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    Clinical Trial Results:
    A Phase 3, Prospective, Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Pharmacokinetics, Safety and Efficacy of Paricalcitol Capsules in Decreasing Serum Intact Parathyroid Hormone Levels in Pediatric Subjects Ages 10 to 16 years with Moderate to Severe Chronic Kidney Disease

    Summary
    EudraCT number
    		 2010-019439-37
    Trial protocol
    		 DE   GB   PT   ES  
    Global end of trial date
    22 Dec 2014

    Results information
    Results version number
    		 v1
    This version publication date
    20 Apr 2016
    First version publication date
    05 Jul 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    M10-149
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01020487
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co.KG
    Sponsor organisation address
    Abbott House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4XE
    Public contact
    Global Medical Information , AbbVie, 001 800-633-9110,
    Scientific contact
    Ann Eldred, AbbVie, ann.eldred@abbvie.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
    22 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of this study are as follows: Part I: To determine the safety, tolerability, and pharmacokinetics of a single dose of 3 mcg paricalcitol capsules in pediatric subjects ages 10 to 16 years with moderate to severe chronic kidney disease (CKD Stages 3 and 4). Part II: To determine the safety and efficacy of paricalcitol capsules as compared to placebo in decreasing serum intact parathyroid hormone (iPTH) in pediatric subjects ages 10 to 16 years with moderate to severe chronic kidney disease (Stages 3 and 4) with 12 weeks double-blinded study drug and a minimum of 12 weeks open-label active drug.
    Protection of trial subjects
    The study was conducted in accordance with the protocol, International Conference on Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical study conduct and the ethical principles that have their origin in the Declaration of Helsinki. The investigator or his/her representative explained the nature of the study to the subject and/or the subject's parent or legal guardian and answer all questions regarding this study. Prior to any study-related screening procedures being performed on the subject, the informed consent and/or assent statement will be reviewed and signed and dated by the subject and/or the subject's parent or legal guardian and the person who administered the informed consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Feb 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    United States: 28
    Country: Number of subjects enrolled
    Singapore: 1
    Worldwide total number of subjects
    47
    EEA total number of subjects
    18
    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)
    7
    Adolescents (12-17 years)
    40
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Part I was an open label, single-dose study evaluating the pharmacokinetics of paricalcitol capsules in pediatric subjects with moderate to severe CKD. Part II consisted of a randomized, double blind, placebo-controlled study to evaluate safety and efficacy of paricalcitol and a 12-week open-label phase wherein all subjects received paricalcitol.

    Pre-assignment
    Screening details
    		 Subjects aged 10 to 16 years, with CKD, Stage 3, (estimated glomerular filtration rate, [eGFR] 30 to 59 mL/min/1.73 m²) or CKD, Stage 4, (eGFR 15 to 29 mL/min/1.73 m², not requiring dialysis), who met the study selection criteria were enrolled in the study.

    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
    No

    Arm title
    		 Part 1: Paricalcitol
    Arm description
    		 Subjects received a single 3 mcg dose of paricalcitol capsules on Study Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paricalcitol
    Investigational medicinal product code
    ABT-358
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    A single 3 mcg dose of paricalcitol capsules (three 1 mcg paricalcitol capsules) on Study Day 1 administered orally with approximately 100 mL of water.

    Arm title
    		 Part 2: Placebo
    Arm description
    		 Subjects received placebo capsules three times a week (TIW) for 12 weeks during the double-blind treatment phase. From Weeks 12 to 24 subjects received open-label paricalcitol at an initial dose of 1 mcg three times a week. Doses could be adjusted based on chemistry evaluations to target Kidney Disease Outcomes Quality Initiatives (KDOQI) target levels.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsules administered 3 times a week.

