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START-CKD: Strategies Using Darbepoetin Alfa to Avoid Transfusions in Chronic Kidney Disease

Sponsor
Amgen (Industry)
Overall Status
Completed
CT.gov ID
NCT01652872
Collaborator
(none)
756
Enrollment
249
Locations
2
Arms
62.7
Actual Duration (Months)
3
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

A phase 3, multicenter, randomized, double-blind, parallel group study. Anemic subjects with chronic kidney disease (CKD) and not on dialysis will be randomized 1:1 to 1 of 2 dosing strategies to evaluate the proportion of subjects receiving at least one red blood cell (RBC) transfusion. In the haemoglobin (Hb)-based titration group, darbepoetin alfa doses will be titrated to maintain Hb ≥ 10.0 grams/deciliter (g/dL). In the fixed dose group, subjects will receive a fixed dose of darbepoetin alfa. Treatment group, darbepoetin alfa doses, and protocol specified Hb concentrations will be blinded. Subjects will be followed for approximately 2 years from the date of randomization.

Condition or Disease Intervention/Treatment Phase
  • Biological: Darbepoetin alfa
  • Other: Placebo
 Phase 3

Detailed Description

The study is a phase 3, multicenter, randomized, double-blind, parallel group study designed to describe the benefits and potential risks of a new treatment strategy using a fixed dose of darbepoetin alfa in subjects with CKD and not on dialysis. Anemic subjects without recent use of an erythropoiesis stimulating agent (ESA) will be randomly allocated 1:1 to treatment with a fixed dose of darbepoetin alfa or to treatment with darbepoetin alfa using a Hb-based titration strategy, which has been the conventional dosing strategy. In the Hb-based titration group, darbepoetin alfa doses will be titrated to maintain Hb ≥ 10.0 g/dL. This study aims to estimate the incidence of RBC transfusions (administered as deemed clinically necessary) in each group and the difference in incidence of RBC transfusions between the 2 groups. In addition, multiple aspects, such as cumulative darbepoetin alfa dose, total number of units of transfusions, Hb concentration, Hb-related parameters (eg, Hb variability, excursions, rate of change), and adverse (eg, cardiovascular) events, will also be considered in order to determine a preferred dosing regimen. Treatment group, darbepoetin alfa doses, and protocol specified Hb concentrations will be blinded to the investigator, subjects and study team. Subjects will be followed for approximately 2 years from the date of randomization.

Study Design

Study Type:
Interventional
Actual Enrollment :
756 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
Strategies Using Darbepoetin Alfa to Avoid Transfusions in Chronic Kidney Disease
Actual Study Start Date :
Jul 30, 2012
Actual Primary Completion Date :
Oct 19, 2017
Actual Study Completion Date :
Oct 19, 2017

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Hb-Based Titration Group

Participants received darbepoetin alfa as a subcutaneous (SC) injection once every 4 weeks (Q4W) for up to 96 weeks. The dose of darbepoetin alfa was titrated based on the Hb concentration on the date of the visit, the corresponding Hb rate of rise (ROR), and the previously assigned dose. Doses were reduced if Hb exceeded 10.5 g/dL or Hb ROR exceeded 1.0 g/dL/4W. When darbepoetin alfa therapy was withheld per the dosing algorithm, placebo was administered. The starting dose of darbepoetin alfa was 0.45 micrograms/kilogram (mcg/kg) and the protocol specified doses ranged from 10 to 300 mcg.

Biological: Darbepoetin alfa
Darbepoetin alfa was presented as single use prefilled syringes (PFS). Investigational product was administered SC Q4W for the duration of the treatment period.
Other Names:
  • Aranesp

    • Other: Placebo
    Placebo was presented as single use PFS. Participants received a SC placebo injection in place of darbepoetin alfa therapy when the dose of study drug was withheld per the dosing algorithm for the duration of the treatment period.
    Experimental: Fixed Dose Group

    Participants received darbepoetin alfa as a SC injection Q4W at the same dose as assigned at the time of randomization for the duration of the 96 week treatment period. There was 1 exception to the fixed dose strategy: if the Hb was > 12.0 g/dL, darbepoetin alfa therapy was withheld and placebo administered. Once the Hb fell to < 10.0 g/dL, darbepoetin alfa therapy resumed at the same dose. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg.

    Biological: Darbepoetin alfa
    Darbepoetin alfa was presented as single use prefilled syringes (PFS). Investigational product was administered SC Q4W for the duration of the treatment period.
    Other Names:
  • Aranesp

    • Other: Placebo
    Placebo was presented as single use PFS. Participants received a SC placebo injection in place of darbepoetin alfa therapy when the dose of study drug was withheld per the dosing algorithm for the duration of the treatment period.

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants in Receipt of 1 or More RBC Transfusions [From randomization until the end of study, up to week 101.]

      The percentage of participants receiving at least 1 RBC transfusion during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach).

    Secondary Outcome Measures

    1. Mean Number of Units of RBC Transfused [From randomization until the end of study, up to week 101.]

      The total number of units of RBC transfused per participant during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach). The mean total number of RBC units transfused per participant is presented.

    2. Time to First RBC Transfusion [From randomization until the end of study, up to week 101.]

      Time to first RBC transfusion during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach). The time to first RBC transfusion is presented using Kaplan-Meier (KM) estimates at 6, 12, 18, and 24 months.

    3. Mean Achieved Hb Concentration While Receiving Investigational Product [From week 13 until the end of study, up to week 101.]

      Average achieved Hb concentration while receiving investigational product was recorded as mean Hb using the area under the curve (AUC) method for each treatment group. The AUC of Hb was calculated according to the trapezoidal method, standardized as daily AUC. Participants with available Hb values from study day 85 (week 13) to the last dose date were included in the calculation.

    4. Geometric Mean Cumulative Dose of Darbepoetin Alfa Per 4 Weeks [From randomization until the end of study, up to week 101.]

      Cumulative doses of darbepoetin alfa adjusted for investigation product exposure time (e.g. mean cumulative darbepoetin alfa dose per 4 weeks) were calculated for each treatment group using the total cumulative dose during the study divided by total number of weeks dosed then multiplied by 4. The geometric mean cumulative dose is presented.

    Eligibility Criteria

    Criteria

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

    • Clinical history of advanced CKD not on dialysis with at least 1 historic estimated glomerular filtration rate (eGFR) < 45.0 mL/mi)/1.73 m2 at least 12 weeks prior to screening

    • Not currently receiving dialysis with an eGFR < 45.0 mL/min/1.73m2, per the central laboratory during screening

    • Chronic anemia due to renal failure

    • Two Hb concentrations < 10.0 g/dL, at least 2 weeks apart during screening using the modified Hb point of care (POC) device

    • Iron replete, defined as a transferrin saturation (TSAT) ≥ 20% and a ferritin ≥ 100 ng/mL, per the central laboratory during screening

    • Vitamin B12 and folate replete, defined as a vitamin B12 level > 180 pg/mL and a folate concentration > 7 nmol/L, per the central laboratory during screening

    • Clinically stable in the opinion of the investigator

    • Subject has provided written informed consent

    Key Exclusion Criteria:

    • Systemic hematologic disease (eg, sickle cell anemia, myelodysplastic syndrome, hematologic malignancy)

    • Current or prior malignancy within 5 years of screening, with the exception of non-melanoma skin cancers and cervical intraepithelial neoplasia

    • Treatment for any malignancy (eg, radiation, chemotherapy, hormone therapy, or biologics) within 5 years of screening, with the exception of locally excised non-melanoma skin cancer or cervical intraepithelial neoplasia

    • Female subject not willing to use highly effective methods of birth control during treatment and for 4 weeks after the end of treatment

    • Subject is pregnant or breast feeding, or might become pregnant during the study or within 4 weeks after the end of treatment

    • Currently receiving intravenous (IV) antibiotics for treatment of an active infection

    • Known Human Immunodeficiency Virus (HIV) positive

    • Currently receiving systemic immunosuppressive therapy with the exception of prednis(ol)one ≤ 10 mg per day (or the steroid equivalent)

    • History of any organ transplant

    • Currently enrolled in another interventional study (eg, studies which require medical device use or drug therapy or with protocol required procedures), or less than 4 weeks since ending another interventional study(s) or receiving investigational agent(s)

    • Known neutralizing anti-erythropoietic protein antibodies

    • Known sensitivity to any of the products to be administered during dosing

    • Previously enrolled in this study

    • Not expected to be available for protocol required study visits or procedures to the best of the subject and investigator's knowledge

    • Subject has any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or comply with all required study procedures

    • Occurrence of stroke or myocardial infarction (MI) within 24 weeks of screening

    • Receipt of RBC transfusion within 8 weeks of screening

    • Occurrence of seizure, clinically relevant active bleeding (eg, gastrointestinal [GI] bleed) or any hospitalization within 8 weeks of screening

    • Receipt of any IV iron therapy within 4 weeks of screening

    • Changes in oral iron therapy within 4 weeks of screening

    • Receipt of ESA therapy within 4 weeks of screening

    • Diagnosis or treatment of malignancy, with the exception of non-melanoma skin cancers and cervical intraepithelial neoplasia during screening

    • Receipt of ESA therapy, RBC transfusions, IV iron therapy during screening

    • Changes in oral iron therapy during screening

    • Occurrence of stroke, MI, seizure, clinically relevant active bleeding (eg, GI bleed), any hospitalization or outpatient surgery during screening

    • Uncontrolled hypertension during screening. Defined in this study, as a mean systolic blood pressure > 140 mmHg at both screening visits, or a mean systolic blood pressure

    /= 160 mmHg at any screening visit, or a mean diastolic blood pressure >/= 90 mmHg at any screening visit.

    • Expected or scheduled change in oral iron therapy or receipt of IV iron therapy within 4 weeks after randomization

    • Expected or scheduled receipt of a RBC transfusion within 8 weeks after randomization

    • Expected or scheduled organ transplant within 24 weeks after randomization

    • Expected or scheduled initiation of dialysis within 24 weeks after randomization

    Contacts and Locations

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    Sponsors and Collaborators

    • Amgen

    Investigators

    • Study Director: MD, Amgen

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT01652872
    Other Study ID Numbers:
    • 20110226
    First Posted:
    Jul 30, 2012
    Last Update Posted:
    Dec 12, 2018
    Last Verified:
    Nov 1, 2018
    Keywords provided by Amgen
    anemia
    chronic kidney disease
    kidney disease
    renal failure
    Additional relevant MeSH terms:
    Kidney Diseases
    Renal Insufficiency, Chronic
    Darbepoetin alfa

    Study Results

    Participant Flow

    Recruitment Details Anemic participants with chronic kidney disease and not on dialysis (CKD-ND) were enrolled at 126 study centers in the United States, from 30 July 2012 to 19 October 2017. The on-study duration was approximately 2 years, comprising of a 2- to 4-week screening period, a 96-week treatment period and a 4-week follow up period.
    Pre-assignment Detail Participants were randomized in a 1:1 ratio to 1 of 2 darbepoetin alfa dosing strategies (hemoglobin [Hb]-based titration group or fixed dose group). Randomization was stratified by red blood cell (RBC) transfusion received within 12 months prior to randomization (yes/no) and site practice setting (nephrology/non-nephrology).
    Arm/Group Title Hb-Based Titration Group Fixed Dose Group
    Arm/Group Description Participants received darbepoetin alfa as a subcutaneous (SC) injection once every 4 weeks (Q4W) for up to 96 weeks. The dose of darbepoetin alfa was titrated based on the Hb concentration on the date of the visit, the corresponding Hb rate of rise (ROR), and the previously assigned dose. Doses were reduced if Hb exceeded 10.5 grams/deciliter (g/dL) or Hb ROR exceeded 1.0 g/dL/4W. When darbepoetin alfa therapy was withheld per the dosing algorithm, placebo was administered. The starting dose of darbepoetin alfa was 0.45 micrograms/kilogram (mcg/kg) and the protocol specified doses ranged from 10 to 300 mcg. Participants received darbepoetin alfa as a SC injection Q4W at the same dose as assigned at the time of randomization for the duration of the 96-week treatment period. There was 1 exception to the fixed dose strategy: if the Hb was > 12.0 g/dL, darbepoetin alfa therapy was withheld and placebo administered. Once the Hb fell to < 10.0 g/dL, darbepoetin alfa therapy resumed at the same dose. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg.
    Period Title: Overall Study
    STARTED 377 379
    Received Investigational Product 377 377
    COMPLETED 232 226
    NOT COMPLETED 145 153

