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PEARL 2: Safety and Efficacy of Peginesatide for the Treatment of Anemia in Participants With Chronic Renal Failure Not on Dialysis

Sponsor
Affymax (Industry)
Overall Status
Completed
CT.gov ID
NCT00598442
Collaborator
Takeda (Industry)
493
Enrollment
64
Locations
3
Arms
25
Duration (Months)
7.7
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the safety and efficacy of peginesatide for the treatment of anemia in participants with chronic kidney disease, who are not on dialysis and not on erythropoiesis stimulating agent (ESA) treatment.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

Anemia associated with chronic kidney disease is due to several factors, primarily the inability of the diseased kidneys to produce adequate amounts of endogenous erythropoietin. Ancillary factors include the shortened lifespan of red blood cells, iron and other nutritional deficiencies, infection, and inflammation. The presence and severity of anemia are related to the duration and extent of kidney failure. Anemia is associated with increased mortality, increased likelihood of hospitalization, reduced cognitive function, and increased left ventricular hypertrophy and heart failure.

Erythropoiesis stimulating agents have been established as a treatment for anemia in chronic renal failure subjects, and have improved the management of anemia over alternatives such as transfusion. Peginesatide is a parenteral formulation developed for the treatment of anemia in patients with chronic kidney disease. Peginesatide binds to and activates the human erythropoietin receptor and stimulates erythropoiesis in human red cell precursors in a manner similar to other known erythropoiesis-stimulating agents.

Study participants received doses of peginesatide administered once every 4 weeks or darbepoetin alfa administered once every 2 weeks. Total commitment time for this study was a 4 week screening period followed by a minimum of 52 weeks of study treatment. Eligible participants were randomized in equal proportions to two peginesatide treatment regimens and one control, darbepoetin alfa, treatment regimen.

To evaluate the cardiovascular safety of peginesatide, a cardiovascular composite safety endpoint (CSE) was defined for use in prospectively planned analyses which combined cardiovascular safety data from the four Phase 3 peginesatide studies (NCT00598273, NCT00597753, NCT00598442, and NCT00597584). The CSE consisted of six events: death, stroke, myocardial infarction, and serious adverse events of congestive heart failure, unstable angina, and arrhythmia. An independent Event Review Committee (ERC) was used to provide blinded adjudication of potential CSE events.

Study Design

Study Type:
Interventional
Actual Enrollment :
493 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
AFX01-13: A Phase 3, Randomized, Active-controlled, Open-label, Multi-center Study of the Safety and Efficacy of Peginesatide for the Correction of Anemia in Patients With Chronic Renal Failure (CRF) Not on Dialysis and Not on Erythropoiesis Stimulating Agent (ESA) Treatment
Study Start Date :
Nov 1, 2007
Actual Primary Completion Date :
Jul 1, 2009
Actual Study Completion Date :
Dec 1, 2009

Arms and Interventions

Arm Intervention/Treatment
Experimental: Peginesatide 0.025 mg/kg

Drug: peginesatide
Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.025 milligram per kilogram (mg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 grams per deciliter (g/dL).
Other Names:
  • Omontys
  • Hematide
  • AF37702 Injection

    		•
    Experimental: Peginesatide 0.04 mg/kg

    Drug: peginesatide
    Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.04 mg/kg and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL.
    Other Names:
  • Omontys
  • Hematide
  • AF37702 Injection

    		•
    Active Comparator: Darbepoetin alfa

    Drug: Darbepoetin alfa
    Participants received darbepoetin alfa by subcutaneous injection once every 2 weeks, as prescribed. The starting dose was 0.75 microgram per kilogram (mcg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL.
    Other Names:
  • Aranesp

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Mean Change in Hemoglobin Between Baseline and the Evaluation Period [Baseline and Weeks 25-36]

      The baseline hemoglobin value is defined as the mean of three hemoglobin values: the two most recent hemoglobin values taken prior to the day of randomization and the value obtained on the day of randomization. The mean hemoglobin during the Evaluation Period for each participant is calculated as the mean of the available hemoglobin values during Study Weeks 25 through 36.

    Secondary Outcome Measures

    1. Proportion of Participants Who Received Red Blood Cell (RBC) Transfusions During the Correction and Evaluation Periods [Weeks 0 to 36]

    2. Proportion of Participants Achieving Hemoglobin Response During the Correction and Evaluation Periods [Weeks 0 to 36]

      A hemoglobin response is defined as a hemoglobin increase of ≥ 1.0 gram per deciliter (g/dL) above baseline and a hemoglobin ≥ 11.0 g/dL without RBC transfusion during the previous 8 weeks.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Chronic renal failure with an estimated glomerular filtration rate < 60 milliliters per minute per 1.73 m^2 and not expected to begin dialysis for at least 12 weeks.