    Investigational medicinal product name
    Paricalcitol
    Investigational medicinal product code
    ABT-358
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The initial dose of paricalcitol was 1 mcg TIW (3 mcg per week). Decisions to maintain, increase or decrease the dose were based on the limited chemistry results generated from the most recent visit. Dose decreases could occur at any time, and dose increases could occur in 1 mcg increments from the previous dose every 4 weeks starting at Treatment Week 16. The maximum allowable dose was therefore 3 mcg TIW.

    Arm title
    		 Part 2: Paricalcitol
    Arm description
    		 Subjects received paricalcitol three times a week for 12 weeks during the double-blind treatment period and during the open-label period (Weeks 12-24). The initial dose of paricalcitol was 1 mcg TIW. Doses could be adjusted based on chemistry evaluations to target KDOQI target levels.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Paricalcitol
    Investigational medicinal product code
    ABT-358
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The initial dose of paricalcitol was 1 mcg TIW (3 mcg per week). Decisions to maintain, increase or decrease the dose were based on the limited chemistry results generated from the most recent visit. Dose decreases could occur at any time, and dose increases could occur in 1 mcg increments from the previous dose every 4 weeks starting at Treatment Week 4. The maximum allowable dose for the first 12 weeks of the study was therefore 3 mcg TIW and the maximum allowable dose for the second 12 weeks of the study was 6 mcg TIW.

    Number of subjects in period 1
    		Part 1: Paricalcitol Part 2: Placebo Part 2: Paricalcitol
    Started
    12
    17
    18
    Received Treatment
    12
    18
    18
    Completed
    12
    12
    12
    Not completed
    0
    6
    7
         Randomized in error
    -
    -
    1
         Consent withdrawn by subject
    -
    -
    1
         Adverse event
    -
    6
    2
         Required a dose reduction
    -
    -
    3
    Joined
    0
    1
    1
         Enrolled in Part 2 after completing Part 1
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Part 1: Paricalcitol
    Reporting group description
    		 Subjects received a single 3 mcg dose of paricalcitol capsules on Study Day 1.

    Reporting group title
    Part 2: Placebo
    Reporting group description
    		 Subjects received placebo capsules three times a week (TIW) for 12 weeks during the double-blind treatment phase. From Weeks 12 to 24 subjects received open-label paricalcitol at an initial dose of 1 mcg three times a week. Doses could be adjusted based on chemistry evaluations to target Kidney Disease Outcomes Quality Initiatives (KDOQI) target levels.

    Reporting group title
    Part 2: Paricalcitol
    Reporting group description
    		 Subjects received paricalcitol three times a week for 12 weeks during the double-blind treatment period and during the open-label period (Weeks 12-24). The initial dose of paricalcitol was 1 mcg TIW. Doses could be adjusted based on chemistry evaluations to target KDOQI target levels.

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Two subjects completed Part 1 and also enrolled in Part 2. These subjects are included in both the Part 1 and part 2 treatment arm Baseline data, but only once in the Worldwide Number of Subjects Enrolled and only once in the Total column.
    Reporting group values
    		 Part 1: Paricalcitol Part 2: Placebo Part 2: Paricalcitol Total
    Number of subjects
    		 12 18 19
    Age categorical
    Units: Subjects
    Age continuous
    Data are provided for all randomized subjects who received at least one dose of study drug.
    Units: years
        arithmetic mean (standard deviation)
    		 13.5 ± 1.98 13.3 ± 1.75 13.9 ± 1.81 -
    Gender categorical
    Units: Subjects
        Female
    		 3 5 6 14
        Male
    		 9 13 13 33
    Chronic Kidney Disease Stage
    Stage 3: estimated glomerular filtration rate, (eGFR) 30 to 59 mL/min/1.73 m²) Stage 4: eGFR 15 to 29 mL/min/1.73 m², not requiring dialysis
    Units: Subjects
        Stage 3
    		 6 11 10 27
        Stage 4
    		 6 7 8 19
        Missing
    		 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Part 1: Paricalcitol
    Reporting group description
    		 Subjects received a single 3 mcg dose of paricalcitol capsules on Study Day 1.