    Baseline Characteristics

    Arm/Group Title Hb-Based Titration Group Fixed Dose Group Total
    Arm/Group Description Participants received darbepoetin alfa as a SC injection, Q4W for up to 96 weeks. The dose of darbepoetin alfa was titrated based on the Hb concentration on the date of the visit, the corresponding Hb ROR, and the previously assigned dose. Doses were reduced if Hb exceeded 10.5 g/dL or Hb ROR exceeded 1.0 g/dL/4W. When darbepoetin alfa therapy was withheld per the dosing algorithm, placebo was administered. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg. Participants received darbepoetin alfa as a SC injection Q4W at the same dose as assigned at the time of randomization for the duration of the 96-week treatment period. There was 1 exception to the fixed dose strategy: if the Hb was > 12.0 g/dL, darbepoetin alfa therapy was withheld and placebo administered. Once the Hb fell to < 10.0 g/dL, darbepoetin alfa therapy resumed at the same dose. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg. Total of all reporting groups
    Overall Participants 377 379 756
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    69.2
    (13.5)
    69.5
    (13.1)
    69.4
    (13.3)
    Age, Customized (Count of Participants)
    18 - 64 years
    129
    34.2%
    134
    35.4%
    263
    34.8%
    65 - 74 years
    97
    25.7%
    96
    25.3%
    193
    25.5%
    75 - 84 years
    105
    27.9%
    97
    25.6%
    202
    26.7%
    >=85 years
    46
    12.2%
    52
    13.7%
    98
    13%
    Sex: Female, Male (Count of Participants)
    Female
    223
    59.2%
    218
    57.5%
    441
    58.3%
    Male
    154
    40.8%
    161
    42.5%
    315
    41.7%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    92
    24.4%
    95
    25.1%
    187
    24.7%
    Not Hispanic or Latino
    285
    75.6%
    284
    74.9%
    569
    75.3%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    American Indian or Alaska Native
    1
    0.3%
    0
    0%
    1
    0.1%
    Asian
    25
    6.6%
    21
    5.5%
    46
    6.1%
    Black or African American
    125
    33.2%
    134
    35.4%
    259
    34.3%
    Native Hawaiian or Other Pacific Islander
    5
    1.3%
    4
    1.1%
    9
    1.2%
    White
    220
    58.4%
    215
    56.7%
    435
    57.5%
    Mixed race/Other
    1
    0.3%
    5
    1.3%
    6
    0.8%
    Previous RBC transfusions (Count of Participants)
    Yes
    145
    38.5%
    140
    36.9%
    285
    37.7%
    No
    232
    61.5%
    239
    63.1%
    471
    62.3%

    Outcome Measures

    1. Primary Outcome
    Title Percentage of Participants in Receipt of 1 or More RBC Transfusions
    Description The percentage of participants receiving at least 1 RBC transfusion during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach).
    Time Frame From randomization until the end of study, up to week 101.

    Outcome Measure Data

    Analysis Population Description
    The full analysis set included all randomized participants who received at least 1 dose of investigational product.
    Arm/Group Title Hb-Based Titration Group Fixed Dose Group
    Arm/Group Description Participants received darbepoetin alfa as a SC injection, Q4W for up to 96 weeks. The dose of darbepoetin alfa was titrated based on the Hb concentration on the date of the visit, the corresponding Hb ROR, and the previously assigned dose. Doses were reduced if Hb exceeded 10.5 g/dL or Hb ROR exceeded 1.0 g/dL/4W. When darbepoetin alfa therapy was withheld per the dosing algorithm, placebo was administered. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg. Participants received darbepoetin alfa as a SC injection Q4W at the same dose as assigned at the time of randomization for the duration of the 96-week treatment period. There was 1 exception to the fixed dose strategy: if the Hb was > 12.0 g/dL, darbepoetin alfa therapy was withheld and placebo administered. Once the Hb fell to < 10.0 g/dL, darbepoetin alfa therapy resumed at the same dose. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg.
    Measure Participants 377 377
    Number (95% Confidence Interval) [Percentage of Participants]
    24.40
    6.5%
    24.14
    6.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Hb-Based Titration Group, Fixed Dose Group
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Treatment Difference
    Estimated Value -0.27
    Confidence Interval (2-Sided) 95%
    -6.39 to 5.85
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference is fixed dose - titration.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Hb-Based Titration Group, Fixed Dose Group
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Risk Ratio (RR)
    Estimated Value 0.998
    Confidence Interval (2-Sided) 95%
    0.776 to 1.285
    Parameter Dispersion Type:
    Value:
    Estimation Comments A risk ratio < 1.0 indicates a lower event rate for the fixed dose group relative to Hb-based titration group.
    2. Secondary Outcome
    Title Mean Number of Units of RBC Transfused
    Description The total number of units of RBC transfused per participant during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach). The mean total number of RBC units transfused per participant is presented.
    Time Frame From randomization until the end of study, up to week 101.

    Outcome Measure Data

    Analysis Population Description
    The full analysis set included all randomized participants who received at least 1 dose of investigational product.
    Arm/Group Title Hb-Based Titration Group Fixed Dose Group
    Arm/Group Description Participants received darbepoetin alfa as a SC injection, Q4W for up to 96 weeks. The dose of darbepoetin alfa was titrated based on the Hb concentration on the date of the visit, the corresponding Hb ROR, and the previously assigned dose. Doses were reduced if Hb exceeded 10.5 g/dL or Hb ROR exceeded 1.0 g/dL/4W. When darbepoetin alfa therapy was withheld per the dosing algorithm, placebo was administered. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg. Participants received darbepoetin alfa as a SC injection Q4W at the same dose as assigned at the time of randomization for the duration of the 96-week treatment period. There was 1 exception to the fixed dose strategy: if the Hb was > 12.0 g/dL, darbepoetin alfa therapy was withheld and placebo administered. Once the Hb fell to < 10.0 g/dL, darbepoetin alfa therapy resumed at the same dose. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg.
    Measure Participants 377 377
    Mean (95% Confidence Interval) [Units of transfused RBC]
    0.71
    0.87
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Hb-Based Titration Group, Fixed Dose Group
    Comments
    Type of Statistical Test Other
    Comments Stratified by RBC transfusion received within 12 months prior to randomization (yes/no) and site practice setting (nephrology/non-nephrology) and accounting for participant exposure time.
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Least Squares Mean (LSM) Ratio
    Estimated Value 1.28
    Confidence Interval (2-Sided) 95%
    0.81 to 2.05
    Parameter Dispersion Type:
    Value:
    Estimation Comments Least Squares Mean (LSM) ratio is fixed dose relative to titration.
    3. Secondary Outcome
    Title Time to First RBC Transfusion
    Description Time to first RBC transfusion during the evaluation period was recorded for each treatment group. The evaluation period began from the date of randomization, and participants were censored at the last dose of investigational product plus 3 months or end of study, whichever was earlier (on-treatment approach). The time to first RBC transfusion is presented using Kaplan-Meier (KM) estimates at 6, 12, 18, and 24 months.
    Time Frame From randomization until the end of study, up to week 101.

    Outcome Measure Data

    Analysis Population Description
    The full analysis set included all randomized participants who received at least 1 dose of investigational product.
    Arm/Group Title Hb-Based Titration Group Fixed Dose Group
    Arm/Group Description Participants received darbepoetin alfa as a SC injection, Q4W for up to 96 weeks. The dose of darbepoetin alfa was titrated based on the Hb concentration on the date of the visit, the corresponding Hb ROR, and the previously assigned dose. Doses were reduced if Hb exceeded 10.5 g/dL or Hb ROR exceeded 1.0 g/dL/4W. When darbepoetin alfa therapy was withheld per the dosing algorithm, placebo was administered. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg. Participants received darbepoetin alfa as a SC injection Q4W at the same dose as assigned at the time of randomization for the duration of the 96-week treatment period. There was 1 exception to the fixed dose strategy: if the Hb was > 12.0 g/dL, darbepoetin alfa therapy was withheld and placebo administered. Once the Hb fell to < 10.0 g/dL, darbepoetin alfa therapy resumed at the same dose. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg.
    Measure Participants 377 377
    KM estimates at month 6
    0.115
    0.136
    KM estimates at month 12
    0.192
    0.204
    KM estimates at month 18
    0.261
    0.246
    KM estimates at month 24
    0.297
    0.289
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Hb-Based Titration Group, Fixed Dose Group
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.01
    Confidence Interval (2-Sided) 95%
    0.76 to 1.35
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio is fixed dose relative to titration.
    4. Secondary Outcome
    Title Mean Achieved Hb Concentration While Receiving Investigational Product
    Description Average achieved Hb concentration while receiving investigational product was recorded as mean Hb using the area under the curve (AUC) method for each treatment group. The AUC of Hb was calculated according to the trapezoidal method, standardized as daily AUC. Participants with available Hb values from study day 85 (week 13) to the last dose date were included in the calculation.
    Time Frame From week 13 until the end of study, up to week 101.

    Outcome Measure Data

    Analysis Population Description
    The full analysis set included all randomized participants who received at least 1 dose of investigational product.
    Arm/Group Title Hb-Based Titration Group Fixed Dose Group
    Arm/Group Description Participants received darbepoetin alfa as a SC injection, Q4W for up to 96 weeks. The dose of darbepoetin alfa was titrated based on the Hb concentration on the date of the visit, the corresponding Hb ROR, and the previously assigned dose. Doses were reduced if Hb exceeded 10.5 g/dL or Hb ROR exceeded 1.0 g/dL/4W. When darbepoetin alfa therapy was withheld per the dosing algorithm, placebo was administered. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg. Participants received darbepoetin alfa as a SC injection Q4W at the same dose as assigned at the time of randomization for the duration of the 96-week treatment period. There was 1 exception to the fixed dose strategy: if the Hb was > 12.0 g/dL, darbepoetin alfa therapy was withheld and placebo administered. Once the Hb fell to < 10.0 g/dL, darbepoetin alfa therapy resumed at the same dose. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg.
    Measure Participants 377 377
    Mean (Standard Error) [g/dL]
    9.71
    (0.04)
    9.41
    (0.05)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Hb-Based Titration Group, Fixed Dose Group
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Median of the difference
    Estimated Value -0.34
    Confidence Interval (2-Sided) 95%
    -0.46 to -0.22
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference is fixed dose - titration.
    Other Statistical Analysis The 2-sided 95% confidence intervals were obtained using a non-parametric Wilcoxon rank-sum statistic.
    5. Secondary Outcome
    Title Geometric Mean Cumulative Dose of Darbepoetin Alfa Per 4 Weeks
    Description Cumulative doses of darbepoetin alfa adjusted for investigation product exposure time (e.g. mean cumulative darbepoetin alfa dose per 4 weeks) were calculated for each treatment group using the total cumulative dose during the study divided by total number of weeks dosed then multiplied by 4. The geometric mean cumulative dose is presented.
    Time Frame From randomization until the end of study, up to week 101.