    2. Two consecutive hemoglobin values ≥ 8.0 g/dL and < 11.0 g/dL within 4 weeks prior to randomization.

    Exclusion Criteria:

    1. Females who are pregnant or breast-feeding.

    2. Treatment with an ESA in the 12 weeks prior to randomization.

    3. Known intolerance to any ESA, parenteral iron supplementation, or pegylated molecule.

    4. Prior chronic hemodialysis or chronic peritoneal dialysis treatment.

    5. Known bleeding or coagulation disorder.

    6. Known hematologic disease or cause of anemia other than renal disease.

    7. Poorly controlled hypertension.

    8. Evidence of active malignancy within one year prior to randomization

    9. A scheduled kidney transplant.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Facility Phoenix Arizona United States 85012
    2 Research Facility Fayetteville Arkansas United States 72703
    3 Research Facility Fountain Valley California United States 92708
    4 Research Facility Fullerton California United States 92835
    5 Research Facility Granada Hills California United States 91344
    6 Research Facility Los Angeles California United States 90022
    7 Research Facility San Diego California United States 92123
    8 Research Facility Whittier California United States 90603
    9 Research Facility Lauderdale Lakes Florida United States 33313
    10 Research Facility Pembroke Pines Florida United States 33028
    11 Research Facility Pinecrest Florida United States 33156
    12 Research Facility Canton Georgia United States 30114
    13 Research Facility Columbus Georgia United States 31904
    14 Research Facility Marietta Georgia United States 30060
    15 Research Facility Caldwell Idaho United States 83605
    16 Research Facility Meridian Idaho United States 83642
    17 Research Facility Chicago Illinois United States 60611
    18 Research Facility Mishawaka Indiana United States 46545
    19 Research Facility Ames Iowa United States 50010
    20 Research Facility Baton Rouge Louisiana United States 70809
    21 Research Facility Lafayette Louisiana United States 70506
    22 Research Facility Rockville Maryland United States 20852
    23 Research Facility Springfield Massachusetts United States 01107
    24 Research Facility Detroit Michigan United States 48202
    25 Research Facility Detroit Michigan United States 48236
    26 Research Facility Flint Michigan United States 48504
    27 Research Facility Petoskey Michigan United States 49770
    28 Research Facility Troy Michigan United States 48098
    29 Research Facility Washington Missouri United States 63090
    30 Research Facility Flushing New York United States 11355
    31 Research Facility Williamsville New York United States 14221
    32 Research Facility Asheville North Carolina United States 28801
    33 Research Facility Columbus Ohio United States 43210
    34 Research Facility Bend Oregon United States 97701
    35 Research Facility Arlington Texas United States 76015
    36 Research Facility Houston Texas United States 77004
    37 Research Facility San Antonio Texas United States 78229
    38 Research Facility Burlington Vermont United States 05401
    39 Research Facility Fairfax Virginia United States 22030
    40 Research Facility Tacoma Washington United States 98405
    41 Research Facility Morgantown West Virginia United States 26506
    42 Research Facility Neenah Wisconsin United States 54956
    43 Research Facility Sofia Bulgaria 1431
    44 Research Facility Sofia Bulgaria 1606
    45 Research Facility Varna Bulgaria 9000
    46 Research Facility Veliko Tarnovo Bulgaria 5000
    47 Research Facility Prague Czech Republic 14021
    48 Research Facility Tabor Czech Republic 39003
    49 Research Facility Zdar nad Sazavou Czech Republic 591 01
    50 Research Facility Demmin Germany 17109
    51 Research Facility Balatonfured Hungary 8230
    52 Research Facility Kistarcsa Hungary 2143
    53 Research Facility Szigetvar Hungary 7900
    54 Research Facility Lecco Italy 23900
    55 Research Facility Pavia Italy 27100
    56 Research Facility Bialystok Poland 15 540
    57 Research Facility Gdansk Poland 80 952
    58 Research Facility Katowice Poland 40 027
    59 Research Facility Zamosc Poland 22 400
    60 Research Facility Ponce Puerto Rico 00717-0634
    61 Research Facility Iasi Romania 700 503
    62 Research Facility Oradea Romania 410469
    63 Research Facility Timisoara Romania 300 736
    64 Research Facility London United Kingdom SE5 9RS

    Sponsors and Collaborators

    • Affymax
    • Takeda

    Investigators

    • Study Director: Vice President, Clinical Development, Affymax

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Affymax
    ClinicalTrials.gov Identifier:
    NCT00598442
    Other Study ID Numbers:
    • AFX01-13
    • 2007-004146-32
    First Posted:
    Jan 21, 2008
    Last Update Posted:
    Feb 12, 2013
    Last Verified:
    Feb 1, 2013
    Keywords provided by Affymax
    anemia
    chronic kidney disease
    CKD
    chronic renal failure
    CRF
    erythropoietin
    EPO
    erythropoiesis stimulating agent
    ESA
    Hematide™
    hemoglobin
    Hb
    Hgb
    Omontys
    peginesatide
    red blood cell
    red blood cell production
    Additional relevant MeSH terms:
    Kidney Diseases
    Renal Insufficiency, Chronic
    Renal Insufficiency
    Kidney Failure, Chronic
    Anemia
    Darbepoetin alfa

