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    Clinical Trial Results:
    An Open-label, Randomised, Active-controlled Multicentre Phase 2 Dose Finding Study to Evaluate the Ability of PA21 to Lower Serum Phosphate Levels and the Tolerability in Patients with Chronic Kidney Disease on Maintenance Haemodialysis

    Summary
    EudraCT number
    		 2008-004748-36
    Trial protocol
    		 DE   CZ   BG  
    Global end of trial date
    13 Oct 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Dec 2016
    First version publication date
    09 Dec 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    PA-CL-03A
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00824460
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Vifor (International) Inc.
    Sponsor organisation address
    Rechenstrasse 37, St. Gallen, Switzerland, CH-9001
    Public contact
    MedInfo , Vifor (Internationa) Inc. , medinfo@viforpharma.com
    Scientific contact
    MedInfo , Vifor (Internationa) Inc. , medinfo@viforpharma.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
    21 Oct 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Oct 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Oct 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the ability of different doses of PA21 to lower serum phosphorus levels in patients with chronic kidney disease (CKD) on maintenance haemodialysis.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the Declaration of Helsinki including amendments in force up to and including the time the study was conducted. The study was conducted in compliance with the International Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP), Committee for Proprietary Medicinal Products Guideline (CPMP/ICH/135/95), and compliant with the European Union Clinical Trial Directive (Directive 2001/20/EC) and/or the Code of Federal Regulations for informed consent and protection of patient rights (21 CFR, Parts 50 and 56).
    Background therapy
    		 -
    Evidence for comparator
    		 A sevelamer hydrochloride (HCl) group was added to assess assay sensitivity and to provide an active control group for comparability of efficacy and tolerability. The dose of sevelamer HCl used in this study was 4.8 g/day; this dose was chosen as it is an approved dose for this product and is commonly used.
    Actual start date of recruitment
    28 Jan 2009
    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
    Czech Republic: 8
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Bulgaria: 23
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Romania: 12
    Country: Number of subjects enrolled
    United States: 21
    Country: Number of subjects enrolled
    Croatia: 40
    Country: Number of subjects enrolled
    Russian Federation: 28
    Country: Number of subjects enrolled
    Switzerland: 5
    Worldwide total number of subjects
    154
    EEA total number of subjects
    100
    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)
    93
    From 65 to 84 years
    59
    85 years and over
    2

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 417 subjects were screened at 60 centres and 154 of them were randomised at 50 centres, in 9 countries.

    Pre-assignment
    Screening details
    		 After a washout period from their previous phosphate binder treatment, suitable subjects were randomised to receive either PA21 or sevelamer (HCl) for 6 weeks. The phases of the study consisted of a screening phase (up to 1 week), a washout phase of 2 weeks, a 6-week treatment phase, and a 2-week run-out phase.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 1.25 g PA21
    Arm description
    		 Daily dose of 1.25 g PA21 (1 tablet taken with the largest meal of the day). All randomized subjects were considered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PA21
    Investigational medicinal product code
    Other name
    Mixture of polynuclear iron(III)-oxyhydroxide, sucrose and starches; Stabilised polynuclear iron oxyhydroxide
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daily dose of 1.25 g PA21 (1 tablet taken with the largest meal of the day).

    Arm title
    		 5.0 g PA21
    Arm description
    		 Daily dose of 5.0 g PA21 (4 tablets of 1.25 g: 2 tablets with the largest meal of the day and 1 tablet each with the 2 smaller meals of the day). All randomized subjects were considered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PA21
    Investigational medicinal product code
    Other name
    Mixture of polynuclear iron(III)-oxyhydroxide, sucrose and starches; Stabilised polynuclear iron oxyhydroxide
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daily dose of 5.0 g PA21 (4 tablets of 1.25 g: 2 tablets with the largest meal of the day and 1 tablet each with the 2 smaller meals of the day).

    Arm title
    		 7.5 g PA21
    Arm description
    		 Daily dose of 7.5 g PA21 (6 tablets of 1.25 g: 2 tablets with each meal of the day). All randomized subjects were considered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PA21
    Investigational medicinal product code
    Other name
    Mixture of polynuclear iron(III)-oxyhydroxide, sucrose and starches; Stabilised polynuclear iron oxyhydroxide
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daily dose of 7.5 g PA21 (6 tablets of 1.25 g: 2 tablets with each meal of the day).

    Arm title
    		 10.0 g PA21
    Arm description
    		 Daily dose of 10.0 g PA21 (8 tablets of 1.25 g: 4 tablets with the largest meal of the day and 2 tablets each with the 2 smaller meals of the day). All randomized subjects were considered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PA21
    Investigational medicinal product code
    Other name
    Mixture of polynuclear iron(III)-oxyhydroxide, sucrose and starches; Stabilised polynuclear iron oxyhydroxide
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daily dose of 10.0 g PA21 (8 tablets of 1.25 g: 4 tablets with the largest meal of the day and 2 tablets each with the 2 smaller meals of the day).

    Arm title
    		 12.5 g PA21
    Arm description
    		 Daily dose of 12.5 g PA21 (10 tablets of 1.25 g: 4 tablets with the largest meal of the day and 3 tablets each with the 2 smaller meals of the day). All randomized subjects were considered.
    Arm type
    		 Experimental

    Investigational medicinal product name
    PA21
    Investigational medicinal product code
    Other name
    Mixture of polynuclear iron(III)-oxyhydroxide, sucrose and starches; Stabilised polynuclear iron oxyhydroxide
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daily dose of 12.5 g PA21 (10 tablets of 1.25 g: 4 tablets with the largest meal of the day and 3 tablets each with the 2 smaller meals of the day).