    Outcome Measure Data

    Analysis Population Description
    The full analysis set included all randomized participants who received at least 1 dose of investigational product.
    Arm/Group Title Hb-Based Titration Group Fixed Dose Group
    Arm/Group Description Participants received darbepoetin alfa as a SC injection, Q4W for up to 96 weeks. The dose of darbepoetin alfa was titrated based on the Hb concentration on the date of the visit, the corresponding Hb ROR, and the previously assigned dose. Doses were reduced if Hb exceeded 10.5 g/dL or Hb ROR exceeded 1.0 g/dL/4W. When darbepoetin alfa therapy was withheld per the dosing algorithm, placebo was administered. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg. Participants received darbepoetin alfa as a SC injection Q4W at the same dose as assigned at the time of randomization for the duration of the 96-week treatment period. There was 1 exception to the fixed dose strategy: if the Hb was > 12.0 g/dL, darbepoetin alfa therapy was withheld and placebo administered. Once the Hb fell to < 10.0 g/dL, darbepoetin alfa therapy resumed at the same dose. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg.
    Measure Participants 377 377
    Geometric Mean (Standard Error) [mcg]
    50.7
    (2.7)
    30.8
    (1.2)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Hb-Based Titration Group
    Comments
    Type of Statistical Test Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Median of the difference
    Estimated Value -22.1
    Confidence Interval (2-Sided) 95%
    -26.1 to -18.1
    Parameter Dispersion Type:
    Value:
    Estimation Comments Difference is fixed dose - titration.
    Other Statistical Analysis The 2-sided 95% confidence intervals were obtained using a non-parametric Wilcoxon rank-sum statistic.