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Peginesatide 0.025 mg/kg Peginesatide 0.04 mg/kg Darbepoetin Alfa
    Arm/Group Description Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.025 milligram per kilogram (mg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 grams per deciliter (g/dL). Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.04 mg/kg and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL. Participants received darbepoetin alfa by subcutaneous injection once every 2 weeks, as prescribed. The starting dose was 0.75 microgram per kilogram (mcg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL.
    Period Title: Overall Study
    STARTED 167 163 163
    COMPLETED 124 124 139
    NOT COMPLETED 43 39 24

    Baseline Characteristics

    Arm/Group Title Peginesatide 0.025 mg/kg Peginesatide 0.04 mg/kg Darbepoetin Alfa Total
    Arm/Group Description Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.025 milligram per kilogram (mg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 grams per deciliter (g/dL). Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.04 mg/kg and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL. Participants received darbepoetin alfa by subcutaneous injection once every 2 weeks, as prescribed. The starting dose was 0.75 microgram per kilogram (mcg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL. Total of all reporting groups
    Overall Participants 167 163 163 493
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    63
    37.7%
    57
    35%
    62
    38%
    182
    36.9%
    >=65 years
    104
    62.3%
    106
    65%
    101
    62%
    311
    63.1%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    68.1
    (12.93)
    68.3
    (13.53)
    67.2
    (15.03)
    67.9
    (13.83)
    Sex: Female, Male (Count of Participants)
    Female
    93
    55.7%
    96
    58.9%
    99
    60.7%
    288
    58.4%
    Male
    74
    44.3%
    67
    41.1%
    64
    39.3%
    205
    41.6%

    Outcome Measures

    1. Primary Outcome
    Title Mean Change in Hemoglobin Between Baseline and the Evaluation Period
    Description The baseline hemoglobin value is defined as the mean of three hemoglobin values: the two most recent hemoglobin values taken prior to the day of randomization and the value obtained on the day of randomization. The mean hemoglobin during the Evaluation Period for each participant is calculated as the mean of the available hemoglobin values during Study Weeks 25 through 36.
    Time Frame Baseline and Weeks 25-36

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Population: All randomized participants who received at least one dose of study medication
    Arm/Group Title Peginesatide 0.025 mg/kg Peginesatide 0.04 mg/kg Darbepoetin Alfa
    Arm/Group Description Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.025 milligram per kilogram (mg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 grams per deciliter (g/dL). Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.04 mg/kg and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL. Participants received darbepoetin alfa by subcutaneous injection once every 2 weeks, as prescribed. The starting dose was 0.75 microgram per kilogram (mcg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL.
    Measure Participants 167 163 163
    Baseline [N=167, 163, 163]
    10.02
    (0.626)
    10.03
    (0.618)
    10.03
    (0.654)
    Evaluation Period [N=151, 145, 150]
    11.55
    (0.741)
    11.71
    (0.855)
    11.40
    (0.728)
    Change from Baseline [N=151, 145, 150]
    1.50
    (0.898)
    1.68
    (0.962)
    1.35
    (1.004)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Peginesatide 0.025 mg/kg, Darbepoetin Alfa
    Comments The sample size for this study was determined based on a two-group evaluation of non-inferiority in means with a non-inferiority margin (Δ) of -1.0 g/dL (one-sided significance level of 0.0125, or, comparably, a two-sided significance level of 0.025). A sample size of 450 (150 per treatment group) provided power greater than 99% for the evaluation of non-inferiority, assuming an expected treatment difference of 0.0 g/dL and a pooled standard deviation of 1.5 g/dL.
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments A non-inferiority margin of -1.0 g/dL was used in the primary efficacy assessments. Non-inferiority was established if the lower limit of the two-sided 97.5% CI for the difference between the means of the primary endpoint (peginesatide minus control ESA) was ≥ -1.0 g/dL.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.14
    Confidence Interval (2-Sided) 97.5%
    -0.09 to 0.36
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.101
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Peginesatide 0.04 mg/kg, Darbepoetin Alfa
    Comments The sample size for this study was determined based on a two-group evaluation of non-inferiority in means with a non-inferiority margin (Δ) of -1.0 g/dL (one-sided significance level of 0.0125, or, comparably, a two-sided significance level of 0.025). A sample size of 450 (150 per treatment group) provided power greater than 99% for the evaluation of non-inferiority, assuming an expected treatment difference of 0.0 g/dL and a pooled standard deviation of 1.5 g/dL.
    Type of Statistical Test Non-Inferiority or Equivalence
    Comments A non-inferiority margin of -1.0 g/dL was used in the primary efficacy assessments. Non-inferiority was established if the lower limit of the two-sided 97.5% CI for the difference between the means of the primary endpoint (peginesatide minus control ESA) was ≥ -1.0 g/dL.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean Difference
    Estimated Value 0.31
    Confidence Interval (2-Sided) 97.5%
    0.08 to 0.54
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.102
    Estimation Comments
    2. Secondary Outcome
    Title Proportion of Participants Who Received Red Blood Cell (RBC) Transfusions During the Correction and Evaluation Periods
    Description
    Time Frame Weeks 0 to 36

