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    Clinical Trial Results:
    A Multicenter, Multiple-dose, Two-arm, Active-controlled, Double-blind, Double-dummy Study to Compare the Therapeutic Efficacy and Safety of Oral Doses of Cinacalcet HCl With Intravenous Doses of AMG 416 in Hemodialysis Subjects With Secondary Hyperparathyroidism

    Summary
    EudraCT number
    		 2013-000192-33
    Trial protocol
    		 PT   IT   CZ   LV   SE   AT   BE   ES   EE   DE   GR   LT   DK   HU   PL  
    Global end of trial date
    08 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Jul 2016
    First version publication date
    16 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20120360
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01896232
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info - Clinical Trials, Amgen (EUROPE) GmbH, MedinfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info - Clinical Trials, Amgen (EUROPE) GmbH, MedinfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Demonstrate that treatment with etelcalcetide (AMG 416) is not inferior to treatment with cinacalcet for lowering plasma intact parathyroid hormone (PTH) levels by > 30% from baseline among subjects with chronic kidney disease (CKD) and secondary hyperparathyroidism (SHPT) who require management with hemodialysis.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. Essential documents are retained in accordance with ICH GCP. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Aug 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 25
    Country: Number of subjects enrolled
    Portugal: 43
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Greece: 30
    Country: Number of subjects enrolled
    Hungary: 50
    Country: Number of subjects enrolled
    Italy: 35
    Country: Number of subjects enrolled
    Latvia: 4
    Country: Number of subjects enrolled
    Lithuania: 28
    Country: Number of subjects enrolled
    New Zealand: 15
    Country: Number of subjects enrolled
    Russian Federation: 97
    Country: Number of subjects enrolled
    Switzerland: 16
    Country: Number of subjects enrolled
    Turkey: 19
    Country: Number of subjects enrolled
    Canada: 28
    Country: Number of subjects enrolled
    United States: 180
    Worldwide total number of subjects
    683
    EEA total number of subjects
    328
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    505
    From 65 to 84 years
    172
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 164 centers in Austria, Belgium, Canada, the Czech Republic, Denmark, Estonia, France, Germany, Greece, Hungary, Italy, Latvia, Lithuania, New Zealand, Poland, Portugal, Russia, Spain, Sweden, Switzerland, Turkey, and the United States. Participants were enrolled from 13 August 2013 to 16 May 2014.

    Pre-assignment
    Screening details
    		 Patients were assessed for eligibility during an 8-week screening phase. Eligible subjects were stratified by screening serum parathyroid hormone (PTH) level (< 900 or ≥ 900 pg/mL) and region (North America or non-North America) and were randomized 1:1 to receive etelcalcetide intravenously (IV) plus oral placebo or oral cinacalcet plus placebo IV.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cinacalcet
    Arm description
    		 Participants were randomized to receive oral cinacalcet once daily and placebo intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks. The starting dose of cinacalcet was 30 mg daily and could have been titrated at weeks 5, 9, 13, and 17 to target predialysis serum PTH ≤ 300 pg/mL but no lower than 100 pg/mL while maintaining corrected calcium (cCa) ≥ 8.3 mg/dL.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cinacalcet
    Investigational medicinal product code
    Other name
    Sensipar®, Mimpara®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cinacalcet was administered orally once a day. The starting dose was 30 mg daily, titrated up to 180 mg daily based on serum PTH and corrected calcium levels.

    Investigational medicinal product name
    Intravenous Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Administered intravenously (IV) three times per week.

    Arm title
    		 Etelcalcetide
    Arm description
    		 Participants were randomized to receive etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session TIW, and daily oral doses of placebo tablets for 26 weeks. The starting dose of etelcalcetide was 5 mg, and could have been titrated at weeks 5, 9, 13, and 17 to target predialysis serum PTH ≤ 300 pg/mL but no lower than 100 pg/mL while maintaining cCa ≥ 8.3 mg/dL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etelcalcetide
    Investigational medicinal product code
    AMG 416
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Administered intravenously three times per week. The starting dose was 5 mg, titrated up to 15 mg based on serum PTH and corrected calcium levels.