    Adverse Events

    Time Frame Treatment Emergent Adverse Events were collected from randomization on study day 1 until 4 weeks after final dose of investigational product (up to 101 weeks).
    Adverse Event Reporting Description Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
    Arm/Group Title Hb-Based Titration Group Fixed Dose Group
    Arm/Group Description Participants received darbepoetin alfa as a SC injection, Q4W for up to 96 weeks. The dose of darbepoetin alfa was titrated based on the Hb concentration on the date of the visit, the corresponding Hb ROR, and the previously assigned dose. Doses were reduced if Hb exceeded 10.5 g/dL or Hb ROR exceeded 1.0 g/dL/4W. When darbepoetin alfa therapy was withheld per the dosing algorithm, placebo was administered. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg. Participants received darbepoetin alfa as a SC injection Q4W at the same dose as assigned at the time of randomization for the duration of the 96-week treatment period. There was 1 exception to the fixed dose strategy: if the Hb was > 12.0 g/dL, darbepoetin alfa therapy was withheld and placebo administered. Once the Hb fell to < 10.0 g/dL, darbepoetin alfa therapy resumed at the same dose. The starting dose of darbepoetin alfa was 0.45 mcg/kg and the protocol specified doses ranged from 10 to 300 mcg.
    All Cause Mortality
    Hb-Based Titration Group Fixed Dose Group
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 38/377 (10.1%) 38/377 (10.1%)
    Serious Adverse Events
    Hb-Based Titration Group Fixed Dose Group
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 190/377 (50.4%) 175/377 (46.4%)
    Blood and lymphatic system disorders
    Anaemia 24/377 (6.4%) 29/377 (7.7%)
    Anaemia of chronic disease 1/377 (0.3%) 0/377 (0%)
    Coagulopathy 0/377 (0%) 1/377 (0.3%)
    Hyperprothrombinaemia 0/377 (0%) 1/377 (0.3%)
    Leukocytosis 1/377 (0.3%) 1/377 (0.3%)
    Leukopenia 0/377 (0%) 1/377 (0.3%)
    Microcytic anaemia 0/377 (0%) 1/377 (0.3%)
    Nephrogenic anaemia 1/377 (0.3%) 0/377 (0%)
    Thrombocytopenia 0/377 (0%) 2/377 (0.5%)
    Cardiac disorders
    Acute coronary syndrome 1/377 (0.3%) 0/377 (0%)
    Acute left ventricular failure 0/377 (0%) 1/377 (0.3%)
    Acute myocardial infarction 5/377 (1.3%) 5/377 (1.3%)
    Angina pectoris 3/377 (0.8%) 2/377 (0.5%)
    Angina unstable 1/377 (0.3%) 1/377 (0.3%)
    Aortic valve stenosis 1/377 (0.3%) 0/377 (0%)
    Atrial fibrillation 0/377 (0%) 2/377 (0.5%)
    Atrial flutter 1/377 (0.3%) 0/377 (0%)
    Atrioventricular block complete 0/377 (0%) 1/377 (0.3%)
    Bradycardia 4/377 (1.1%) 1/377 (0.3%)
    Cardiac arrest 3/377 (0.8%) 3/377 (0.8%)
    Cardiac disorder 0/377 (0%) 1/377 (0.3%)
    Cardiac failure 11/377 (2.9%) 7/377 (1.9%)
    Cardiac failure acute 2/377 (0.5%) 2/377 (0.5%)
    Cardiac failure chronic 1/377 (0.3%) 0/377 (0%)
    Cardiac failure congestive 28/377 (7.4%) 17/377 (4.5%)
    Cardiac ventricular thrombosis 1/377 (0.3%) 0/377 (0%)
    Cardiogenic shock 1/377 (0.3%) 0/377 (0%)
    Coronary artery disease 1/377 (0.3%) 3/377 (0.8%)
    Diastolic dysfunction 1/377 (0.3%) 0/377 (0%)
    Hypertensive heart disease 1/377 (0.3%) 0/377 (0%)
    Ischaemic cardiomyopathy 1/377 (0.3%) 0/377 (0%)
    Left ventricular dysfunction 0/377 (0%) 1/377 (0.3%)
    Left ventricular failure 1/377 (0.3%) 3/377 (0.8%)
    Mitral valve stenosis 0/377 (0%) 1/377 (0.3%)
    Myocardial infarction 5/377 (1.3%) 1/377 (0.3%)
    Myocardial ischaemia 1/377 (0.3%) 0/377 (0%)
    Nodal arrhythmia 0/377 (0%) 1/377 (0.3%)
    Sinus arrest 1/377 (0.3%) 0/377 (0%)
    Sinus bradycardia 1/377 (0.3%) 0/377 (0%)
    Tachyarrhythmia 0/377 (0%) 1/377 (0.3%)
    Congenital, familial and genetic disorders
    Gastrointestinal arteriovenous malformation 0/377 (0%) 1/377 (0.3%)
    Endocrine disorders
    Hypothyroidism 1/377 (0.3%) 2/377 (0.5%)
    Gastrointestinal disorders
    Abdominal distension 0/377 (0%) 1/377 (0.3%)
    Abdominal pain 1/377 (0.3%) 3/377 (0.8%)
    Ascites 0/377 (0%) 1/377 (0.3%)
    Colitis 0/377 (0%) 1/377 (0.3%)
    Constipation 1/377 (0.3%) 0/377 (0%)
    Diarrhoea 1/377 (0.3%) 4/377 (1.1%)
    Diarrhoea haemorrhagic 1/377 (0.3%) 0/377 (0%)
    Diverticulum 1/377 (0.3%) 1/377 (0.3%)
    Diverticulum intestinal haemorrhagic 1/377 (0.3%) 0/377 (0%)
    Duodenal ulcer 0/377 (0%) 1/377 (0.3%)
    Gastritis 1/377 (0.3%) 0/377 (0%)
    Gastrointestinal haemorrhage 8/377 (2.1%) 6/377 (1.6%)
    Gastrooesophageal reflux disease 0/377 (0%) 2/377 (0.5%)
    Haemorrhoidal haemorrhage 0/377 (0%) 2/377 (0.5%)
    Ileus paralytic 0/377 (0%) 1/377 (0.3%)
    Impaired gastric emptying 1/377 (0.3%) 0/377 (0%)
    Large intestine polyp 1/377 (0.3%) 0/377 (0%)
    Lower gastrointestinal haemorrhage 1/377 (0.3%) 0/377 (0%)
    Melaena 1/377 (0.3%) 1/377 (0.3%)
    Nausea 1/377 (0.3%) 0/377 (0%)
    Oesophagitis 0/377 (0%) 1/377 (0.3%)
    Pancreatic mass 1/377 (0.3%) 0/377 (0%)
    Pancreatitis 1/377 (0.3%) 1/377 (0.3%)
    Pancreatitis acute 3/377 (0.8%) 1/377 (0.3%)
    Pancreatitis chronic 1/377 (0.3%) 0/377 (0%)
    Small intestinal obstruction 0/377 (0%) 2/377 (0.5%)
    Upper gastrointestinal haemorrhage 1/377 (0.3%) 0/377 (0%)
    Vomiting 2/377 (0.5%) 4/377 (1.1%)
    General disorders
    Asthenia 4/377 (1.1%) 0/377 (0%)
    Chest discomfort 1/377 (0.3%) 0/377 (0%)
    Chest pain 1/377 (0.3%) 3/377 (0.8%)
    Death 2/377 (0.5%) 0/377 (0%)
    Fatigue 1/377 (0.3%) 0/377 (0%)
    Generalised oedema 2/377 (0.5%) 2/377 (0.5%)
    Hypothermia 0/377 (0%) 2/377 (0.5%)
    Influenza like illness 1/377 (0.3%) 0/377 (0%)
    Non-cardiac chest pain 6/377 (1.6%) 1/377 (0.3%)
    Oedema peripheral 4/377 (1.1%) 2/377 (0.5%)
    Peripheral swelling 1/377 (0.3%) 0/377 (0%)
    Pneumatosis 0/377 (0%) 1/377 (0.3%)
    Pyrexia 2/377 (0.5%) 0/377 (0%)
    Hepatobiliary disorders
    Cholelithiasis 2/377 (0.5%) 2/377 (0.5%)
    Hepatic cirrhosis 2/377 (0.5%) 0/377 (0%)
    Infections and infestations
    Abscess limb 0/377 (0%) 1/377 (0.3%)
    Bacteraemia 1/377 (0.3%) 0/377 (0%)
    Bacterial sepsis 0/377 (0%) 1/377 (0.3%)
    Brain abscess 1/377 (0.3%) 0/377 (0%)
    Bronchitis 3/377 (0.8%) 1/377 (0.3%)
    Cellulitis 3/377 (0.8%) 5/377 (1.3%)
    Cholecystitis infective 1/377 (0.3%) 0/377 (0%)
    Device related infection 0/377 (0%) 1/377 (0.3%)
    Diverticulitis 2/377 (0.5%) 0/377 (0%)
    Emphysematous pyelonephritis 1/377 (0.3%) 0/377 (0%)
    Escherichia infection 0/377 (0%) 1/377 (0.3%)
    Escherichia urinary tract infection 1/377 (0.3%) 1/377 (0.3%)
    Gangrene 1/377 (0.3%) 1/377 (0.3%)
    Gastroenteritis 3/377 (0.8%) 1/377 (0.3%)
    Influenza 1/377 (0.3%) 0/377 (0%)
    Mycobacterium kansasii infection 1/377 (0.3%) 0/377 (0%)
    Osteomyelitis 2/377 (0.5%) 3/377 (0.8%)
    Osteomyelitis acute 1/377 (0.3%) 0/377 (0%)
    Pneumonia 15/377 (4%) 18/377 (4.8%)
    Pneumonia bacterial 0/377 (0%) 2/377 (0.5%)
    Pyelonephritis 0/377 (0%) 1/377 (0.3%)
    Pyelonephritis acute 0/377 (0%) 1/377 (0.3%)
    Pyuria 0/377 (0%) 1/377 (0.3%)
    Sepsis 6/377 (1.6%) 3/377 (0.8%)
    Septic shock 1/377 (0.3%) 2/377 (0.5%)
    Staphylococcal abscess 0/377 (0%) 1/377 (0.3%)
    Staphylococcal infection 0/377 (0%) 2/377 (0.5%)
    Staphylococcal sepsis 0/377 (0%) 1/377 (0.3%)
    Streptococcal urinary tract infection 0/377 (0%) 1/377 (0.3%)
    Upper respiratory tract infection 1/377 (0.3%) 0/377 (0%)
    Urinary tract infection 9/377 (2.4%) 11/377 (2.9%)
    Urinary tract infection bacterial 2/377 (0.5%) 2/377 (0.5%)
    Injury, poisoning and procedural complications
    Acetabulum fracture 0/377 (0%) 1/377 (0.3%)
    Alcohol poisoning 0/377 (0%) 1/377 (0.3%)
    Anaemia postoperative 0/377 (0%) 1/377 (0.3%)
    Clavicle fracture 1/377 (0.3%) 0/377 (0%)
    Contusion 1/377 (0.3%) 0/377 (0%)
    Fall 10/377 (2.7%) 2/377 (0.5%)
    Femur fracture 4/377 (1.1%) 0/377 (0%)
    Fractured sacrum 1/377 (0.3%) 0/377 (0%)
    Haematuria traumatic 1/377 (0.3%) 0/377 (0%)
    Head injury 2/377 (0.5%) 0/377 (0%)
    Hip fracture 1/377 (0.3%) 1/377 (0.3%)
    Humerus fracture 1/377 (0.3%) 0/377 (0%)
    Overdose 1/377 (0.3%) 0/377 (0%)
    Patella fracture 1/377 (0.3%) 0/377 (0%)
    Pelvic fracture 1/377 (0.3%) 0/377 (0%)
    Post procedural complication 0/377 (0%) 1/377 (0.3%)
    Post procedural haemorrhage 0/377 (0%) 1/377 (0.3%)
    Procedural haemorrhage 0/377 (0%) 1/377 (0.3%)
    Rib fracture 1/377 (0.3%) 1/377 (0.3%)
    Road traffic accident 1/377 (0.3%) 0/377 (0%)
    Spinal compression fracture 0/377 (0%) 1/377 (0.3%)
    Subarachnoid haemorrhage 1/377 (0.3%) 0/377 (0%)
    Subdural haematoma 1/377 (0.3%) 0/377 (0%)
    Tibia fracture 0/377 (0%) 1/377 (0.3%)
    Wrist fracture 1/377 (0.3%) 0/377 (0%)
    Investigations
    Acid base balance abnormal 0/377 (0%) 1/377 (0.3%)
    Blood creatinine increased 1/377 (0.3%) 0/377 (0%)
    Blood potassium increased 0/377 (0%) 1/377 (0.3%)
    ECG signs of myocardial ischaemia 1/377 (0.3%) 0/377 (0%)
    International normalised ratio increased 0/377 (0%) 1/377 (0.3%)
    Platelet count decreased 0/377 (0%) 1/377 (0.3%)
    Transaminases increased 0/377 (0%) 1/377 (0.3%)
    Troponin increased 1/377 (0.3%) 0/377 (0%)
    Urine output decreased 0/377 (0%) 1/377 (0.3%)
    Weight decreased 1/377 (0.3%) 0/377 (0%)