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Population: All randomized participants who received at least one dose of study medication
    Arm/Group Title Peginesatide 0.025 mg/kg Peginesatide 0.04 mg/kg Darbepoetin Alfa
    Arm/Group Description Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.025 milligram per kilogram (mg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 grams per deciliter (g/dL). Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.04 mg/kg and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL. Participants received darbepoetin alfa by subcutaneous injection once every 2 weeks, as prescribed. The starting dose was 0.75 microgram per kilogram (mcg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL.
    Measure Participants 167 163 163
    Number [percentage of participants]
    0.114
    0.1%
    0.104
    0.1%
    0.049
    0%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Peginesatide 0.025 mg/kg, Darbepoetin Alfa
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Risk Ratio (RR)
    Estimated Value 2.28
    Confidence Interval (2-Sided) 95%
    1.04 to 5.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Peginesatide 0.04 mg/kg, Darbepoetin Alfa
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Risk Ratio (RR)
    Estimated Value 2.10
    Confidence Interval (2-Sided) 95%
    0.94 to 4.69
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Proportion of Participants Achieving Hemoglobin Response During the Correction and Evaluation Periods
    Description A hemoglobin response is defined as a hemoglobin increase of ≥ 1.0 gram per deciliter (g/dL) above baseline and a hemoglobin ≥ 11.0 g/dL without RBC transfusion during the previous 8 weeks.
    Time Frame Weeks 0 to 36