    Investigational medicinal product name
    Oral Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once a day.

    Number of subjects in period 1
    		Cinacalcet Etelcalcetide
    Started
    343
    340
    Received Treatment
    341
    338
    Completed
    294
    287
    Not completed
    49
    53
         Consent withdrawn by subject
    32
    31
         Death
    6
    10
         Lost to follow-up
    9
    12
         Sponsor decision
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cinacalcet
    Reporting group description
    		 Participants were randomized to receive oral cinacalcet once daily and placebo intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks. The starting dose of cinacalcet was 30 mg daily and could have been titrated at weeks 5, 9, 13, and 17 to target predialysis serum PTH ≤ 300 pg/mL but no lower than 100 pg/mL while maintaining corrected calcium (cCa) ≥ 8.3 mg/dL.

    Reporting group title
    Etelcalcetide
    Reporting group description
    		 Participants were randomized to receive etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session TIW, and daily oral doses of placebo tablets for 26 weeks. The starting dose of etelcalcetide was 5 mg, and could have been titrated at weeks 5, 9, 13, and 17 to target predialysis serum PTH ≤ 300 pg/mL but no lower than 100 pg/mL while maintaining cCa ≥ 8.3 mg/dL.

    Reporting group values
    		 Cinacalcet Etelcalcetide Total
    Number of subjects
    		 343 340 683
    Age categorical
    Units: Subjects
        < 65 years
    		 243 262 505
        ≥ 65 years
    		 100 78 178
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.3 ( 14.4 ) 54 ( 13.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 151 148 299
        Male
    		 192 192 384
    Race
    Units: Subjects
        Asian
    		 7 9 16
        Black (or African American)
    		 52 54 106
        Native Hawaiian or Other Pacific Islander
    		 3 6 9
        White
    		 277 261 538
        Other
    		 4 10 14
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    		 41 38 79
        Not Hispanic/Latino
    		 302 302 604
    Stratification Factor: Screening Serum Parathyroid Hormone (PTH)
    Units: Subjects
        < 900 pg/mL
    		 171 169 340
        ≥ 900 pg/mL
    		 172 171 343
    Stratification Factor: Region
    Units: Subjects
        North America
    		 105 103 208
        Non-North America
    		 238 237 475
    Parathyroid Hormone
    Units: pg/mL
        arithmetic mean (standard deviation)
    		 1138.71 ( 706.77 ) 1092.12 ( 622.81 ) -
    Corrected Calcium
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 9.58 ( 0.67 ) 9.67 ( 0.71 ) -
    Phosphorus
    Data available for 341 and 337 in each treatment group respectively.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 5.82 ( 1.58 ) 5.81 ( 1.69 ) -
    Corrected Calcium Phosphorus Product (cCa x P)
    Data available for 341 and 337 participants in each treatment group respectively.
    Units: mg²/dL²
        arithmetic mean (standard deviation)
    		 55.65 ( 15.37 ) 56.36 ( 17.15 ) -

    End points

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    End points reporting groups
    Reporting group title
    Cinacalcet
    Reporting group description
    		 Participants were randomized to receive oral cinacalcet once daily and placebo intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks. The starting dose of cinacalcet was 30 mg daily and could have been titrated at weeks 5, 9, 13, and 17 to target predialysis serum PTH ≤ 300 pg/mL but no lower than 100 pg/mL while maintaining corrected calcium (cCa) ≥ 8.3 mg/dL.

    Reporting group title
    Etelcalcetide
    Reporting group description
    		 Participants were randomized to receive etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session TIW, and daily oral doses of placebo tablets for 26 weeks. The starting dose of etelcalcetide was 5 mg, and could have been titrated at weeks 5, 9, 13, and 17 to target predialysis serum PTH ≤ 300 pg/mL but no lower than 100 pg/mL while maintaining cCa ≥ 8.3 mg/dL.