    Reporting group title
    Part 2: Placebo
    Reporting group description
    		 Subjects received placebo capsules three times a week (TIW) for 12 weeks during the double-blind treatment phase. From Weeks 12 to 24 subjects received open-label paricalcitol at an initial dose of 1 mcg three times a week. Doses could be adjusted based on chemistry evaluations to target Kidney Disease Outcomes Quality Initiatives (KDOQI) target levels.

    Reporting group title
    Part 2: Paricalcitol
    Reporting group description
    		 Subjects received paricalcitol three times a week for 12 weeks during the double-blind treatment period and during the open-label period (Weeks 12-24). The initial dose of paricalcitol was 1 mcg TIW. Doses could be adjusted based on chemistry evaluations to target KDOQI target levels.

    Primary: Part 1: Paricalcitol Maximum Observed Plasma Concentration (Cmax)

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    End point title
    		 Part 1: Paricalcitol Maximum Observed Plasma Concentration (Cmax) [1] [2]
    End point description
    End point type
    Primary
    End point timeframe
    Blood samples were collected at hour 0, 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours after dosing.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses were not performed for PK paramters
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic analyses were assessed in Part 1 of the study only
    End point values
    		 Part 1: Paricalcitol
    Number of subjects analysed
    12
    Units: ng/mL
        arithmetic mean (standard deviation)
    0.13 ± 0.052
    No statistical analyses for this end point

    Primary: Part 1: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-∞)

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    End point title
    		 Part 1: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-∞) [3] [4]
    End point description
    End point type
    Primary
    End point timeframe
    Blood samples were collected at hour 0, 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours after dosing.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses were not performed for PK parameters
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic analyses were assessed in Part 1 of the study only
    End point values
    		 Part 1: Paricalcitol
    Number of subjects analysed
    12
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    2.87 ± 0.84
    No statistical analyses for this end point

    Primary: Part 2: Percentage of Subjects Achieving Two Consecutive Reductions at Least 30% from Baseline in iPTH

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    End point title
    		 Part 2: Percentage of Subjects Achieving Two Consecutive Reductions at Least 30% from Baseline in iPTH [5]
    End point description
    The primary efficacy endpoint was the percentage of subjects who achieved two consecutive ≥ 30% reductions from Baseline in intact parathyroid hormone (iPTH) levels during the 12 week double-blind portion of the study regardless of CKD stage.
    End point type
    Primary
    End point timeframe
    12-week double-blind treatment period
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy was assessed in Part 2 of the study only
    End point values
    		 Part 2: Placebo Part 2: Paricalcitol
    Number of subjects analysed
    18 [6]
    18 [7]
    Units: percentage of subjects
        number (not applicable)
    0
    27.8
    Notes
    [6] - Intent-to-treat dataset
    [7] - Intent-to-treat dataset
    Statistical analysis title
    		 Primary Analysis
    Comparison groups
    Part 2: Placebo v Part 2: Paricalcitol
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.045
    Method
    		 Fisher exact
    Parameter type
    		 Difference
    Point estimate
    27.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.5
         upper limit
    		 52.8

    Secondary: Part 2: Percentage of Subjects Achieving a Final iPTH Within KDOQI Target Ranges

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    End point title
    		 Part 2: Percentage of Subjects Achieving a Final iPTH Within KDOQI Target Ranges [8]
    End point description
    The Kidney Disease Outcomes Quality Initiatives (KDOQI) Pediatric Subcommittee on Practice Guidelines for Bone Metabolism and Disease in Children with CKD target range for intact parathyroid hormone (iPTH): CKD Stage 3: 35 – 69 pg/mL; CKD Stage 4: 70 – 110 pg/mL.
    End point type
    Secondary
    End point timeframe
    Week 12
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy was assessed in Part 2 of the study only
    End point values
    		 Part 2: Placebo Part 2: Paricalcitol
    Number of subjects analysed
    18
    18
    Units: percentage of subjects
        number (not applicable)
    11.1
    33.3
    Statistical analysis title
    		 Treatment Comparison
    Comparison groups
    Part 2: Placebo v Part 2: Paricalcitol
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.128 [9]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [9] - Cochran-Mantel-Haenszel (CHM) test, adjusting for CKD Stage.