    Outcome Measure Data

    Analysis Population Description
    Full Analysis Population: All randomized participants who received at least one dose of study medication
    Arm/Group Title Peginesatide 0.025 mg/kg Peginesatide 0.04 mg/kg Darbepoetin Alfa
    Arm/Group Description Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.025 milligram per kilogram (mg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 grams per deciliter (g/dL). Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.04 mg/kg and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL. Participants received darbepoetin alfa by subcutaneous injection once every 2 weeks, as prescribed. The starting dose was 0.75 microgram per kilogram (mcg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL.
    Measure Participants 167 163 163
    Number [percentage of participants]
    0.910
    0.5%
    0.933
    0.6%
    0.951
    0.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Peginesatide 0.025 mg/kg, Darbepoetin Alfa
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Risk Ratio (RR)
    Estimated Value 0.96
    Confidence Interval (2-Sided) 95%
    0.90 to 1.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Peginesatide 0.04 mg/kg, Darbepoetin Alfa
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Risk Ratio (RR)
    Estimated Value 0.98
    Confidence Interval (2-Sided) 95%
    0.93 to 1.04
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Peginesatide 0.025 mg/kg Peginesatide 0.04 mg/kg Darbepoetin Alfa
    Arm/Group Description Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.025 milligram per kilogram (mg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 grams per deciliter (g/dL). Participants received peginesatide by subcutaneous injection once every 4 weeks. The starting dose was 0.04 mg/kg and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL. Participants received darbepoetin alfa by subcutaneous injection once every 2 weeks, as prescribed. The starting dose was 0.75 microgram per kilogram (mcg/kg) and was adjusted throughout the study to maintain a hemoglobin target range of 11.0-12.0 g/dL.
    All Cause Mortality
    Peginesatide 0.025 mg/kg Peginesatide 0.04 mg/kg Darbepoetin Alfa
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Peginesatide 0.025 mg/kg Peginesatide 0.04 mg/kg Darbepoetin Alfa
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 86/167 (51.5%) 80/163 (49.1%) 70/163 (42.9%)
    Blood and lymphatic system disorders
    Anaemia 7/167 (4.2%) 6/163 (3.7%) 4/163 (2.5%)
    Haemorrhagic anaemia 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Heparin-induced thrombocytopenia 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Leukocytosis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Pancytopenia 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Thrombocytopenia 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Cardiac disorders
    Cardiac failure congestive 7/167 (4.2%) 18/163 (11%) 12/163 (7.4%)
    Acute myocardial infarction 5/167 (3%) 4/163 (2.5%) 2/163 (1.2%)
    Atrial fibrillation 1/167 (0.6%) 5/163 (3.1%) 4/163 (2.5%)
    Cardiac arrest 5/167 (3%) 2/163 (1.2%) 3/163 (1.8%)
    Myocardial infarction 4/167 (2.4%) 2/163 (1.2%) 4/163 (2.5%)
    Bradycardia 4/167 (2.4%) 5/163 (3.1%) 0/163 (0%)
    Coronary artery disease 2/167 (1.2%) 1/163 (0.6%) 3/163 (1.8%)
    Angina pectoris 1/167 (0.6%) 3/163 (1.8%) 1/163 (0.6%)
    Angina unstable 3/167 (1.8%) 2/163 (1.2%) 0/163 (0%)
    Cardiac failure 2/167 (1.2%) 2/163 (1.2%) 1/163 (0.6%)
    Acute coronary syndrome 1/167 (0.6%) 2/163 (1.2%) 0/163 (0%)
    Coronary artery occlusion 2/167 (1.2%) 1/163 (0.6%) 0/163 (0%)
    Sick sinus syndrome 1/167 (0.6%) 2/163 (1.2%) 0/163 (0%)
    Cardiomyopathy 1/167 (0.6%) 0/163 (0%) 1/163 (0.6%)
    Ischaemic cardiomyopathy 1/167 (0.6%) 1/163 (0.6%) 0/163 (0%)
    Tachycardia 1/167 (0.6%) 0/163 (0%) 1/163 (0.6%)
    Aortic valve stenosis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Arrhythmia 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Arteriosclerosis coronary artery 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Atrial flutter 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Atrioventricular block 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Atrioventricular block complete 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Atrioventricular block second degree 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Cardio-respiratory arrest 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Cardiogenic shock 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Cardiomegaly 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Cor pulmonale 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Intracardiac thrombus 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Myocardial ischaemia 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Palpitations 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Pericardial effusion 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Pericarditis 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Supraventricular tachycardia 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Congenital, familial and genetic disorders
    Gastrointestinal angiodysplasia 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Vitello-intestinal duct remnant 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Endocrine disorders
    Hyperthyroidism 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Hypothyroidism 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Eye disorders
    Cataract 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Gastrointestinal disorders
    Gastrointestinal haemorrhage 2/167 (1.2%) 5/163 (3.1%) 2/163 (1.2%)
    Pancreatitis acute 2/167 (1.2%) 2/163 (1.2%) 0/163 (0%)
    Pancreatitis 1/167 (0.6%) 2/163 (1.2%) 0/163 (0%)
    Rectal haemorrhage 3/167 (1.8%) 0/163 (0%) 0/163 (0%)
    Abdominal pain 0/167 (0%) 1/163 (0.6%) 1/163 (0.6%)
    Haematemesis 1/167 (0.6%) 1/163 (0.6%) 0/163 (0%)
    Lower gastrointestinal haemorrhage 2/167 (1.2%) 0/163 (0%) 0/163 (0%)
    Retroperitoneal haematoma 0/167 (0%) 0/163 (0%) 2/163 (1.2%)
    Small intestinal obstruction 1/167 (0.6%) 1/163 (0.6%) 0/163 (0%)
    Vomiting 0/167 (0%) 1/163 (0.6%) 1/163 (0.6%)