    Primary: Percentage of Participants With > 30% Reduction From Baseline in Mean Parathyroid Hormone During the Efficacy Assessment Phase

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    End point title
    		 Percentage of Participants With > 30% Reduction From Baseline in Mean Parathyroid Hormone During the Efficacy Assessment Phase
    End point description
    End point type
    Primary
    End point timeframe
    Baseline and the efficacy assessment phase (EAP; defined as Weeks 20 to 27, inclusive).
    End point values
    		 Cinacalcet Etelcalcetide
    Number of subjects analysed
    310 [1]
    298 [2]
    Units: percentage of participants
        number (not applicable)
    63.9
    77.9
    Notes
    [1] - Subjects with PTH data during the EAP
    [2] - Subjects with PTH data during the EAP
    Statistical analysis title
    		 Non-inferiority Analysis
    Statistical analysis description
    The analysis was conducted on the Full Analysis Set (FAS), defined as all randomized participants. Imputation under the non-inferiority null method was applied to participants who did not have data during the EAP. The actual number of subjects included in the analysis is 683. The Mantel-Haenszel estimator was used to calculate the treatment difference between the proportions (Cinacalcet - Etelcalcetide) stratified by screening PTH level and region.
    Comparison groups
    Etelcalcetide v Cinacalcet
    Number of subjects included in analysis
    608
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Stratified Treatment Difference
    Point estimate
    -10.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.45
         upper limit
    		 -3.51
    Notes
    [3] - Etelcalcetide was considered non-inferior to cinacalcet if the upper bound of the 2-sided 95% confidence interval (CI) of the treatment difference (cinacalcet - etelcalcetide) was < 12%, the prespecified margin for non-inferiority.

    Secondary: Percentage of Participants With > 50% Reduction From Baseline in Mean PTH During the Efficacy Assessment Phase

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    End point title
    		 Percentage of Participants With > 50% Reduction From Baseline in Mean PTH During the Efficacy Assessment Phase
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase (Weeks 20 to 27, inclusive).
    End point values
    		 Cinacalcet Etelcalcetide
    Number of subjects analysed
    343
    340
    Units: percentage of participants
        number (not applicable)
    40.2
    52.4
    Statistical analysis title
    		 Superiority Analysis
    Statistical analysis description
    The analysis was conducted on the full analysis set. Participants were considered as non-responders if they did not have PTH data during the EAP (ie, non-responder imputation). Achievement of > 50% reduction in mean predialysis serum PTH from baseline during the EAP was analyzed using the Cochran-Mantel-Haenszel (CMH) test stratified by screening PTH level and region. The CMH-stratified odds ratio is Etelcalcetide : Cinacalcet.
    Comparison groups
    Etelcalcetide v Cinacalcet
    Number of subjects included in analysis
    683
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.21
         upper limit
    		 2.23

    Secondary: Percentage of Participants With > 30% Reduction From Baseline in Mean PTH During the Efficacy Assessment Phase

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    End point title
    		 Percentage of Participants With > 30% Reduction From Baseline in Mean PTH During the Efficacy Assessment Phase
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase (Week 20 to Week 27)
    End point values
    		 Cinacalcet Etelcalcetide
    Number of subjects analysed
    343
    340
    Units: percentage of participants
        number (not applicable)
    57.7
    68.2
    Statistical analysis title
    		 Superiority Analysis
    Statistical analysis description
    The analysis was conducted on the full analysis set. Participants were considered as non-responders if they did not have PTH data during the EAP (ie, non-responder imputation). Achievement of > 30% reduction in mean predialysis serum PTH from baseline during the EAP was analyzed using the Cochran-Mantel-Haenszel test stratified by screening PTH level and region. The CMH-stratified odds ratio is Etelcalcetide : Cinacalcet.
    Comparison groups
    Etelcalcetide v Cinacalcet
    Number of subjects included in analysis
    683
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.16
         upper limit
    		 2.17

    Secondary: Mean Number of Days of Vomiting or Nausea per Week in the First 8 Weeks