    Metabolism and nutrition disorders
    Acidosis 1/377 (0.3%) 0/377 (0%)
    Acidosis hyperchloraemic 0/377 (0%) 1/377 (0.3%)
    Decreased appetite 2/377 (0.5%) 0/377 (0%)
    Dehydration 5/377 (1.3%) 4/377 (1.1%)
    Diabetes mellitus inadequate control 1/377 (0.3%) 0/377 (0%)
    Diabetic ketoacidosis 2/377 (0.5%) 2/377 (0.5%)
    Failure to thrive 1/377 (0.3%) 1/377 (0.3%)
    Fluid overload 10/377 (2.7%) 5/377 (1.3%)
    Gout 2/377 (0.5%) 1/377 (0.3%)
    Hypercalcaemia 1/377 (0.3%) 1/377 (0.3%)
    Hyperglycaemia 4/377 (1.1%) 1/377 (0.3%)
    Hyperinsulinaemic hypoglycaemia 1/377 (0.3%) 0/377 (0%)
    Hyperkalaemia 10/377 (2.7%) 11/377 (2.9%)
    Hypocalcaemia 1/377 (0.3%) 0/377 (0%)
    Hypoglycaemia 4/377 (1.1%) 8/377 (2.1%)
    Hypokalaemia 0/377 (0%) 2/377 (0.5%)
    Hypomagnesaemia 2/377 (0.5%) 2/377 (0.5%)
    Hyponatraemia 1/377 (0.3%) 3/377 (0.8%)
    Hypophosphataemia 1/377 (0.3%) 0/377 (0%)
    Metabolic acidosis 2/377 (0.5%) 1/377 (0.3%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/377 (0%) 2/377 (0.5%)
    Back pain 1/377 (0.3%) 0/377 (0%)
    Costochondritis 0/377 (0%) 1/377 (0.3%)
    Flank pain 0/377 (0%) 2/377 (0.5%)
    Lumbar spinal stenosis 1/377 (0.3%) 0/377 (0%)
    Muscular weakness 1/377 (0.3%) 2/377 (0.5%)
    Osteoarthritis 0/377 (0%) 3/377 (0.8%)
    Pain in extremity 0/377 (0%) 1/377 (0.3%)
    Psoriatic arthropathy 1/377 (0.3%) 0/377 (0%)
    Rhabdomyolysis 0/377 (0%) 1/377 (0.3%)
    Systemic lupus erythematosus 0/377 (0%) 1/377 (0.3%)
    Tenosynovitis 1/377 (0.3%) 0/377 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia 0/377 (0%) 1/377 (0.3%)
    Gastric cancer 1/377 (0.3%) 0/377 (0%)
    Gastrointestinal tract adenoma 0/377 (0%) 1/377 (0.3%)
    Hepatocellular carcinoma 0/377 (0%) 1/377 (0.3%)
    Invasive ductal breast carcinoma 1/377 (0.3%) 0/377 (0%)
    Lung adenocarcinoma 1/377 (0.3%) 0/377 (0%)
    Lung cancer metastatic 1/377 (0.3%) 0/377 (0%)
    Metastatic lymphoma 1/377 (0.3%) 0/377 (0%)
    Non-Hodgkin's lymphoma 1/377 (0.3%) 0/377 (0%)
    Non-small cell lung cancer stage I 0/377 (0%) 1/377 (0.3%)
    Pancreatic carcinoma metastatic 0/377 (0%) 1/377 (0.3%)
    Papillary thyroid cancer 0/377 (0%) 1/377 (0.3%)
    Prostate cancer 0/377 (0%) 2/377 (0.5%)
    Squamous cell carcinoma of lung 2/377 (0.5%) 0/377 (0%)
    Thymoma 1/377 (0.3%) 0/377 (0%)
    Thyroid cancer 0/377 (0%) 1/377 (0.3%)
    Nervous system disorders
    Brain oedema 1/377 (0.3%) 0/377 (0%)
    Carotid artery stenosis 0/377 (0%) 1/377 (0.3%)
    Cerebral arteriosclerosis 0/377 (0%) 1/377 (0.3%)
    Cerebral haematoma 1/377 (0.3%) 0/377 (0%)
    Cerebral haemorrhage 2/377 (0.5%) 0/377 (0%)
    Cerebrovascular accident 1/377 (0.3%) 2/377 (0.5%)
    Dementia 0/377 (0%) 1/377 (0.3%)
    Dizziness 0/377 (0%) 3/377 (0.8%)
    Dysarthria 0/377 (0%) 2/377 (0.5%)
    Encephalopathy 2/377 (0.5%) 1/377 (0.3%)
    Haemorrhage intracranial 2/377 (0.5%) 0/377 (0%)
    Hemiparesis 1/377 (0.3%) 0/377 (0%)
    Hepatic encephalopathy 2/377 (0.5%) 1/377 (0.3%)
    Hydrocephalus 1/377 (0.3%) 0/377 (0%)
    Hypertensive encephalopathy 1/377 (0.3%) 0/377 (0%)
    Hypoxic-ischaemic encephalopathy 0/377 (0%) 1/377 (0.3%)
    Metabolic encephalopathy 1/377 (0.3%) 1/377 (0.3%)
    Migraine 0/377 (0%) 1/377 (0.3%)
    Paraesthesia 0/377 (0%) 1/377 (0.3%)
    Partial seizures 1/377 (0.3%) 0/377 (0%)
    Presyncope 1/377 (0.3%) 0/377 (0%)
    Seizure 2/377 (0.5%) 0/377 (0%)
    Syncope 5/377 (1.3%) 6/377 (1.6%)
    Transient ischaemic attack 0/377 (0%) 2/377 (0.5%)
    Unresponsive to stimuli 1/377 (0.3%) 0/377 (0%)
    Product Issues
    Device leakage 0/377 (0%) 1/377 (0.3%)
    Device malfunction 0/377 (0%) 1/377 (0.3%)
    Psychiatric disorders
    Anxiety 0/377 (0%) 1/377 (0.3%)
    Delirium 1/377 (0.3%) 0/377 (0%)
    Depression 2/377 (0.5%) 2/377 (0.5%)
    Drug abuse 0/377 (0%) 1/377 (0.3%)
    Mental status changes 2/377 (0.5%) 2/377 (0.5%)
    Renal and urinary disorders
    Acute kidney injury 34/377 (9%) 24/377 (6.4%)
    Azotaemia 1/377 (0.3%) 3/377 (0.8%)
    Chronic kidney disease 5/377 (1.3%) 4/377 (1.1%)
    End stage renal disease 12/377 (3.2%) 6/377 (1.6%)
    Hydronephrosis 1/377 (0.3%) 0/377 (0%)
    Nephropathy 1/377 (0.3%) 0/377 (0%)
    Renal failure 7/377 (1.9%) 5/377 (1.3%)
    Renal impairment 2/377 (0.5%) 0/377 (0%)
    Renal mass 0/377 (0%) 1/377 (0.3%)
    Renal tubular necrosis 1/377 (0.3%) 1/377 (0.3%)
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 0/377 (0%) 1/377 (0.3%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 5/377 (1.3%) 3/377 (0.8%)
    Asthma 0/377 (0%) 2/377 (0.5%)
    Atelectasis 0/377 (0%) 1/377 (0.3%)
    Chronic obstructive pulmonary disease 7/377 (1.9%) 3/377 (0.8%)
    Dyspnoea 3/377 (0.8%) 7/377 (1.9%)
    Dyspnoea exertional 0/377 (0%) 1/377 (0.3%)
    Epistaxis 1/377 (0.3%) 0/377 (0%)
    Hypercapnia 1/377 (0.3%) 0/377 (0%)
    Interstitial lung disease 1/377 (0.3%) 0/377 (0%)
    Oropharyngeal pain 1/377 (0.3%) 0/377 (0%)
    Pickwickian syndrome 1/377 (0.3%) 0/377 (0%)
    Pleural effusion 3/377 (0.8%) 6/377 (1.6%)
    Pleural fibrosis 1/377 (0.3%) 0/377 (0%)
    Pneumonia aspiration 0/377 (0%) 1/377 (0.3%)
    Pneumothorax 0/377 (0%) 1/377 (0.3%)
    Pulmonary congestion 2/377 (0.5%) 0/377 (0%)
    Pulmonary embolism 0/377 (0%) 1/377 (0.3%)
    Pulmonary oedema 4/377 (1.1%) 4/377 (1.1%)
    Respiratory arrest 1/377 (0.3%) 0/377 (0%)
    Respiratory disorder 1/377 (0.3%) 0/377 (0%)
    Respiratory distress 0/377 (0%) 1/377 (0.3%)
    Respiratory failure 6/377 (1.6%) 4/377 (1.1%)
    Sinus congestion 1/377 (0.3%) 0/377 (0%)
    Skin and subcutaneous tissue disorders
    Diabetic foot 1/377 (0.3%) 1/377 (0.3%)
    Eczema 1/377 (0.3%) 0/377 (0%)
    Rash erythematous 1/377 (0.3%) 0/377 (0%)
    Surgical and medical procedures
    Dialysis 0/377 (0%) 1/377 (0.3%)
    Vascular disorders
    Accelerated hypertension 0/377 (0%) 1/377 (0.3%)
    Aneurysm 0/377 (0%) 1/377 (0.3%)
    Aortic aneurysm 1/377 (0.3%) 1/377 (0.3%)
    Aortic stenosis 0/377 (0%) 1/377 (0.3%)
    Deep vein thrombosis 3/377 (0.8%) 2/377 (0.5%)
    Diastolic hypertension 0/377 (0%) 1/377 (0.3%)
    Embolism 1/377 (0.3%) 1/377 (0.3%)
    Hypertension 6/377 (1.6%) 3/377 (0.8%)
    Hypertensive crisis 4/377 (1.1%) 2/377 (0.5%)
    Hypertensive emergency 0/377 (0%) 1/377 (0.3%)
    Hypotension 4/377 (1.1%) 4/377 (1.1%)
    Intermittent claudication 0/377 (0%) 1/377 (0.3%)
    Malignant hypertension 0/377 (0%) 1/377 (0.3%)
    Orthostatic hypotension 1/377 (0.3%) 0/377 (0%)
    Peripheral arterial occlusive disease 1/377 (0.3%) 2/377 (0.5%)
    Peripheral artery occlusion 0/377 (0%) 1/377 (0.3%)
    Thrombosis 1/377 (0.3%) 0/377 (0%)
    Other (Not Including Serious) Adverse Events
    Hb-Based Titration Group Fixed Dose Group
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 292/377 (77.5%) 300/377 (79.6%)
    Blood and lymphatic system disorders
    Anaemia 19/377 (5%) 36/377 (9.5%)
    Anaemia of chronic disease 0/377 (0%) 1/377 (0.3%)
    Hilar lymphadenopathy 1/377 (0.3%) 0/377 (0%)
    Iron deficiency anaemia 2/377 (0.5%) 4/377 (1.1%)
    Leukocytosis 3/377 (0.8%) 5/377 (1.3%)
    Lymphadenitis 1/377 (0.3%) 0/377 (0%)
    Microcytic anaemia 1/377 (0.3%) 0/377 (0%)
    Neutropenia 0/377 (0%) 1/377 (0.3%)
    Pancytopenia 1/377 (0.3%) 2/377 (0.5%)
    Pernicious anaemia 0/377 (0%) 1/377 (0.3%)
    Splenomegaly 1/377 (0.3%) 1/377 (0.3%)
    Thrombocytopenia 2/377 (0.5%) 6/377 (1.6%)
    Cardiac disorders
    Angina pectoris 2/377 (0.5%) 0/377 (0%)
    Angina unstable 0/377 (0%) 1/377 (0.3%)
    Aortic valve incompetence 0/377 (0%) 1/377 (0.3%)
    Aortic valve sclerosis 1/377 (0.3%) 1/377 (0.3%)
    Arrhythmia 0/377 (0%) 1/377 (0.3%)
    Arteriosclerosis coronary artery 0/377 (0%) 1/377 (0.3%)
    Atrial fibrillation 2/377 (0.5%) 4/377 (1.1%)
    Atrial flutter 1/377 (0.3%) 0/377 (0%)
    Atrioventricular block second degree 0/377 (0%) 1/377 (0.3%)
    Bradycardia 5/377 (1.3%) 4/377 (1.1%)
    Bundle branch block right 0/377 (0%) 1/377 (0.3%)
    Cardiac failure 4/377 (1.1%) 6/377 (1.6%)
    Cardiac failure acute 1/377 (0.3%) 2/377 (0.5%)
    Cardiac failure congestive 3/377 (0.8%) 5/377 (1.3%)
    Cardiomegaly 2/377 (0.5%) 7/377 (1.9%)
    Cardiomyopathy 1/377 (0.3%) 1/377 (0.3%)
    Coronary artery disease 1/377 (0.3%) 1/377 (0.3%)
    Diastolic dysfunction 2/377 (0.5%) 0/377 (0%)
    Dilatation atrial 0/377 (0%) 1/377 (0.3%)
    Ischaemic cardiomyopathy 0/377 (0%) 1/377 (0.3%)
    Left ventricular dilatation 0/377 (0%) 1/377 (0.3%)
    Left ventricular failure 0/377 (0%) 1/377 (0.3%)
    Mitral valve calcification 0/377 (0%) 1/377 (0.3%)
    Mitral valve incompetence 1/377 (0.3%) 1/377 (0.3%)
    Myocardial infarction 3/377 (0.8%) 0/377 (0%)
    Myocardial ischaemia 0/377 (0%) 1/377 (0.3%)
    Palpitations 1/377 (0.3%) 3/377 (0.8%)
    Pulmonary valve incompetence 1/377 (0.3%) 1/377 (0.3%)
    Tachycardia 1/377 (0.3%) 1/377 (0.3%)
    Tricuspid valve incompetence 1/377 (0.3%) 2/377 (0.5%)
    Congenital, familial and genetic disorders
    Pyloric stenosis 0/377 (0%) 1/377 (0.3%)
    Vascular malformation 0/377 (0%) 1/377 (0.3%)
    Ear and labyrinth disorders
    Cerumen impaction 1/377 (0.3%) 1/377 (0.3%)
    Ear discomfort 0/377 (0%) 1/377 (0.3%)