    Secondary: Part 2: Change from Baseline in iPTH to each Post-baseline Visit

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    End point title
    		 Part 2: Change from Baseline in iPTH to each Post-baseline Visit [10]
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 2, 4, 8 and 12
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy was assessed in Part 2 of the study only
    End point values
    		 Part 2: Placebo Part 2: Paricalcitol
    Number of subjects analysed
    18
    18
    Units: pg/mL
    least squares mean (standard error)
        Week 2 (n=15, 16)
    50.39 ± 15.186
    -12.16 ± 14.695
        Week 4 (n=18, 16)
    57.16 ± 20.813
    -11.27 ± 22.117
        Week 8 (n=18, 13)
    57.31 ± 22.099
    -12.79 ± 24.814
        Week 12 (n=15, 12)
    71.47 ± 17.661
    -17.05 ± 19.186
    Statistical analysis title
    		 Overall Comparison
    Comparison groups
    Part 2: Paricalcitol v Part 2: Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference
    Point estimate
    -72.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -108.05
         upper limit
    		 -36.75
    Notes
    [11] - Mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement.
    Statistical analysis title
    		 Week 2 Comparison
    Comparison groups
    Part 2: Paricalcitol v Part 2: Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference
    Point estimate
    -62.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -105.6
         upper limit
    		 -19.49
    Notes
    [12] - Mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement.
    Statistical analysis title
    		 Week 4 Comparison
    Comparison groups
    Part 2: Paricalcitol v Part 2: Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.032 [13]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference
    Point estimate
    -68.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -130.39
         upper limit
    		 -6.47
    Notes
    [13] - Mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement.
    Statistical analysis title
    		 Week 8 Comparison
    Comparison groups
    Part 2: Paricalcitol v Part 2: Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference
    Point estimate
    -70.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -137.82
         upper limit
    		 -2.37
    Notes
    [14] - Mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement.
    Statistical analysis title
    		 Week 12 Comparison
    Comparison groups
    Part 2: Paricalcitol v Part 2: Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [15]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference
    Point estimate
    -88.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -142.04
         upper limit
    		 -35.01
    Notes
    [15] - Mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement.

    Secondary: Part 2: Percentage of Subjects Achieving a Final Calcium Within KDOQI Target Ranges

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    End point title
    		 Part 2: Percentage of Subjects Achieving a Final Calcium Within KDOQI Target Ranges [16]
    End point description
    The KDOQI target ranges for calcium are: to maintain within the normal range for age (years): Age 6 – 12: 9.4 – 10.2 mg/dL (2.35 – 2.55 mmol/L); Age 13 – 20: 8.8 – 10.2 mg/dL (2.20 – 2.55 mmol/L).
    End point type
    Secondary
    End point timeframe
    Week 12
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy was assessed in Part 2 of the study only
    End point values
    		 Part 2: Placebo Part 2: Paricalcitol
    Number of subjects analysed
    18
    18
    Units: percentage of subjects
        number (not applicable)
    94.4
    83.3
    Statistical analysis title
    		 Treatment Comparison
    Comparison groups
    Part 2: Placebo v Part 2: Paricalcitol
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.327 [17]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [17] - Cochran-Mantel-Haenszel (CHM) test, adjusting for CKD Stage.