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    End point title
    		 Mean Number of Days of Vomiting or Nausea per Week in the First 8 Weeks
    End point description
    Participants completed the Nausea/Vomiting Symptom Assessment (NVSA) questionnaire daily. This questionnaire asked participants to indicate the severity of nausea on a scale from 0 (no nausea) to 10 (as severe as can be imagined) and if they had vomited in the past 24 hours. A day of vomiting or nausea was defined as those where the severity of nausea score was > 0 or where the episodes of vomiting score was > 0. For participants providing less than 7 days of responses to NVSA questions in any given week, data from that week did not contribute to the analysis.
    End point type
    Secondary
    End point timeframe
    First 8 weeks
    End point values
    		 Cinacalcet Etelcalcetide
    Number of subjects analysed
    324
    331
    Units: days/week
        least squares mean (standard error)
    0.3 ( 0.03 )
    0.4 ( 0.04 )
    Statistical analysis title
    		 Superiority Analysis
    Statistical analysis description
    Analyzed using a generalized linear mixed model with Poisson regression, including screening value of the number of days of nausea and vomiting, treatment, stratification factors (screening PTH level and region), study weeks, and treatment by study weeks as covariates. The full analysis set with available data was used for this analysis. The treatment rate ratio is Etelcalcetide : Cinacalcet.
    Comparison groups
    Etelcalcetide v Cinacalcet
    Number of subjects included in analysis
    655
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.27
    Method
    		 Generalized Linear Mixed Model
    Parameter type
    		 Treatment Rate Ratio
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.49
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15

    Secondary: Percent Change From Baseline in Mean Corrected Calcium During the Efficacy Assessment Phase

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    End point title
    		 Percent Change From Baseline in Mean Corrected Calcium During the Efficacy Assessment Phase
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase (weeks 20 - 27)
    End point values
    		 Cinacalcet Etelcalcetide
    Number of subjects analysed
    310
    298
    Units: percent change
        arithmetic mean (standard error)
    -6.28 ( 0.44 )
    -9.83 ( 0.49 )
    Statistical analysis title
    		 Analysis of Treatment Difference
    Statistical analysis description
    The analysis was conducted on the full analysis set using a repeated measures mixed effects model, including treatment group, randomization stratification factors (screening PTH level and region), study week, and study week by treatment as fixed effects. Treatment difference is Etelcalcetide - Cinacalcet.
    Comparison groups
    Etelcalcetide v Cinacalcet
    Number of subjects included in analysis
    608
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -3.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.76
         upper limit
    		 -2.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.65

    Secondary: Percentage of Participants With Mean Predialysis Serum Phosphorus ≤ 4.5 mg/dL During the Efficacy Assessment Phase

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    End point title
    		 Percentage of Participants With Mean Predialysis Serum Phosphorus ≤ 4.5 mg/dL During the Efficacy Assessment Phase
    End point description
    End point type
    Secondary
    End point timeframe
    Efficacy assessment phase (weeks 20 - 27)
    End point values
    		 Cinacalcet Etelcalcetide
    Number of subjects analysed
    343
    340
    Units: percentage of participants
        number (not applicable)
    29.2
    32.1
    Statistical analysis title
    		 Analysis of Treatment Difference
    Statistical analysis description
    The analysis was conducted on the full analysis set using a CMH test stratified by screening PTH level and region. Participants with no phosphorus assessments during the EAP were considered non-responders. The CMH-stratified odds ratio is Etelcalcetide : Cinacalcet.
    Comparison groups
    Etelcalcetide v Cinacalcet
    Number of subjects included in analysis
    683
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.83
         upper limit
    		 1.59

    Secondary: Mean Severity of Nausea in the First 8 Weeks

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    End point title
    		 Mean Severity of Nausea in the First 8 Weeks
    End point description
    Severity of nausea was assessed using the Nausea and Vomiting Symptom Assessment questionnaire which asked participants to rate the severity of nausea on a scale from 0 (no nausea) to 10 (as severe as can be imagined). For each participant, the mean severity of nausea was calculated by averaging all available daily severities (including zeroes) reported in the first 8 weeks.
    End point type
    Secondary
    End point timeframe
    First 8 weeks
    End point values
    		 Cinacalcet Etelcalcetide
    Number of subjects analysed
    339
    339
    Units: units on a scale
        least squares mean (standard error)
    0.48 ( 0.06 )
    0.45 ( 0.06 )
    Statistical analysis title
    		 Analysis of Treatment Difference
    Statistical analysis description
    Analyzed using an analysis of covariance (ANCOVA) model adjusted for screening PTH level and region. The full analysis set with available data was used for this analysis. Treatment difference is Etelcalcetide - Cinacalcet.
    Comparison groups
    Etelcalcetide v Cinacalcet
    Number of subjects included in analysis
    678
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.08