    Abdominal pain upper 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Alcoholic pancreatitis 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Ascites 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Caecitis 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Colitis 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Colonic pseudo-obstruction 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Constipation 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Diabetic gastroparesis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Diarrhoea 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Diverticular perforation 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Diverticulum intestinal haemorrhagic 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Duodenal ulcer haemorrhage 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Dyspepsia 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Gastric hypomotility 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Gastritis erosive 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Gastritis haemorrhagic 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Gastroduodenal ulcer 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Gastrointestinal pain 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Gastrooesophageal reflux disease 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Haematochezia 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Impaired gastric emptying 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Intestinal mass 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Large intestinal haemorrhage 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Large intestine perforation 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Nausea 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Peritonitis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Umbilical hernia, obstructive 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Uraemic gastropathy 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Volvulus 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    General disorders
    Non-cardiac chest pain 2/167 (1.2%) 4/163 (2.5%) 1/163 (0.6%)
    Pyrexia 1/167 (0.6%) 1/163 (0.6%) 2/163 (1.2%)
    Generalised oedema 1/167 (0.6%) 2/163 (1.2%) 0/163 (0%)
    Asthenia 2/167 (1.2%) 0/163 (0%) 0/163 (0%)
    Chest pain 0/167 (0%) 1/163 (0.6%) 1/163 (0.6%)
    Multi-organ failure 2/167 (1.2%) 0/163 (0%) 0/163 (0%)
    Brain death 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Cyst 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Fatigue 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    General physical health deterioration 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Hypothermia 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Local swelling 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Oedema peripheral 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Pain 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Sudden death 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Hepatobiliary disorders
    Cholelithiasis 0/167 (0%) 3/163 (1.8%) 1/163 (0.6%)
    Cholecystitis 0/167 (0%) 2/163 (1.2%) 0/163 (0%)
    Bile duct stone 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Cholangitis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Cholecystitis acute 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Cholecystitis chronic 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Hepatic failure 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Hepatic ischaemia 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Jaundice 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Liver disorder 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Immune system disorders
    Transplant rejection 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Infections and infestations
    Pneumonia 4/167 (2.4%) 11/163 (6.7%) 5/163 (3.1%)
    Urinary tract infection 5/167 (3%) 5/163 (3.1%) 1/163 (0.6%)
    Cellulitis 4/167 (2.4%) 2/163 (1.2%) 3/163 (1.8%)
    Lobar pneumonia 3/167 (1.8%) 2/163 (1.2%) 0/163 (0%)
    Sepsis 0/167 (0%) 3/163 (1.8%) 2/163 (1.2%)
    Gastroenteritis 1/167 (0.6%) 2/163 (1.2%) 1/163 (0.6%)
    Osteomyelitis 1/167 (0.6%) 2/163 (1.2%) 1/163 (0.6%)
    Bacteraemia 0/167 (0%) 2/163 (1.2%) 1/163 (0.6%)
    Wound infection 2/167 (1.2%) 1/163 (0.6%) 0/163 (0%)
    Gangrene 1/167 (0.6%) 1/163 (0.6%) 0/163 (0%)
    Gastroenteritis viral 0/167 (0%) 2/163 (1.2%) 0/163 (0%)
    Localised infection 0/167 (0%) 2/163 (1.2%) 0/163 (0%)
    Staphylococcal infection 0/167 (0%) 1/163 (0.6%) 1/163 (0.6%)
    Urinary tract infection bacterial 0/167 (0%) 1/163 (0.6%) 1/163 (0.6%)
    Abdominal sepsis 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Arthritis bacterial 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Bacterial pyelonephritis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Bronchitis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Bronchopneumonia 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Cellulitis of male external genital organ 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Clostridium difficile colitis 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Clostridium difficile sepsis 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Device related infection 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Diabetic foot infection 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Diabetic gangrene 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Diverticulitis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Herpes zoster 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Labyrinthitis 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Necrotising fasciitis 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Osteomyelitis bacterial 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Perihepatic abscess 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Perineal abscess 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Pneumonia cryptococcal 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Pyelonephritis 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Pyelonephritis acute 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Septic shock 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Staphylococcal bacteraemia 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Staphylococcal sepsis 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Streptococcal bacteraemia 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Subcutaneous abscess 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Urinary tract infection enterococcal 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Urinary tract infection pseudomonal 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Injury, poisoning and procedural complications
    Hip fracture 0/167 (0%) 2/163 (1.2%) 1/163 (0.6%)
    Scapula fracture 0/167 (0%) 2/163 (1.2%) 0/163 (0%)
    Skin laceration 0/167 (0%) 0/163 (0%) 2/163 (1.2%)
    Subdural haematoma 0/167 (0%) 1/163 (0.6%) 1/163 (0.6%)