    Secondary: Part 2: Percentage of Subjects Achieving a Final Phosphorus Within KDOQI Target Ranges

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    End point title
    		 Part 2: Percentage of Subjects Achieving a Final Phosphorus Within KDOQI Target Ranges [18]
    End point description
    The KDOQI target ranges of serum phosphorus are to maintain at or above age appropriate lower limits and no higher than the age-appropriate upper limits: Age 6 – 12: 3.6 – 5.8 mg/dL (1.16 – 1.87 mmol/L); Age 13 – 20: 2.3 – 4.5 mg/dL (0.74 – 1.45 mmol/L).
    End point type
    Secondary
    End point timeframe
    Week 12
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy was assessed in Part 2 of the study only
    End point values
    		 Part 2: Placebo Part 2: Paricalcitol
    Number of subjects analysed
    18
    18
    Units: percentage of subjects
        number (not applicable)
    72.2
    50
    Statistical analysis title
    		 Treatment Comparison
    Comparison groups
    Part 2: Paricalcitol v Part 2: Placebo
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.194 [19]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [19] - Cochran-Mantel-Haenszel (CHM) test, adjusting for CKD Stage.

    Secondary: Part 2: Change From Baseline in First Morning Void (FMV) Urinary Albumin to Creatinine Ratio (UACR)

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    End point title
    		 Part 2: Change From Baseline in First Morning Void (FMV) Urinary Albumin to Creatinine Ratio (UACR) [20]
    End point description
    The mean change from Baseline in FMV UACR on a log scale to each post baseline visit.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8 and 12
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Efficacy was assessed in Part 2 of the study only
    End point values
    		 Part 2: Placebo Part 2: Paricalcitol
    Number of subjects analysed
    15 [21]
    16 [22]
    Units: mg/g
    least squares mean (standard error)
        Week 4 (n=15, 13)
    -0.12 ± 0.126
    -0.13 ± 0.132
        Week 8 (n=14, 11)
    -0.13 ± 0.141
    -0.01 ± 0.155
        Week 12 (n=12, 10)
    -0.08 ± 0.259
    0.22 ± 0.292
    Notes
    [21] - Intent-to-treat dataset with available Baseline data
    [22] - Intent-to-treat dataset with available Baseline data
    Statistical analysis title
    		 Overall Comparison
    Comparison groups
    Part 2: Placebo v Part 2: Paricalcitol
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.469 [23]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference
    Point estimate
    0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 0.53
    Notes
    [23] - A mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement
    Statistical analysis title
    		 Week 4 Comparison
    Comparison groups
    Part 2: Placebo v Part 2: Paricalcitol
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.975 [24]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.39
         upper limit
    		 0.37
    Notes
    [24] - A mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement
    Statistical analysis title
    		 Week 8 Comparison
    Comparison groups
    Part 2: Placebo v Part 2: Paricalcitol
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.567 [25]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.56
    Notes
    [25] - A mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement
    Statistical analysis title
    		 Week 12 Comparison
    Comparison groups
    Part 2: Placebo v Part 2: Paricalcitol
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.462 [26]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 1.12
    Notes
    [26] - A mixed effects repeated measures analysis using all the longitudinal observations across the visits including the fixed categorical effects of treatment, visit, and treatment-by-visit interaction, and the continuous covariate of baseline measurement

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events reported from the time of study drug administration through 30 days following discontinuation of study drug administration were collected.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Part 1: Paricalcitol
    Reporting group description
    		 Subjects received a single 3 mcg dose of paricalcitol capsules on Study Day 1.

    Reporting group title
    Part 2: Placebo
    Reporting group description
    		 Subjects received placebo capsules three times a week for 12 weeks during the double-blind treatment phase.

    Reporting group title
    Part 2: Paricalcitol
    Reporting group description
    		 Subjects received paricalcitol three times a week (TIW) for 12 weeks during the double-blind treatment period. The initial dose of paricalcitol was 1 mcg TIW. Doses could be adjusted based on chemistry evaluations to target Kidney Disease Outcomes Quality Initiatives (KDOQI) levels.

    Reporting group title
    Part 2: Placebo/Paricalcitol
    Reporting group description
    		 Subjects who received placebo in the double-blind treatment phase received open-label paricalcitol at an initial dose of 1 mcg three times a week in the open-label treatment phase (Weeks 12-24). Doses could be adjusted based on chemistry evaluations to target KDOQI levels.