    Secondary: Mean Number of Episodes of Vomiting per Week in the First 8 Weeks

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    End point title
    		 Mean Number of Episodes of Vomiting per Week in the First 8 Weeks
    End point description
    The number of vomiting episodes was assessed using the Nausea and Vomiting Symptom Assessment questionnaire which asks participants on a daily basis how many times they vomited in the past 24 hours. The number of episodes in a week is the sum of all reported daily episodes in the week. For participants providing less than 7 days of responses to NVSA questions in any given week, data from that week did not contribute to the analysis.
    End point type
    Secondary
    End point timeframe
    First 8 weeks
    End point values
    		 Cinacalcet Etelcalcetide
    Number of subjects analysed
    324
    331
    Units: vomiting episodes
        least squares mean (standard error)
    0.1 ( 0.02 )
    0.2 ( 0.02 )
    Statistical analysis title
    		 Analysis of Treatment Rate Ratio
    Statistical analysis description
    This analysis was conducted in the full analysis set using a generalized linear mixed model with Poisson regression including screening value of the number of episodes of vomiting, treatment, stratification factors (screening PTH level and region), study weeks, and treatment by study weeks as covariates. The treatment rate ratio is Etelcalcetide : Cinacalcet.
    Comparison groups
    Etelcalcetide v Cinacalcet
    Number of subjects included in analysis
    655
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment Rate Ratio
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.22

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 until 30 days after the last dose; the treatment period was 26 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Cinacalcet
    Reporting group description
    		 Participants received oral cinacalcet once daily and placebo intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks. The starting dose of cinacalcet was 30 mg daily and could have been titrated at weeks 5, 9, 13, and 17 to target predialysis serum PTH ≤ 300 pg/mL but no lower than 100 pg/mL while maintaining corrected calcium (cCa) ≥ 8.3 mg/dL.

    Reporting group title
    Etelcalcetide
    Reporting group description
    		 Participants received etelcalcetide administered by intravenous bolus injection at the end of each hemodialysis session TIW, and daily oral doses of placebo tablets for 26 weeks. The starting dose of etelcalcetide was 5 mg, and could have been titrated at weeks 5, 9, 13, and 17 to target predialysis serum PTH ≤ 300 pg/mL but no lower than 100 pg/mL while maintaining cCa ≥ 8.3 mg/dL.