    Avulsion fracture 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Clavicle fracture 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Complications of transplanted kidney 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Concussion 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Drug toxicity 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Facial bones fracture 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Fall 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Femoral neck fracture 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Femur fracture 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Hand fracture 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Head injury 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Multiple injuries 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Perirenal haematoma 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Procedural pain 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Rib fracture 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Seroma 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Spinal compression fracture 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Wound 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Wound dehiscence 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Investigations
    Anticoagulation drug level above therapeutic 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Coagulation time prolonged 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Ejection fraction decreased 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Metabolism and nutrition disorders
    Hypoglycaemia 1/167 (0.6%) 6/163 (3.7%) 6/163 (3.7%)
    Hyperkalaemia 6/167 (3.6%) 2/163 (1.2%) 4/163 (2.5%)
    Dehydration 3/167 (1.8%) 4/163 (2.5%) 0/163 (0%)
    Diabetic ketoacidosis 2/167 (1.2%) 1/163 (0.6%) 2/163 (1.2%)
    Fluid overload 1/167 (0.6%) 1/163 (0.6%) 2/163 (1.2%)
    Diabetes mellitus inadequate control 1/167 (0.6%) 2/163 (1.2%) 0/163 (0%)
    Metabolic acidosis 0/167 (0%) 1/163 (0.6%) 1/163 (0.6%)
    Diabetes mellitus 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Diabetic foot 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Failure to thrive 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Fluid retention 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Gout 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Hyperglycaemia 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Hyperuricaemia 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Hypervolaemia 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Hyponatraemia 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Hypovolaemia 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Ketoacidosis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Neuroglycopenia 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Musculoskeletal and connective tissue disorders
    Back pain 2/167 (1.2%) 2/163 (1.2%) 0/163 (0%)
    Diabetic amyotrophy 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Intervertebral disc protrusion 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Lumbar spinal stenosis 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Musculoskeletal chest pain 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Musculoskeletal stiffness 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Osteoarthritis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Osteolysis 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Pain in extremity 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Rhabdomyolysis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Spinal column stenosis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer 1/167 (0.6%) 0/163 (0%) 1/163 (0.6%)
    Acute myeloid leukaemia 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Breast cancer metastatic 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Colon cancer metastatic 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Lung cancer metastatic 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Lung squamous cell carcinoma stage unspecified 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Seborrhoeic keratosis 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Transitional cell carcinoma 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Nervous system disorders
    Syncope 1/167 (0.6%) 3/163 (1.8%) 1/163 (0.6%)
    Cerebrovascular accident 3/167 (1.8%) 1/163 (0.6%) 0/163 (0%)
    Transient ischaemic attack 0/167 (0%) 1/163 (0.6%) 3/163 (1.8%)
    Headache 1/167 (0.6%) 0/163 (0%) 1/163 (0.6%)
    Lacunar infarction 1/167 (0.6%) 1/163 (0.6%) 0/163 (0%)
    Presyncope 0/167 (0%) 2/163 (1.2%) 0/163 (0%)
    Carotid artery stenosis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Cerebral haemorrhage 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Cerebral infarction 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Convulsion 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Dizziness 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Encephalopathy 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Grand mal convulsion 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Hypoxic encephalopathy 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Migraine 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Neuropathy peripheral 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Subarachnoid haemorrhage 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Tremor 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Uraemic encephalopathy 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Vocal cord paralysis 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Psychiatric disorders
    Mental status changes 1/167 (0.6%) 1/163 (0.6%) 3/163 (1.8%)
    Suicide attempt 1/167 (0.6%) 0/163 (0%) 1/163 (0.6%)
    Agitation 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Depression 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Hallucination 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Psychotic disorder 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Schizoaffective disorder 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Substance abuse 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Renal and urinary disorders
    Renal failure acute 11/167 (6.6%) 11/163 (6.7%) 5/163 (3.1%)
    Renal failure chronic 10/167 (6%) 6/163 (3.7%) 8/163 (4.9%)
    Renal failure 2/167 (1.2%) 2/163 (1.2%) 1/163 (0.6%)
    Azotaemia 2/167 (1.2%) 1/163 (0.6%) 1/163 (0.6%)
    Renal impairment 0/167 (0%) 1/163 (0.6%) 1/163 (0.6%)
    Acute prerenal failure 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Glomerulonephritis chronic 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Obstructive uropathy 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Renal pain 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Urinary retention 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 0/167 (0%) 1/163 (0.6%) 3/163 (1.8%)