    Ear pain 0/377 (0%) 2/377 (0.5%)
    Hypoacusis 0/377 (0%) 3/377 (0.8%)
    Vertigo 4/377 (1.1%) 5/377 (1.3%)
    Endocrine disorders
    Adrenal mass 1/377 (0.3%) 0/377 (0%)
    Hyperadrenalism 0/377 (0%) 1/377 (0.3%)
    Hyperparathyroidism 2/377 (0.5%) 1/377 (0.3%)
    Hyperparathyroidism secondary 3/377 (0.8%) 3/377 (0.8%)
    Hypothyroidism 3/377 (0.8%) 5/377 (1.3%)
    Secondary hyperthyroidism 1/377 (0.3%) 0/377 (0%)
    Eye disorders
    Astigmatism 1/377 (0.3%) 0/377 (0%)
    Blepharitis 1/377 (0.3%) 0/377 (0%)
    Blindness unilateral 0/377 (0%) 1/377 (0.3%)
    Cataract 6/377 (1.6%) 4/377 (1.1%)
    Cataract cortical 1/377 (0.3%) 0/377 (0%)
    Cataract nuclear 1/377 (0.3%) 0/377 (0%)
    Conjunctival haemorrhage 1/377 (0.3%) 1/377 (0.3%)
    Diabetic retinal oedema 1/377 (0.3%) 0/377 (0%)
    Diabetic retinopathy 1/377 (0.3%) 2/377 (0.5%)
    Dry eye 1/377 (0.3%) 3/377 (0.8%)
    Eye allergy 1/377 (0.3%) 0/377 (0%)
    Eye haemorrhage 1/377 (0.3%) 1/377 (0.3%)
    Glaucoma 1/377 (0.3%) 2/377 (0.5%)
    Hypermetropia 1/377 (0.3%) 0/377 (0%)
    Iritis 0/377 (0%) 1/377 (0.3%)
    Lacrimation increased 0/377 (0%) 1/377 (0.3%)
    Macular degeneration 1/377 (0.3%) 0/377 (0%)
    Ophthalmoplegia 0/377 (0%) 1/377 (0.3%)
    Presbyopia 1/377 (0.3%) 0/377 (0%)
    Retinal detachment 1/377 (0.3%) 0/377 (0%)
    Retinal haemorrhage 0/377 (0%) 1/377 (0.3%)
    Retinal tear 1/377 (0.3%) 0/377 (0%)
    Retinopathy 0/377 (0%) 1/377 (0.3%)
    Vision blurred 1/377 (0.3%) 1/377 (0.3%)
    Vitreous haemorrhage 1/377 (0.3%) 3/377 (0.8%)
    Gastrointestinal disorders
    Abdominal discomfort 2/377 (0.5%) 0/377 (0%)
    Abdominal distension 1/377 (0.3%) 2/377 (0.5%)
    Abdominal hernia 2/377 (0.5%) 0/377 (0%)
    Abdominal pain 6/377 (1.6%) 6/377 (1.6%)
    Abdominal pain lower 1/377 (0.3%) 0/377 (0%)
    Abdominal pain upper 6/377 (1.6%) 1/377 (0.3%)
    Anal fissure 1/377 (0.3%) 0/377 (0%)
    Ascites 1/377 (0.3%) 0/377 (0%)
    Change of bowel habit 0/377 (0%) 1/377 (0.3%)
    Constipation 11/377 (2.9%) 17/377 (4.5%)
    Dental caries 1/377 (0.3%) 2/377 (0.5%)
    Diabetic gastroparesis 0/377 (0%) 1/377 (0.3%)
    Diarrhoea 22/377 (5.8%) 19/377 (5%)
    Diverticulum 0/377 (0%) 1/377 (0.3%)
    Diverticulum intestinal 1/377 (0.3%) 2/377 (0.5%)
    Dry mouth 1/377 (0.3%) 1/377 (0.3%)
    Dyspepsia 1/377 (0.3%) 3/377 (0.8%)
    Dysphagia 3/377 (0.8%) 3/377 (0.8%)
    Flatulence 1/377 (0.3%) 1/377 (0.3%)
    Food poisoning 0/377 (0%) 1/377 (0.3%)
    Gastric ulcer 0/377 (0%) 1/377 (0.3%)
    Gastritis 3/377 (0.8%) 7/377 (1.9%)
    Gastritis erosive 1/377 (0.3%) 0/377 (0%)
    Gastrointestinal haemorrhage 1/377 (0.3%) 3/377 (0.8%)
    Gastrooesophageal reflux disease 6/377 (1.6%) 8/377 (2.1%)
    Gingival bleeding 1/377 (0.3%) 0/377 (0%)
    Haematemesis 0/377 (0%) 1/377 (0.3%)
    Haematochezia 0/377 (0%) 1/377 (0.3%)
    Haemorrhoidal haemorrhage 0/377 (0%) 1/377 (0.3%)
    Haemorrhoids 2/377 (0.5%) 3/377 (0.8%)
    Hiatus hernia 2/377 (0.5%) 4/377 (1.1%)
    Hyperchlorhydria 1/377 (0.3%) 0/377 (0%)
    Impaired gastric emptying 0/377 (0%) 1/377 (0.3%)
    Inguinal hernia 1/377 (0.3%) 2/377 (0.5%)
    Large intestine polyp 1/377 (0.3%) 2/377 (0.5%)
    Lip swelling 1/377 (0.3%) 0/377 (0%)
    Nausea 27/377 (7.2%) 22/377 (5.8%)
    Oesophageal food impaction 0/377 (0%) 1/377 (0.3%)
    Oesophagitis 0/377 (0%) 1/377 (0.3%)
    Parotid gland enlargement 1/377 (0.3%) 0/377 (0%)
    Rectal haemorrhage 1/377 (0.3%) 4/377 (1.1%)
    Toothache 3/377 (0.8%) 4/377 (1.1%)
    Umbilical hernia 0/377 (0%) 1/377 (0.3%)
    Vomiting 17/377 (4.5%) 12/377 (3.2%)
    General disorders
    Asthenia 17/377 (4.5%) 15/377 (4%)
    Chest discomfort 3/377 (0.8%) 0/377 (0%)
    Chest pain 8/377 (2.1%) 10/377 (2.7%)
    Chills 5/377 (1.3%) 2/377 (0.5%)
    Cyst 0/377 (0%) 1/377 (0.3%)
    Drug intolerance 0/377 (0%) 1/377 (0.3%)
    Fatigue 17/377 (4.5%) 21/377 (5.6%)
    Feeling cold 1/377 (0.3%) 0/377 (0%)
    Gait disturbance 0/377 (0%) 1/377 (0.3%)
    Generalised oedema 1/377 (0.3%) 0/377 (0%)
    Hypothermia 1/377 (0.3%) 1/377 (0.3%)
    Influenza like illness 3/377 (0.8%) 3/377 (0.8%)
    Injection site oedema 1/377 (0.3%) 0/377 (0%)
    Injection site pain 1/377 (0.3%) 1/377 (0.3%)
    Localised oedema 0/377 (0%) 1/377 (0.3%)
    Malaise 1/377 (0.3%) 2/377 (0.5%)
    Nodule 1/377 (0.3%) 0/377 (0%)
    Non-cardiac chest pain 2/377 (0.5%) 2/377 (0.5%)
    Oedema 17/377 (4.5%) 18/377 (4.8%)
    Oedema peripheral 35/377 (9.3%) 29/377 (7.7%)
    Pain 5/377 (1.3%) 4/377 (1.1%)
    Peripheral swelling 8/377 (2.1%) 9/377 (2.4%)
    Polyp 2/377 (0.5%) 0/377 (0%)
    Pyrexia 6/377 (1.6%) 4/377 (1.1%)
    Sluggishness 0/377 (0%) 1/377 (0.3%)
    Swelling 1/377 (0.3%) 1/377 (0.3%)
    Systemic inflammatory response syndrome 0/377 (0%) 1/377 (0.3%)
    Temperature intolerance 0/377 (0%) 1/377 (0.3%)
    Thirst 2/377 (0.5%) 0/377 (0%)
    Vaccination site bruising 0/377 (0%) 1/377 (0.3%)
    Hepatobiliary disorders
    Autoimmune hepatitis 0/377 (0%) 1/377 (0.3%)
    Biliary tract disorder 0/377 (0%) 1/377 (0.3%)
    Cholecystitis acute 0/377 (0%) 1/377 (0.3%)
    Cholelithiasis 2/377 (0.5%) 3/377 (0.8%)
    Hepatic cirrhosis 1/377 (0.3%) 1/377 (0.3%)
    Immune system disorders
    Drug hypersensitivity 1/377 (0.3%) 0/377 (0%)
    Food allergy 0/377 (0%) 1/377 (0.3%)
    Hypersensitivity 1/377 (0.3%) 2/377 (0.5%)
    Seasonal allergy 2/377 (0.5%) 3/377 (0.8%)
    Infections and infestations
    Abdominal abscess 1/377 (0.3%) 0/377 (0%)
    Abscess 0/377 (0%) 2/377 (0.5%)
    Abscess limb 1/377 (0.3%) 1/377 (0.3%)
    Abscess neck 1/377 (0.3%) 0/377 (0%)
    Abscess oral 0/377 (0%) 1/377 (0.3%)
    Acute sinusitis 5/377 (1.3%) 2/377 (0.5%)
    Appendicitis perforated 1/377 (0.3%) 0/377 (0%)
    Bacteraemia 1/377 (0.3%) 0/377 (0%)
    Bacteriuria 1/377 (0.3%) 1/377 (0.3%)
    Blister infected 1/377 (0.3%) 0/377 (0%)
    Body tinea 0/377 (0%) 2/377 (0.5%)
    Bronchitis 19/377 (5%) 15/377 (4%)
    Candida infection 1/377 (0.3%) 0/377 (0%)
    Cellulitis 8/377 (2.1%) 9/377 (2.4%)
    Chikungunya virus infection 1/377 (0.3%) 0/377 (0%)
    Chronic sinusitis 0/377 (0%) 1/377 (0.3%)
    Clostridium difficile colitis 0/377 (0%) 1/377 (0.3%)
    Coccidioidomycosis 1/377 (0.3%) 0/377 (0%)
    Conjunctivitis 1/377 (0.3%) 2/377 (0.5%)
    Conjunctivitis bacterial 1/377 (0.3%) 1/377 (0.3%)
    Cystitis 2/377 (0.5%) 4/377 (1.1%)
    Diabetic foot infection 1/377 (0.3%) 0/377 (0%)
    Diverticulitis 0/377 (0%) 2/377 (0.5%)
    Ear infection 0/377 (0%) 1/377 (0.3%)
    Enterococcal bacteraemia 1/377 (0.3%) 0/377 (0%)
    Escherichia urinary tract infection 0/377 (0%) 1/377 (0.3%)
    Eye infection 1/377 (0.3%) 1/377 (0.3%)
    Fungal skin infection 4/377 (1.1%) 2/377 (0.5%)
    Furuncle 1/377 (0.3%) 2/377 (0.5%)
    Gastric ulcer helicobacter 1/377 (0.3%) 0/377 (0%)
    Gastroenteritis 3/377 (0.8%) 1/377 (0.3%)
    Gastroenteritis viral 2/377 (0.5%) 3/377 (0.8%)
    Genital candidiasis 1/377 (0.3%) 0/377 (0%)
    Gingivitis 1/377 (0.3%) 0/377 (0%)
    Helicobacter gastritis 1/377 (0.3%) 0/377 (0%)
    Helicobacter infection 0/377 (0%) 2/377 (0.5%)
    Herpes virus infection 1/377 (0.3%) 0/377 (0%)
    Herpes zoster 6/377 (1.6%) 5/377 (1.3%)
    Infected cyst 1/377 (0.3%) 0/377 (0%)
    Influenza 4/377 (1.1%) 5/377 (1.3%)
    Laryngitis 1/377 (0.3%) 1/377 (0.3%)
    Localised infection 3/377 (0.8%) 1/377 (0.3%)
    Lower respiratory tract infection 0/377 (0%) 1/377 (0.3%)
    Lung infection 3/377 (0.8%) 0/377 (0%)
    Mastoiditis 1/377 (0.3%) 0/377 (0%)
    Nail infection 0/377 (0%) 1/377 (0.3%)
    Nasopharyngitis 8/377 (2.1%) 16/377 (4.2%)
    Oesophageal candidiasis 1/377 (0.3%) 0/377 (0%)
    Onychomycosis 1/377 (0.3%) 0/377 (0%)
    Oral candidiasis 2/377 (0.5%) 1/377 (0.3%)
    Osteomyelitis 1/377 (0.3%) 0/377 (0%)
    Otitis externa 2/377 (0.5%) 0/377 (0%)
    Otitis media acute 1/377 (0.3%) 0/377 (0%)
    Paronychia 2/377 (0.5%) 0/377 (0%)
    Periorbital abscess 1/377 (0.3%) 0/377 (0%)
    Pharyngitis 1/377 (0.3%) 3/377 (0.8%)
    Pharyngitis streptococcal 1/377 (0.3%) 0/377 (0%)
    Pneumonia 5/377 (1.3%) 5/377 (1.3%)
    Pneumonia bacterial 1/377 (0.3%) 0/377 (0%)
    Postoperative wound infection 0/377 (0%) 1/377 (0.3%)
    Pulmonary sepsis 0/377 (0%) 1/377 (0.3%)
    Pyelonephritis 0/377 (0%) 1/377 (0.3%)
    Pyoderma 0/377 (0%) 1/377 (0.3%)
    Pyuria 2/377 (0.5%) 0/377 (0%)
    Rhinitis 0/377 (0%) 1/377 (0.3%)
    Sebaceous gland infection 0/377 (0%) 1/377 (0.3%)
    Sinusitis 6/377 (1.6%) 6/377 (1.6%)
    Sinusitis bacterial 2/377 (0.5%) 0/377 (0%)
    Skin infection 2/377 (0.5%) 1/377 (0.3%)
    Staphylococcal bacteraemia 1/377 (0.3%) 0/377 (0%)
    Subcutaneous abscess 1/377 (0.3%) 1/377 (0.3%)
    Tooth abscess 2/377 (0.5%) 4/377 (1.1%)
    Tooth infection 1/377 (0.3%) 3/377 (0.8%)
    Trichomoniasis 1/377 (0.3%) 1/377 (0.3%)
    Upper respiratory tract infection 19/377 (5%) 26/377 (6.9%)
    Urinary tract infection 38/377 (10.1%) 35/377 (9.3%)
    Urinary tract infection bacterial 1/377 (0.3%) 3/377 (0.8%)
    Urinary tract infection enterococcal 0/377 (0%) 1/377 (0.3%)
    Urinary tract infection pseudomonal 1/377 (0.3%) 0/377 (0%)
    Viral diarrhoea 1/377 (0.3%) 0/377 (0%)
    Viral infection 2/377 (0.5%) 1/377 (0.3%)