    Serious adverse events
    		 Cinacalcet Etelcalcetide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    93 / 341 (27.27%)
    85 / 338 (25.15%)
         number of deaths (all causes)
    6
    9
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder neoplasm
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal cancer
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic arteriosclerosis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brachiocephalic vein stenosis
         subjects affected / exposed
    2 / 341 (0.59%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial thrombosis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 341 (0.29%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 341 (0.00%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 341 (0.29%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous stenosis
         subjects affected / exposed
    2 / 341 (0.59%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 341 (0.29%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sopor
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood calcium decreased
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colonoscopy
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula aneurysm
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site complication
         subjects affected / exposed
    2 / 341 (0.59%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site haemorrhage
         subjects affected / exposed
    0 / 341 (0.00%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous graft site haemorrhage
         subjects affected / exposed
    2 / 341 (0.59%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodialysis complication
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    3 / 341 (0.88%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney rupture
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural fistula
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    3 / 341 (0.88%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft thrombosis
         subjects affected / exposed
    3 / 341 (0.88%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft occlusion
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular injury
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Congenital, familial and genetic disorders
    Cerebrovascular arteriovenous malformation
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 341 (0.59%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    2 / 341 (0.59%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 341 (0.59%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 341 (0.88%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    0 / 341 (0.00%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Cardiac failure congestive
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve disease
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    2 / 341 (0.59%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amputation stump pain
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 341 (1.17%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Antiphospholipid syndrome
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic gastroparesis
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis haemorrhagic
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 341 (0.00%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis haemorrhagic
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 341 (0.00%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 341 (0.00%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Brown tumour
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    2 / 341 (0.59%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 341 (0.59%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 341 (0.59%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous graft site abscess
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 341 (0.88%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    3 / 341 (0.88%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 341 (0.59%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 341 (0.00%)
    4 / 338 (1.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 341 (0.29%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected fistula
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngolaryngeal abscess
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    1 / 341 (0.29%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst infection
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    4 / 341 (1.17%)
    3 / 338 (0.89%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 341 (0.59%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Calciphylaxis
         subjects affected / exposed
    1 / 341 (0.29%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes with hyperosmolarity
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 341 (0.29%)
    2 / 338 (0.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 341 (0.00%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    5 / 341 (1.47%)
    1 / 338 (0.30%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 341 (0.29%)
    0 / 338 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cinacalcet Etelcalcetide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    259 / 341 (75.95%)
    278 / 338 (82.25%)
    Investigations
    Blood calcium decreased
         subjects affected / exposed
    203 / 341 (59.53%)
    232 / 338 (68.64%)
         occurrences all number
    347
    376
    Vascular disorders
    Hypertension
         subjects affected / exposed
    22 / 341 (6.45%)
    20 / 338 (5.92%)
         occurrences all number
    26
    30
    Hypotension
         subjects affected / exposed
    10 / 341 (2.93%)
    21 / 338 (6.21%)
         occurrences all number
    11
    30
    Nervous system disorders
    Headache
         subjects affected / exposed
    24 / 341 (7.04%)
    21 / 338 (6.21%)
         occurrences all number
    34
    31
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    11 / 341 (3.23%)
    17 / 338 (5.03%)
         occurrences all number
    14
    19
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    34 / 341 (9.97%)
    21 / 338 (6.21%)
         occurrences all number
    47
    24
    Nausea
         subjects affected / exposed
    77 / 341 (22.58%)
    62 / 338 (18.34%)
         occurrences all number
    172
    150
    Vomiting
         subjects affected / exposed
    46 / 341 (13.49%)
    44 / 338 (13.02%)
         occurrences all number
    99
    72
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    13 / 341 (3.81%)
    17 / 338 (5.03%)
         occurrences all number
    16
    19
    Muscle spasms
         subjects affected / exposed
    20 / 341 (5.87%)
    22 / 338 (6.51%)
         occurrences all number
    32
    29
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    8 / 341 (2.35%)
    17 / 338 (5.03%)
         occurrences all number
    9
    19

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2013
    - Allowed initiation of AMG 416 administration Monday to Friday, instead of the previous restriction of Wednesday or Thursday only. - Allowed adjustment of vitamin D for hypocalcemia during the study. - Provided a recommended sequence of interventions for treating hypocalcemia with reference to the modification of oral calcium supplements, dialysate calcium concentration, and then vitamin D. - Clarified that AMG 416 was not to be administered subcutaneously or by any route other than IV, and that it was not to be administered concurrently with other IV medications. - Changed the assay for PTH testing from plasma to serum to be consistent with previous AMG 416 studies.
    30 Aug 2013
    - Addressed 4 main issues: o Updated inclusion/exclusion criteria to facilitate enrollment challenges and to align with updated male contraception for both investigational products. o Addressed regulatory authority comments on the analysis of the primary endpoint. o Updated serious adverse event reporting language. o Updated miscellaneous study conduct procedures. - Changed the eligibility criteria from 2 consecutive PTH concentrations > 600 pg/mL to 1 PTH concentration > 500 pg/mL. - Changed the inclusion criteria to allow changes (up to 50%) in the maximum dose for protocol-specified concomitant therapies (vitamin D, calcium supplements, and phosphate binders).
    17 Oct 2014
    - Added a key secondary endpoint based on efficacy and reprioritized the order of sequential statistical testing of the key secondary endpoints based on the results of recently-concluded, phase 3, placebo-controlled AMG 416 Studies 20120229 and 20120230, for which an indirect comparison was made to concluded phase 3, placebo-controlled studies of cinacalcet.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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