    Pleural effusion 1/167 (0.6%) 1/163 (0.6%) 2/163 (1.2%)
    Pneumonia aspiration 2/167 (1.2%) 1/163 (0.6%) 1/163 (0.6%)
    Respiratory arrest 2/167 (1.2%) 2/163 (1.2%) 0/163 (0%)
    Dyspnoea 2/167 (1.2%) 0/163 (0%) 1/163 (0.6%)
    Pulmonary oedema 3/167 (1.8%) 0/163 (0%) 0/163 (0%)
    Respiratory failure 2/167 (1.2%) 0/163 (0%) 1/163 (0.6%)
    Acute respiratory failure 0/167 (0%) 1/163 (0.6%) 1/163 (0.6%)
    Asthma 0/167 (0%) 1/163 (0.6%) 1/163 (0.6%)
    Pulmonary congestion 0/167 (0%) 0/163 (0%) 2/163 (1.2%)
    Pulmonary embolism 1/167 (0.6%) 1/163 (0.6%) 0/163 (0%)
    Bronchitis chronic 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Epistaxis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Hypoxia 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Pulmonary cavitation 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Pulmonary fibrosis 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Skin and subcutaneous tissue disorders
    Skin ulcer 2/167 (1.2%) 0/163 (0%) 0/163 (0%)
    Diabetic ulcer 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Exfoliative rash 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Leukocytoclastic vasculitis 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Stasis dermatitis 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Vascular disorders
    Hypotension 1/167 (0.6%) 1/163 (0.6%) 4/163 (2.5%)
    Hypertensive crisis 3/167 (1.8%) 2/163 (1.2%) 0/163 (0%)
    Deep vein thrombosis 0/167 (0%) 3/163 (1.8%) 1/163 (0.6%)
    Hypertension 2/167 (1.2%) 1/163 (0.6%) 1/163 (0.6%)
    Aortic aneurysm 2/167 (1.2%) 0/163 (0%) 1/163 (0.6%)
    Hypertensive emergency 1/167 (0.6%) 2/163 (1.2%) 0/163 (0%)
    Haematoma 0/167 (0%) 2/163 (1.2%) 0/163 (0%)
    Accelerated hypertension 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Angiopathy 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Aortic aneurysm rupture 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Aortic stenosis 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Arterial occlusive disease 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Cardiovascular insufficiency 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Malignant hypertension 0/167 (0%) 1/163 (0.6%) 0/163 (0%)
    Orthostatic hypotension 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Peripheral ischaemia 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Peripheral vascular disorder 0/167 (0%) 0/163 (0%) 1/163 (0.6%)
    Vascular pseudoaneurysm 1/167 (0.6%) 0/163 (0%) 0/163 (0%)
    Other (Not Including Serious) Adverse Events
    Peginesatide 0.025 mg/kg Peginesatide 0.04 mg/kg Darbepoetin Alfa
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 142/167 (85%) 134/163 (82.2%) 134/163 (82.2%)
    Blood and lymphatic system disorders
    Anaemia 13/167 (7.8%) 9/163 (5.5%) 4/163 (2.5%)
    Endocrine disorders
    Hyperparathyroidism 8/167 (4.8%) 4/163 (2.5%) 9/163 (5.5%)
    Hyperparathyroidism secondary 5/167 (3%) 9/163 (5.5%) 6/163 (3.7%)
    Gastrointestinal disorders
    Nausea 27/167 (16.2%) 25/163 (15.3%) 27/163 (16.6%)
    Diarrhoea 22/167 (13.2%) 21/163 (12.9%) 32/163 (19.6%)
    Vomiting 17/167 (10.2%) 23/163 (14.1%) 15/163 (9.2%)
    Constipation 12/167 (7.2%) 16/163 (9.8%) 18/163 (11%)
    Gastrooesophageal reflux disease 12/167 (7.2%) 9/163 (5.5%) 5/163 (3.1%)
    Abdominal pain 9/167 (5.4%) 5/163 (3.1%) 7/163 (4.3%)
    Abdominal pain upper 8/167 (4.8%) 6/163 (3.7%) 9/163 (5.5%)
    General disorders
    Oedema peripheral 45/167 (26.9%) 26/163 (16%) 34/163 (20.9%)
    Fatigue 15/167 (9%) 18/163 (11%) 14/163 (8.6%)
    Asthenia 12/167 (7.2%) 8/163 (4.9%) 8/163 (4.9%)
    Pain 10/167 (6%) 2/163 (1.2%) 3/163 (1.8%)
    Infections and infestations
    Nasopharyngitis 22/167 (13.2%) 19/163 (11.7%) 24/163 (14.7%)
    Urinary tract infection 22/167 (13.2%) 22/163 (13.5%) 22/163 (13.5%)
    Upper respiratory tract infection 12/167 (7.2%) 15/163 (9.2%) 19/163 (11.7%)
    Bronchitis 5/167 (3%) 14/163 (8.6%) 13/163 (8%)
    Sinusitis 5/167 (3%) 5/163 (3.1%) 12/163 (7.4%)
    Injury, poisoning and procedural complications
    Fall 16/167 (9.6%) 11/163 (6.7%) 10/163 (6.1%)
    Contusion 13/167 (7.8%) 11/163 (6.7%) 5/163 (3.1%)
    Metabolism and nutrition disorders
    Hyperkalaemia 23/167 (13.8%) 24/163 (14.7%) 23/163 (14.1%)
    Hyperphosphataemia 16/167 (9.6%) 6/163 (3.7%) 15/163 (9.2%)
    Gout 11/167 (6.6%) 4/163 (2.5%) 9/163 (5.5%)
    Hypoglycaemia 10/167 (6%) 11/163 (6.7%) 6/163 (3.7%)
    Iron deficiency 10/167 (6%) 4/163 (2.5%) 4/163 (2.5%)
    Metabolic acidosis 10/167 (6%) 3/163 (1.8%) 8/163 (4.9%)
    Anorexia 9/167 (5.4%) 4/163 (2.5%) 7/163 (4.3%)
    Hypokalaemia 6/167 (3.6%) 7/163 (4.3%) 9/163 (5.5%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 23/167 (13.8%) 16/163 (9.8%) 14/163 (8.6%)
    Back pain 21/167 (12.6%) 18/163 (11%) 10/163 (6.1%)
    Pain in extremity 14/167 (8.4%) 17/163 (10.4%) 17/163 (10.4%)
    Musculoskeletal pain 9/167 (5.4%) 10/163 (6.1%) 7/163 (4.3%)
    Muscle spasms 8/167 (4.8%) 4/163 (2.5%) 14/163 (8.6%)
    Nervous system disorders
    Dizziness 17/167 (10.2%) 20/163 (12.3%) 20/163 (12.3%)
    Headache 15/167 (9%) 15/163 (9.2%) 12/163 (7.4%)
    Psychiatric disorders
    Insomnia 13/167 (7.8%) 7/163 (4.3%) 7/163 (4.3%)
    Depression 11/167 (6.6%) 7/163 (4.3%) 7/163 (4.3%)
    Anxiety 10/167 (6%) 7/163 (4.3%) 3/163 (1.8%)
    Renal and urinary disorders
    Renal failure chronic 9/167 (5.4%) 4/163 (2.5%) 13/163 (8%)
    Respiratory, thoracic and mediastinal disorders
    Cough 16/167 (9.6%) 17/163 (10.4%) 15/163 (9.2%)
    Dyspnoea 12/167 (7.2%) 17/163 (10.4%) 16/163 (9.8%)
    Vascular disorders
    Hypertension 32/167 (19.2%) 24/163 (14.7%) 34/163 (20.9%)
    Hypotension 15/167 (9%) 13/163 (8%) 18/163 (11%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The first publication of the primary safety and efficacy results will include data from all appropriate study sites. Either after the first multicenter publication, or following 36 months after the completion of the study, Investigators are free to publish; such publications may not contain Sponsor Confidential Information and may be subject to Sponsor review 60 days prior to submission for publication.

    Results Point of Contact

    Name/Title Vice President, Clinical Development
    Organization Affymax
    Phone 650-812-8700
    Email info@affymax.com
    Responsible Party:
    Affymax
    ClinicalTrials.gov Identifier:
    NCT00598442
    Other Study ID Numbers:
    • AFX01-13
    • 2007-004146-32
    First Posted:
    Jan 21, 2008
    Last Update Posted:
    Feb 12, 2013
    Last Verified:
    Feb 1, 2013