    Viral rhinitis 1/377 (0.3%) 0/377 (0%)
    Viral upper respiratory tract infection 0/377 (0%) 1/377 (0.3%)
    Vulvovaginitis 0/377 (0%) 1/377 (0.3%)
    Wound infection 1/377 (0.3%) 1/377 (0.3%)
    Wound infection staphylococcal 1/377 (0.3%) 0/377 (0%)
    Injury, poisoning and procedural complications
    Animal scratch 0/377 (0%) 1/377 (0.3%)
    Ankle fracture 1/377 (0.3%) 1/377 (0.3%)
    Arteriovenous fistula site complication 1/377 (0.3%) 0/377 (0%)
    Arthropod bite 1/377 (0.3%) 2/377 (0.5%)
    Back injury 0/377 (0%) 1/377 (0.3%)
    Burns second degree 0/377 (0%) 1/377 (0.3%)
    Chest injury 1/377 (0.3%) 2/377 (0.5%)
    Clavicle fracture 0/377 (0%) 1/377 (0.3%)
    Contusion 8/377 (2.1%) 16/377 (4.2%)
    Craniocerebral injury 1/377 (0.3%) 0/377 (0%)
    Exposure to toxic agent 1/377 (0.3%) 0/377 (0%)
    Eye contusion 0/377 (0%) 1/377 (0.3%)
    Fall 26/377 (6.9%) 22/377 (5.8%)
    Foot fracture 2/377 (0.5%) 1/377 (0.3%)
    Forearm fracture 1/377 (0.3%) 0/377 (0%)
    Foreign body 1/377 (0.3%) 0/377 (0%)
    Hand fracture 0/377 (0%) 1/377 (0.3%)
    Head injury 3/377 (0.8%) 0/377 (0%)
    Humerus fracture 1/377 (0.3%) 4/377 (1.1%)
    Incisional hernia 0/377 (0%) 1/377 (0.3%)
    Injury 0/377 (0%) 1/377 (0.3%)
    Intestinal anastomosis complication 0/377 (0%) 1/377 (0.3%)
    Joint dislocation 1/377 (0.3%) 0/377 (0%)
    Joint injury 0/377 (0%) 3/377 (0.8%)
    Laceration 6/377 (1.6%) 8/377 (2.1%)
    Ligament sprain 3/377 (0.8%) 2/377 (0.5%)
    Limb fracture 1/377 (0.3%) 0/377 (0%)
    Limb injury 0/377 (0%) 4/377 (1.1%)
    Lip injury 0/377 (0%) 1/377 (0.3%)
    Muscle strain 3/377 (0.8%) 3/377 (0.8%)
    Nail avulsion 0/377 (0%) 1/377 (0.3%)
    Post procedural haemorrhage 0/377 (0%) 1/377 (0.3%)
    Postoperative respiratory failure 0/377 (0%) 1/377 (0.3%)
    Procedural nausea 0/377 (0%) 1/377 (0.3%)
    Rib fracture 0/377 (0%) 2/377 (0.5%)
    Road traffic accident 2/377 (0.5%) 2/377 (0.5%)
    Skin abrasion 1/377 (0.3%) 3/377 (0.8%)
    Skin injury 0/377 (0%) 2/377 (0.5%)
    Soft tissue injury 1/377 (0.3%) 0/377 (0%)
    Spinal column injury 0/377 (0%) 1/377 (0.3%)
    Tendon rupture 1/377 (0.3%) 0/377 (0%)
    Thermal burn 0/377 (0%) 2/377 (0.5%)
    Tooth avulsion 1/377 (0.3%) 0/377 (0%)
    Traumatic haematoma 0/377 (0%) 1/377 (0.3%)
    Traumatic haemorrhage 1/377 (0.3%) 0/377 (0%)
    Vaccination complication 1/377 (0.3%) 0/377 (0%)
    Wound 4/377 (1.1%) 3/377 (0.8%)
    Wound dehiscence 0/377 (0%) 1/377 (0.3%)
    Wrist fracture 1/377 (0.3%) 1/377 (0.3%)
    Investigations
    Anticoagulation drug level above therapeutic 0/377 (0%) 1/377 (0.3%)
    Blood bicarbonate decreased 0/377 (0%) 1/377 (0.3%)
    Blood creatine increased 2/377 (0.5%) 0/377 (0%)
    Blood creatinine increased 1/377 (0.3%) 1/377 (0.3%)
    Blood glucose increased 1/377 (0.3%) 1/377 (0.3%)
    Blood iron decreased 1/377 (0.3%) 0/377 (0%)
    Blood parathyroid hormone increased 1/377 (0.3%) 0/377 (0%)
    Blood phosphorus increased 2/377 (0.5%) 0/377 (0%)
    Blood potassium abnormal 1/377 (0.3%) 0/377 (0%)
    Blood potassium increased 0/377 (0%) 1/377 (0.3%)
    Blood pressure abnormal 1/377 (0.3%) 0/377 (0%)
    Blood pressure diastolic 0/377 (0%) 1/377 (0.3%)
    Blood pressure diastolic increased 0/377 (0%) 1/377 (0.3%)
    Blood pressure increased 24/377 (6.4%) 16/377 (4.2%)
    Blood pressure systolic increased 1/377 (0.3%) 2/377 (0.5%)
    Carbon dioxide decreased 1/377 (0.3%) 0/377 (0%)
    Cardiac murmur 0/377 (0%) 1/377 (0.3%)
    Cardiac stress test abnormal 1/377 (0.3%) 0/377 (0%)
    Computerised tomogram abnormal 1/377 (0.3%) 0/377 (0%)
    Electrocardiogram T wave abnormal 0/377 (0%) 1/377 (0.3%)
    Endoscopy gastrointestinal normal 0/377 (0%) 1/377 (0.3%)
    Haemoglobin decreased 1/377 (0.3%) 1/377 (0.3%)
    Hepatic enzyme increased 1/377 (0.3%) 0/377 (0%)
    International normalised ratio increased 1/377 (0.3%) 0/377 (0%)
    Occult blood positive 0/377 (0%) 1/377 (0.3%)
    Prostatic specific antigen increased 0/377 (0%) 1/377 (0.3%)
    Protein total increased 0/377 (0%) 1/377 (0.3%)
    Serum ferritin decreased 1/377 (0.3%) 0/377 (0%)
    Thyroid function test abnormal 1/377 (0.3%) 0/377 (0%)
    Troponin increased 1/377 (0.3%) 1/377 (0.3%)
    Tuberculin test positive 0/377 (0%) 1/377 (0.3%)
    Urine output decreased 0/377 (0%) 1/377 (0.3%)
    Vitamin D decreased 0/377 (0%) 2/377 (0.5%)
    Weight decreased 3/377 (0.8%) 3/377 (0.8%)
    Weight increased 1/377 (0.3%) 1/377 (0.3%)
    Metabolism and nutrition disorders
    Abnormal loss of weight 1/377 (0.3%) 0/377 (0%)
    Acidosis 5/377 (1.3%) 2/377 (0.5%)
    Decreased appetite 7/377 (1.9%) 13/377 (3.4%)
    Dehydration 6/377 (1.6%) 7/377 (1.9%)
    Diabetes mellitus 2/377 (0.5%) 1/377 (0.3%)
    Diabetes mellitus inadequate control 1/377 (0.3%) 1/377 (0.3%)
    Diabetic ketoacidosis 0/377 (0%) 1/377 (0.3%)
    Dyslipidaemia 0/377 (0%) 1/377 (0.3%)
    Failure to thrive 0/377 (0%) 1/377 (0.3%)
    Fluid imbalance 0/377 (0%) 1/377 (0.3%)
    Fluid overload 5/377 (1.3%) 6/377 (1.6%)
    Gout 12/377 (3.2%) 10/377 (2.7%)
    Hypercalcaemia 0/377 (0%) 5/377 (1.3%)
    Hypercholesterolaemia 0/377 (0%) 1/377 (0.3%)
    Hyperglycaemia 8/377 (2.1%) 3/377 (0.8%)
    Hyperhomocysteinaemia 0/377 (0%) 1/377 (0.3%)
    Hyperkalaemia 18/377 (4.8%) 39/377 (10.3%)
    Hyperlipidaemia 1/377 (0.3%) 0/377 (0%)
    Hypernatraemia 1/377 (0.3%) 2/377 (0.5%)
    Hyperphosphataemia 7/377 (1.9%) 7/377 (1.9%)
    Hypervolaemia 1/377 (0.3%) 0/377 (0%)
    Hypoalbuminaemia 0/377 (0%) 1/377 (0.3%)
    Hypocalcaemia 3/377 (0.8%) 3/377 (0.8%)
    Hypoglycaemia 10/377 (2.7%) 11/377 (2.9%)
    Hypokalaemia 4/377 (1.1%) 6/377 (1.6%)
    Hyponatraemia 3/377 (0.8%) 4/377 (1.1%)
    Iron deficiency 4/377 (1.1%) 6/377 (1.6%)
    Iron overload 0/377 (0%) 1/377 (0.3%)
    Lactic acidosis 1/377 (0.3%) 0/377 (0%)
    Malnutrition 1/377 (0.3%) 1/377 (0.3%)
    Metabolic acidosis 6/377 (1.6%) 13/377 (3.4%)
    Metabolic alkalosis 0/377 (0%) 1/377 (0.3%)
    Pseudohyponatraemia 0/377 (0%) 1/377 (0.3%)
    Type 2 diabetes mellitus 1/377 (0.3%) 1/377 (0.3%)
    Vitamin B12 deficiency 2/377 (0.5%) 0/377 (0%)
    Vitamin D deficiency 5/377 (1.3%) 5/377 (1.3%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 17/377 (4.5%) 22/377 (5.8%)
    Arthritis 5/377 (1.3%) 3/377 (0.8%)
    Back pain 12/377 (3.2%) 21/377 (5.6%)
    Bone pain 1/377 (0.3%) 0/377 (0%)
    Bursitis 2/377 (0.5%) 1/377 (0.3%)
    CREST syndrome 1/377 (0.3%) 0/377 (0%)
    Cervical spinal stenosis 0/377 (0%) 1/377 (0.3%)
    Chronic kidney disease-mineral and bone disorder 1/377 (0.3%) 0/377 (0%)
    Costochondritis 1/377 (0.3%) 0/377 (0%)
    Enthesopathy 0/377 (0%) 1/377 (0.3%)
    Exostosis 2/377 (0.5%) 0/377 (0%)
    Flank pain 2/377 (0.5%) 7/377 (1.9%)
    Foot deformity 0/377 (0%) 1/377 (0.3%)
    Gouty arthritis 1/377 (0.3%) 1/377 (0.3%)
    Intervertebral disc degeneration 0/377 (0%) 1/377 (0.3%)
    Joint effusion 1/377 (0.3%) 1/377 (0.3%)
    Joint stiffness 0/377 (0%) 1/377 (0.3%)
    Joint swelling 2/377 (0.5%) 2/377 (0.5%)
    Limb mass 0/377 (0%) 1/377 (0.3%)
    Lumbar spinal stenosis 1/377 (0.3%) 0/377 (0%)
    Muscle spasms 7/377 (1.9%) 12/377 (3.2%)
    Muscular weakness 1/377 (0.3%) 3/377 (0.8%)
    Musculoskeletal chest pain 4/377 (1.1%) 2/377 (0.5%)
    Musculoskeletal pain 4/377 (1.1%) 7/377 (1.9%)
    Musculoskeletal stiffness 0/377 (0%) 4/377 (1.1%)
    Myalgia 2/377 (0.5%) 5/377 (1.3%)
    Myofascial pain syndrome 1/377 (0.3%) 0/377 (0%)
    Neck pain 3/377 (0.8%) 2/377 (0.5%)
    Neuropathic arthropathy 0/377 (0%) 1/377 (0.3%)
    Osteoarthritis 3/377 (0.8%) 5/377 (1.3%)
    Osteopenia 1/377 (0.3%) 1/377 (0.3%)
    Osteoporosis 0/377 (0%) 2/377 (0.5%)
    Pain in extremity 12/377 (3.2%) 12/377 (3.2%)
    Patellofemoral pain syndrome 0/377 (0%) 1/377 (0.3%)
    Plantar fasciitis 1/377 (0.3%) 3/377 (0.8%)
    Polymyositis 1/377 (0.3%) 0/377 (0%)
    Rhabdomyolysis 1/377 (0.3%) 0/377 (0%)
    Rotator cuff syndrome 2/377 (0.5%) 0/377 (0%)
    Spinal column stenosis 0/377 (0%) 1/377 (0.3%)
    Spinal osteoarthritis 1/377 (0.3%) 0/377 (0%)
    Synovial cyst 0/377 (0%) 2/377 (0.5%)
    Systemic lupus erythematosus 1/377 (0.3%) 1/377 (0.3%)
    Tendonitis 2/377 (0.5%) 0/377 (0%)
    Trigger finger 1/377 (0.3%) 0/377 (0%)
    Vertebral foraminal stenosis 0/377 (0%) 1/377 (0.3%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia 0/377 (0%) 1/377 (0.3%)
    Adenoma benign 0/377 (0%) 1/377 (0.3%)
    Basal cell carcinoma 2/377 (0.5%) 4/377 (1.1%)
    Bladder cancer 0/377 (0%) 1/377 (0.3%)
    Bowen's disease 0/377 (0%) 2/377 (0.5%)
    Colon adenoma 0/377 (0%) 1/377 (0.3%)
    Haemangioma 0/377 (0%) 1/377 (0.3%)
    Large intestine benign neoplasm 0/377 (0%) 1/377 (0.3%)
    Lip squamous cell carcinoma 0/377 (0%) 1/377 (0.3%)
    Melanocytic naevus 1/377 (0.3%) 0/377 (0%)
    Myelodysplastic syndrome 0/377 (0%) 1/377 (0.3%)
    Neoplasm skin 0/377 (0%) 1/377 (0.3%)
    Plasma cell myeloma 1/377 (0.3%) 0/377 (0%)
    Prostate cancer 0/377 (0%) 1/377 (0.3%)
    Rectal cancer 0/377 (0%) 1/377 (0.3%)
    Renal haemangioma 1/377 (0.3%) 0/377 (0%)
    Seborrhoeic keratosis 1/377 (0.3%) 2/377 (0.5%)
    Small cell lung cancer 1/377 (0.3%) 0/377 (0%)
