/1685 (0.18%) 
Loss of consciousness  1  0/833 (0.00%)  3/1685 (0.18%) 
Migraine  1  1/833 (0.12%)  1/1685 (0.06%) 
Monoparesis  1  0/833 (0.00%)  1/1685 (0.06%) 
Nervous system disorder  1  0/833 (0.00%)  1/1685 (0.06%) 
Neuralgia  1  1/833 (0.12%)  3/1685 (0.18%) 
Neuropathy peripheral  1  40/833 (4.80%)  57/1685 (3.38%) 
Paraesthesia  1  14/833 (1.68%)  26/1685 (1.54%) 
Peripheral motor neuropathy  1  3/833 (0.36%)  4/1685 (0.24%) 
Peripheral sensory neuropathy  1  21/833 (2.52%)  39/1685 (2.31%) 
Polyneuropathy  1  5/833 (0.60%)  6/1685 (0.36%) 
Poor quality sleep  1  1/833 (0.12%)  2/1685 (0.12%) 
Presyncope  1  0/833 (0.00%)  1/1685 (0.06%) 
Psychomotor hyperactivity  1  0/833 (0.00%)  2/1685 (0.12%) 
Sciatica  1  1/833 (0.12%)  0/1685 (0.00%) 
Seizure  1  3/833 (0.36%)  4/1685 (0.24%) 
Sensory disturbance  1  0/833 (0.00%)  1/1685 (0.06%) 
Somnolence  1  1/833 (0.12%)  4/1685 (0.24%) 
Syncope  1  3/833 (0.36%)  10/1685 (0.59%) 
Tremor  1  2/833 (0.24%)  4/1685 (0.24%) 
Product Issues     
Device leakage  1  0/833 (0.00%)  1/1685 (0.06%) 
Psychiatric disorders     
Agitation  1  1/833 (0.12%)  0/1685 (0.00%) 
Anxiety  1  9/833 (1.08%)  18/1685 (1.07%) 
Anxiety disorder  1  1/833 (0.12%)  0/1685 (0.00%) 
Anxiety disorder due to a general medical condition  1  0/833 (0.00%)  1/1685 (0.06%) 
Confusional state  1  4/833 (0.48%)  6/1685 (0.36%) 
Delirium  1  0/833 (0.00%)  1/1685 (0.06%) 
Depressed mood  1  2/833 (0.24%)  0/1685 (0.00%) 
Depression  1  8/833 (0.96%)  11/1685 (0.65%) 
Dysphoria  1  0/833 (0.00%)  1/1685 (0.06%) 
Flight of ideas  1  0/833 (0.00%)  1/1685 (0.06%) 
Hallucination  1  0/833 (0.00%)  1/1685 (0.06%) 
Hyposomnia  1  1/833 (0.12%)  2/1685 (0.12%) 
Initial insomnia  1  0/833 (0.00%)  1/1685 (0.06%) 
Insomnia  1  22/833 (2.64%)  41/1685 (2.43%) 
Insomnia related to another mental condition  1  0/833 (0.00%)  1/1685 (0.06%) 
Mental disorder  1  0/833 (0.00%)  1/1685 (0.06%) 
Mental status changes  1  0/833 (0.00%)  2/1685 (0.12%) 
Mood swings  1  1/833 (0.12%)  0/1685 (0.00%) 
Organic brain syndrome  1  1/833 (0.12%)  0/1685 (0.00%) 
Restlessness  1  1/833 (0.12%)  0/1685 (0.00%) 
Sleep disorder  1  3/833 (0.36%)  1/1685 (0.06%) 
Tic  1  0/833 (0.00%)  1/1685 (0.06%) 
Renal and urinary disorders     
Acute kidney injury  1  3/833 (0.36%)  5/1685 (0.30%) 
Anuria  1  0/833 (0.00%)  1/1685 (0.06%) 
Bladder dilatation  1  1/833 (0.12%)  0/1685 (0.00%) 
Calculus bladder  1  0/833 (0.00%)  1/1685 (0.06%) 
Chronic kidney disease  1  1/833 (0.12%)  1/1685 (0.06%) 
Dysuria  1  1/833 (0.12%)  11/1685 (0.65%) 
Glycosuria  1  1/833 (0.12%)  0/1685 (0.00%) 
Haematuria  1  0/833 (0.00%)  1/1685 (0.06%) 
Nephrolithiasis  1  0/833 (0.00%)  1/1685 (0.06%) 
Nephropathy  1  0/833 (0.00%)  2/1685 (0.12%) 
Nocturia  1  0/833 (0.00%)  1/1685 (0.06%) 
Oliguria  1  0/833 (0.00%)  4/1685 (0.24%) 
Pollakiuria  1  3/833 (0.36%)  2/1685 (0.12%) 
Proteinuria  1  2/833 (0.24%)  2/1685 (0.12%) 
Renal failure  1  5/833 (0.60%)  5/1685 (0.30%) 
Renal impairment  1  1/833 (0.12%)  4/1685 (0.24%) 
Renal pain  1  0/833 (0.00%)  3/1685 (0.18%) 
Urinary hesitation  1  1/833 (0.12%)  1/1685 (0.06%) 
Urinary incontinence  1  0/833 (0.00%)  4/1685 (0.24%) 
Urinary retention  1  3/833 (0.36%)  1/1685 (0.06%) 
Reproductive system and breast disorders     
Benign prostatic hyperplasia  1  1/833 (0.12%)  2/1685 (0.12%) 
Breast mass  1  0/833 (0.00%)  1/1685 (0.06%) 
Breast pain  1  1/833 (0.12%)  0/1685 (0.00%) 
Breast swelling  1  1/833 (0.12%)  0/1685 (0.00%) 
Menorrhagia  1  0/833 (0.00%)  1/1685 (0.06%) 
Pelvic pain  1  3/833 (0.36%)  0/1685 (0.00%) 
Postmenopausal haemorrhage  1  0/833 (0.00%)  1/1685 (0.06%) 
Prostatitis  1  0/833 (0.00%)  1/1685 (0.06%) 
Scrotal oedema  1  0/833 (0.00%)  1/1685 (0.06%) 
Vaginal haemorrhage  1  0/833 (0.00%)  1/1685 (0.06%) 
Vulvovaginal pruritus  1  1/833 (0.12%)  0/1685 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Allergic respiratory symptom  1  0/833 (0.00%)  1/1685 (0.06%) 
Apnoea  1  0/833 (0.00%)  2/1685 (0.12%) 
Aspiration  1  0/833 (0.00%)  1/1685 (0.06%) 
Asthma  1  2/833 (0.24%)  3/1685 (0.18%) 
Atelectasis  1  1/833 (0.12%)  2/1685 (0.12%) 
Bronchial haemorrhage  1  1/833 (0.12%)  0/1685 (0.00%) 
Bronchial hyperreactivity  1  0/833 (0.00%)  1/1685 (0.06%) 
Bronchial obstruction  1  0/833 (0.00%)  1/1685 (0.06%) 
Bronchiectasis  1  0/833 (0.00%)  1/1685 (0.06%) 
Bronchitis chronic  1  0/833 (0.00%)  1/1685 (0.06%) 
Bronchospasm  1  2/833 (0.24%)  5/1685 (0.30%) 
Bronchostenosis  1  1/833 (0.12%)  1/1685 (0.06%) 
Chronic obstructive pulmonary disease  1  1/833 (0.12%)  9/1685 (0.53%) 
Cough  1  52/833 (6.24%)  147/1685 (8.72%) 
Dry throat  1  0/833 (0.00%)  1/1685 (0.06%) 
Dysphonia  1