    Reporting group title
    Part 2: Paricalcitol/Paricalcitol
    Reporting group description
    		 Subjects who received paricalcitol during the double-blind treatment period continued to receive paricalcitol three times a week during the open-label period (Weeks 12-24).

    Serious adverse events
    		 Part 1: Paricalcitol Part 2: Placebo Part 2: Paricalcitol Part 2: Placebo/Paricalcitol Part 2: Paricalcitol/Paricalcitol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    1 / 13 (7.69%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive Crisis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Homicidal Ideation
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Failure Chronic
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Viral Infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part 1: Paricalcitol Part 2: Placebo Part 2: Paricalcitol Part 2: Placebo/Paricalcitol Part 2: Paricalcitol/Paricalcitol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 12 (16.67%)
    15 / 18 (83.33%)
    7 / 18 (38.89%)
    14 / 16 (87.50%)
    7 / 13 (53.85%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    General disorders and administration site conditions
    Feeling Hot
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Oedema Peripheral
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Cough
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    2
    2
    Epistaxis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    1
    1
    Nasal Congestion
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Wheezing
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    2
    Psychiatric disorders
    Thinking Abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Investigations
    Blood Potassium Increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Vitamin D Decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    1 / 13 (7.69%)
         occurrences all number
    1
    2
    0
    1
    1
    Syncope
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Iron Deficiency Anaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 16 (12.50%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    Toothache
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Cold Sweat
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    0
    0
    1
    Ingrowing Nail
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Micturition Urgency
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Renal Failure Chronic
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    2 / 16 (12.50%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Muscle Spasms
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    0
    1
    Infections and infestations
    Acute Sinusitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Herpes Simplex
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Impetigo
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    2 / 13 (15.38%)
         occurrences all number
    0
    3
    0
    1
    2
    Otitis Media
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Paronychia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Pharyngitis Streptococcal
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 16 (12.50%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    Rhinitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    3 / 18 (16.67%)
    0 / 16 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    3
    0
    1
    Tooth Infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 16 (12.50%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    4
    0
    Viral Infection
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Hypercalcaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    4 / 16 (25.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    1
    4
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    3 / 16 (18.75%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 16 (12.50%)
    0 / 13 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Metabolic Acidosis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Sep 2009
    Amendment 1 revised the 6 month treatment phase to a 12 week, double-blind treatment period followed by a 12 week, open-label treatment period. Revision of the treatment periods was made to address the concerns of both physicians and parents with continuation in the placebo arm of subjects with secondary hyperparathyroidism, while treatment for this disease state was already established and is part of current clinical practice.
    01 Oct 2009
    Amendment 2 clarified throughout the document that the initial dose for the Safety and Efficacy Portion, Part 2 of the study was to be based on the PK data from the first 6 subjects that completed the PK Portion, Part 1.
    08 Apr 2010
    Amendment 3 added EudraCT number (2010-019439-37) as this clinical trial was submitted to the European regulatory authorities and conducted in the U.S. Europe, Latin America, and Singapore.
    25 May 2010
    With Amendment 4 the primary and secondary efficacy endpoints involving assessments based on two consecutive iPTH measurements were changed to assessments based on the final iPTH measurement since scheduling of study visits was changed to be less frequent than scheduled biweekly visits. In previous communication with Food and Drug Agency (FDA), it was clear that either two consecutive time points or the last time point as the primary endpoint was acceptable to the FDA. Since the original sample size calculation was based on parameter estimates obtained from simulations run on the achievement of two consecutive iPTH values within KDOQI iPTH limits, these were conservative estimates for a final response rate. Therefore, the sample size was not changed in this amendment.
    20 Aug 2012
    Amendment 5 changed the enrollment target from 72 to 36 subjects, with a maximum of 12 transplant subjects.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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