    Squamous cell carcinoma 1/377 (0.3%) 1/377 (0.3%)
    Squamous cell carcinoma of skin 1/377 (0.3%) 3/377 (0.8%)
    Thyroid cancer 0/377 (0%) 2/377 (0.5%)
    Uterine leiomyoma 1/377 (0.3%) 0/377 (0%)
    Nervous system disorders
    Altered state of consciousness 1/377 (0.3%) 0/377 (0%)
    Amnesia 0/377 (0%) 1/377 (0.3%)
    Aphasia 0/377 (0%) 1/377 (0.3%)
    Balance disorder 1/377 (0.3%) 1/377 (0.3%)
    Burning sensation 1/377 (0.3%) 0/377 (0%)
    Carpal tunnel syndrome 2/377 (0.5%) 0/377 (0%)
    Cerebral atrophy 1/377 (0.3%) 0/377 (0%)
    Cerebral small vessel ischaemic disease 1/377 (0.3%) 0/377 (0%)
    Cerebrovascular accident 0/377 (0%) 2/377 (0.5%)
    Dementia 1/377 (0.3%) 0/377 (0%)
    Diabetic neuropathy 3/377 (0.8%) 2/377 (0.5%)
    Disturbance in attention 0/377 (0%) 1/377 (0.3%)
    Dizziness 13/377 (3.4%) 28/377 (7.4%)
    Dizziness postural 1/377 (0.3%) 3/377 (0.8%)
    Dysarthria 2/377 (0.5%) 0/377 (0%)
    Dysgeusia 0/377 (0%) 1/377 (0.3%)
    Encephalopathy 0/377 (0%) 1/377 (0.3%)
    Headache 16/377 (4.2%) 14/377 (3.7%)
    Hyperaesthesia 0/377 (0%) 1/377 (0.3%)
    Hypoaesthesia 1/377 (0.3%) 6/377 (1.6%)
    IIIrd nerve paralysis 0/377 (0%) 1/377 (0.3%)
    Lethargy 1/377 (0.3%) 0/377 (0%)
    Memory impairment 0/377 (0%) 1/377 (0.3%)
    Migraine 1/377 (0.3%) 1/377 (0.3%)
    Migraine with aura 0/377 (0%) 1/377 (0.3%)
    Nerve compression 1/377 (0.3%) 0/377 (0%)
    Neuralgia 1/377 (0.3%) 0/377 (0%)
    Neuropathy peripheral 1/377 (0.3%) 2/377 (0.5%)
    Paraesthesia 1/377 (0.3%) 1/377 (0.3%)
    Polyneuropathy 1/377 (0.3%) 0/377 (0%)
    Presyncope 1/377 (0.3%) 2/377 (0.5%)
    Restless legs syndrome 0/377 (0%) 1/377 (0.3%)
    Sciatica 1/377 (0.3%) 3/377 (0.8%)
    Seizure 0/377 (0%) 1/377 (0.3%)
    Somnolence 2/377 (0.5%) 0/377 (0%)
    Syncope 3/377 (0.8%) 3/377 (0.8%)
    Tremor 1/377 (0.3%) 3/377 (0.8%)
    Psychiatric disorders
    Anxiety 7/377 (1.9%) 3/377 (0.8%)
    Confusional state 2/377 (0.5%) 0/377 (0%)
    Delirium 0/377 (0%) 2/377 (0.5%)
    Depressed mood 2/377 (0.5%) 2/377 (0.5%)
    Depression 5/377 (1.3%) 6/377 (1.6%)
    Hallucination 2/377 (0.5%) 0/377 (0%)
    Insomnia 6/377 (1.6%) 11/377 (2.9%)
    Mental status changes 2/377 (0.5%) 5/377 (1.3%)
    Paranoia 1/377 (0.3%) 0/377 (0%)
    Stress 0/377 (0%) 1/377 (0.3%)
    Renal and urinary disorders
    Acute kidney injury 10/377 (2.7%) 6/377 (1.6%)
    Anuria 1/377 (0.3%) 0/377 (0%)
    Azotaemia 3/377 (0.8%) 0/377 (0%)
    Bladder mass 0/377 (0%) 1/377 (0.3%)
    Bladder outlet obstruction 1/377 (0.3%) 0/377 (0%)
    Chronic kidney disease 9/377 (2.4%) 14/377 (3.7%)
    Dysuria 4/377 (1.1%) 5/377 (1.3%)
    End stage renal disease 4/377 (1.1%) 5/377 (1.3%)
    Haematuria 3/377 (0.8%) 2/377 (0.5%)
    Hydronephrosis 0/377 (0%) 2/377 (0.5%)
    Hypertonic bladder 0/377 (0%) 1/377 (0.3%)
    Microalbuminuria 0/377 (0%) 1/377 (0.3%)
    Nephrolithiasis 0/377 (0%) 1/377 (0.3%)
    Nephropathy 1/377 (0.3%) 2/377 (0.5%)
    Nocturia 0/377 (0%) 1/377 (0.3%)
    Pollakiuria 1/377 (0.3%) 1/377 (0.3%)
    Polyuria 3/377 (0.8%) 1/377 (0.3%)
    Proteinuria 0/377 (0%) 2/377 (0.5%)
    Renal atrophy 1/377 (0.3%) 0/377 (0%)
    Renal cyst 2/377 (0.5%) 2/377 (0.5%)
    Renal failure 1/377 (0.3%) 2/377 (0.5%)
    Renal impairment 2/377 (0.5%) 3/377 (0.8%)
    Renal mass 1/377 (0.3%) 0/377 (0%)
    Urethral stenosis 0/377 (0%) 1/377 (0.3%)
    Urinary incontinence 2/377 (0.5%) 1/377 (0.3%)
    Urinary retention 2/377 (0.5%) 1/377 (0.3%)
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 0/377 (0%) 3/377 (0.8%)
    Breast mass 1/377 (0.3%) 0/377 (0%)
    Breast ulceration 0/377 (0%) 1/377 (0.3%)
    Cervical cyst 1/377 (0.3%) 0/377 (0%)
    Dysmenorrhoea 0/377 (0%) 1/377 (0.3%)
    Erectile dysfunction 0/377 (0%) 1/377 (0.3%)
    Menstruation irregular 1/377 (0.3%) 0/377 (0%)
    Ovarian cyst ruptured 0/377 (0%) 1/377 (0.3%)
    Sexual dysfunction 0/377 (0%) 1/377 (0.3%)
    Vaginal discharge 1/377 (0.3%) 0/377 (0%)
    Vaginal haemorrhage 1/377 (0.3%) 0/377 (0%)
    Vulvovaginal discomfort 1/377 (0.3%) 0/377 (0%)
    Vulvovaginal pruritus 1/377 (0.3%) 0/377 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure 1/377 (0.3%) 0/377 (0%)
    Allergic sinusitis 0/377 (0%) 1/377 (0.3%)
    Apnoea 0/377 (0%) 1/377 (0.3%)
    Asthma 2/377 (0.5%) 1/377 (0.3%)
    Atelectasis 0/377 (0%) 1/377 (0.3%)
    Bronchitis chronic 1/377 (0.3%) 0/377 (0%)
    Bronchospasm 1/377 (0.3%) 0/377 (0%)
    Chronic obstructive pulmonary disease 1/377 (0.3%) 3/377 (0.8%)
    Cough 17/377 (4.5%) 20/377 (5.3%)
    Dyspnoea 15/377 (4%) 21/377 (5.6%)
    Dyspnoea exertional 1/377 (0.3%) 5/377 (1.3%)
    Epistaxis 4/377 (1.1%) 4/377 (1.1%)
    Lung infiltration 0/377 (0%) 1/377 (0.3%)
    Nasal congestion 2/377 (0.5%) 4/377 (1.1%)
    Nasal polyps 1/377 (0.3%) 0/377 (0%)
    Oropharyngeal pain 7/377 (1.9%) 2/377 (0.5%)
    Paranasal sinus discomfort 0/377 (0%) 1/377 (0.3%)
    Pleural effusion 2/377 (0.5%) 7/377 (1.9%)
    Pneumonia aspiration 0/377 (0%) 1/377 (0.3%)
    Productive cough 1/377 (0.3%) 3/377 (0.8%)
    Pulmonary congestion 0/377 (0%) 1/377 (0.3%)
    Pulmonary fibrosis 1/377 (0.3%) 0/377 (0%)
    Pulmonary haemorrhage 1/377 (0.3%) 0/377 (0%)
    Pulmonary hypertension 0/377 (0%) 2/377 (0.5%)
    Pulmonary mass 2/377 (0.5%) 0/377 (0%)
    Pulmonary oedema 3/377 (0.8%) 3/377 (0.8%)
    Rales 0/377 (0%) 1/377 (0.3%)
    Respiratory failure 0/377 (0%) 1/377 (0.3%)
    Respiratory tract congestion 2/377 (0.5%) 1/377 (0.3%)
    Rhinitis allergic 1/377 (0.3%) 1/377 (0.3%)
    Rhinorrhoea 1/377 (0.3%) 2/377 (0.5%)
    Sinus congestion 5/377 (1.3%) 1/377 (0.3%)
    Sinus disorder 1/377 (0.3%) 0/377 (0%)
    Sleep apnoea syndrome 4/377 (1.1%) 0/377 (0%)
    Snoring 1/377 (0.3%) 0/377 (0%)
    Throat irritation 0/377 (0%) 1/377 (0.3%)
    Upper-airway cough syndrome 0/377 (0%) 1/377 (0.3%)
    Wheezing 1/377 (0.3%) 1/377 (0.3%)
    Skin and subcutaneous tissue disorders
    Actinic keratosis 0/377 (0%) 1/377 (0.3%)
    Alopecia 2/377 (0.5%) 0/377 (0%)
    Angioedema 1/377 (0.3%) 0/377 (0%)
    Blister 3/377 (0.8%) 1/377 (0.3%)
    Decubitus ulcer 1/377 (0.3%) 2/377 (0.5%)
    Dermal cyst 1/377 (0.3%) 0/377 (0%)
    Dermatitis 2/377 (0.5%) 3/377 (0.8%)
    Dermatitis contact 1/377 (0.3%) 1/377 (0.3%)
    Diabetic foot 0/377 (0%) 1/377 (0.3%)
    Drug reaction with eosinophilia and systemic symptoms 1/377 (0.3%) 0/377 (0%)
    Dry skin 0/377 (0%) 1/377 (0.3%)
    Ecchymosis 2/377 (0.5%) 4/377 (1.1%)
    Eczema 1/377 (0.3%) 0/377 (0%)
    Erythema multiforme 0/377 (0%) 1/377 (0.3%)
    Hair texture abnormal 0/377 (0%) 1/377 (0.3%)
    Ingrowing nail 1/377 (0.3%) 2/377 (0.5%)
    Lentigo 0/377 (0%) 2/377 (0.5%)
    Nail bed bleeding 0/377 (0%) 1/377 (0.3%)
    Night sweats 1/377 (0.3%) 0/377 (0%)
    Onychoclasis 1/377 (0.3%) 0/377 (0%)
    Petechiae 0/377 (0%) 1/377 (0.3%)
    Prurigo 0/377 (0%) 1/377 (0.3%)
    Pruritus 7/377 (1.9%) 7/377 (1.9%)
    Pruritus generalised 2/377 (0.5%) 6/377 (1.6%)
    Purpura senile 0/377 (0%) 1/377 (0.3%)
    Rash 8/377 (2.1%) 10/377 (2.7%)
    Rash generalised 2/377 (0.5%) 0/377 (0%)
    Rash maculo-papular 0/377 (0%) 1/377 (0.3%)
    Rash pruritic 2/377 (0.5%) 1/377 (0.3%)
    Skin discolouration 0/377 (0%) 1/377 (0.3%)
    Skin disorder 0/377 (0%) 1/377 (0.3%)
    Skin fissures 1/377 (0.3%) 0/377 (0%)
    Skin irritation 0/377 (0%) 1/377 (0.3%)
    Skin ulcer 2/377 (0.5%) 6/377 (1.6%)
    Stasis dermatitis 0/377 (0%) 2/377 (0.5%)
    Swelling face 1/377 (0.3%) 0/377 (0%)
    Urticaria 1/377 (0.3%) 1/377 (0.3%)
    Surgical and medical procedures
    Arteriovenous fistula operation 1/377 (0.3%) 2/377 (0.5%)
    Carpal tunnel decompression 1/377 (0.3%) 0/377 (0%)
    Cataract operation 2/377 (0.5%) 3/377 (0.8%)
    Catheter placement 0/377 (0%) 2/377 (0.5%)
    Knee arthroplasty 1/377 (0.3%) 0/377 (0%)
    Nephrostomy 1/377 (0.3%) 0/377 (0%)
    Sinus operation 1/377 (0.3%) 0/377 (0%)
    Toe operation 0/377 (0%) 1/377 (0.3%)
    Tooth extraction 3/377 (0.8%) 0/377 (0%)
    Vascular disorders
    Angiopathy 1/377 (0.3%) 0/377 (0%)
    Aortic aneurysm 0/377 (0%) 1/377 (0.3%)
    Arteriovenous fistula 0/377 (0%) 1/377 (0.3%)
    Blood pressure fluctuation 1/377 (0.3%) 0/377 (0%)
    Diastolic hypotension 0/377 (0%) 1/377 (0.3%)
    Haematoma 1/377 (0.3%) 2/377 (0.5%)
    Hypertension 46/377 (12.2%) 40/377 (10.6%)
    Hypertensive crisis 1/377 (0.3%) 0/377 (0%)
    Hypotension 6/377 (1.6%) 22/377 (5.8%)
    Intermittent claudication 1/377 (0.3%) 0/377 (0%)
    Orthostatic hypotension 1/377 (0.3%) 2/377 (0.5%)
    Peripheral arterial occlusive disease 1/377 (0.3%) 1/377 (0.3%)
    Peripheral vascular disorder 1/377 (0.3%) 0/377 (0%)
    Peripheral venous disease 1/377 (0.3%) 0/377 (0%)
    Thrombophlebitis superficial 1/377 (0.3%) 0/377 (0%)
    Varicose vein 1/377 (0.3%) 1/377 (0.3%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.

    Results Point of Contact

    Name/Title Study Director
    Organization Amgen Inc.
    Phone 866-572-6436
    Email medinfo@amgen.com
    Responsible Party:
    Amgen
    ClinicalTrials.gov Identifier:
    NCT01652872
    Other Study ID Numbers:
    • 20110226
    First Posted:
    Jul 30, 2012
    Last Update Posted:
    Dec 12, 2018
    Last Verified:
    Nov 1, 2018