    Arm title
    		 Sevelamer HCl
    Arm description
    		 Daily dose of 4.8 g sevelamer HCl (6 tablets of 800 mg: divided in 3 doses with meals). All randomized subjects were considered.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sevelamer HCl
    Investigational medicinal product code
    Other name
    Renagel®; Poly(allylamine-co-N,N’-diallyl-1,3-diamino-2- hydroxypropane) hydrochloride
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daily dose of 4.8 g sevelamer HCl (6 tablets of 800 mg: divided in 3 doses with meals).

    Number of subjects in period 1
    		1.25 g PA21 5.0 g PA21 7.5 g PA21 10.0 g PA21 12.5 g PA21 Sevelamer HCl
    Started
    26
    26
    25
    27
    24
    26
    Completed
    18
    17
    20
    15
    15
    18
    Not completed
    8
    9
    5
    12
    9
    8
         Adverse event, serious fatal
    -
    1
    -
    -
    -
    -
         Consent withdrawn by subject
    1
    -
    1
    2
    1
    -
         Adverse event, non-fatal
    -
    -
    -
    1
    1
    2
         Subject protocol noncompliance
    -
    -
    -
    -
    1
    -
         Kidney Transplant
    -
    -
    -
    -
    -
    1
         Prohibited medication
    -
    -
    -
    -
    -
    2
         Predefined criteria within protocol
    7
    7
    3
    9
    6
    3
         Refusal of Treatment
    -
    -
    1
    -
    -
    -
         Protocol deviation
    -
    1
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    1.25 g PA21
    Reporting group description
    		 Daily dose of 1.25 g PA21 (1 tablet taken with the largest meal of the day). All randomized subjects were considered.

    Reporting group title
    5.0 g PA21
    Reporting group description
    		 Daily dose of 5.0 g PA21 (4 tablets of 1.25 g: 2 tablets with the largest meal of the day and 1 tablet each with the 2 smaller meals of the day). All randomized subjects were considered.

    Reporting group title
    7.5 g PA21
    Reporting group description
    		 Daily dose of 7.5 g PA21 (6 tablets of 1.25 g: 2 tablets with each meal of the day). All randomized subjects were considered.

    Reporting group title
    10.0 g PA21
    Reporting group description
    		 Daily dose of 10.0 g PA21 (8 tablets of 1.25 g: 4 tablets with the largest meal of the day and 2 tablets each with the 2 smaller meals of the day). All randomized subjects were considered.

    Reporting group title
    12.5 g PA21
    Reporting group description
    		 Daily dose of 12.5 g PA21 (10 tablets of 1.25 g: 4 tablets with the largest meal of the day and 3 tablets each with the 2 smaller meals of the day). All randomized subjects were considered.

    Reporting group title
    Sevelamer HCl
    Reporting group description
    		 Daily dose of 4.8 g sevelamer HCl (6 tablets of 800 mg: divided in 3 doses with meals). All randomized subjects were considered.

    Reporting group values
    		 1.25 g PA21 5.0 g PA21 7.5 g PA21 10.0 g PA21 12.5 g PA21 Sevelamer HCl Total
    Number of subjects
    		 26 26 25 27 24 26 154
    Age categorical
    All randomised patients were considered.
    Units: Subjects
        Adults (18-64 years)
    		 14 18 14 17 14 16 93
        From 65-84 years
    		 12 7 10 10 10 10 59
        85 years and over
    		 0 1 1 0 0 0 2
    Age continuous
    The safety set was considered: all randomised subjects who received at least 1 dose of study treatment. Subjects were included in the analysis according to the treatment received. N=154.
    Units: years
        arithmetic mean (standard deviation)
    		 60.1 ( 12.29 ) 59.7 ( 13.8 ) 61.9 ( 13.71 ) 60.6 ( 12.74 ) 59.3 ( 12.32 ) 61.1 ( 11 ) -
    Gender categorical
    All randomised patients were considered.
    Units: Subjects
        Female
    		 9 7 9 10 11 11 57
        Male
    		 17 19 16 17 13 15 97

    End points

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    End points reporting groups
    Reporting group title
    1.25 g PA21
    Reporting group description
    		 Daily dose of 1.25 g PA21 (1 tablet taken with the largest meal of the day). All randomized subjects were considered.

    Reporting group title
    5.0 g PA21
    Reporting group description
    		 Daily dose of 5.0 g PA21 (4 tablets of 1.25 g: 2 tablets with the largest meal of the day and 1 tablet each with the 2 smaller meals of the day). All randomized subjects were considered.

    Reporting group title
    7.5 g PA21
    Reporting group description
    		 Daily dose of 7.5 g PA21 (6 tablets of 1.25 g: 2 tablets with each meal of the day). All randomized subjects were considered.

    Reporting group title
    10.0 g PA21
    Reporting group description
    		 Daily dose of 10.0 g PA21 (8 tablets of 1.25 g: 4 tablets with the largest meal of the day and 2 tablets each with the 2 smaller meals of the day). All randomized subjects were considered.

    Reporting group title
    12.5 g PA21
    Reporting group description
    		 Daily dose of 12.5 g PA21 (10 tablets of 1.25 g: 4 tablets with the largest meal of the day and 3 tablets each with the 2 smaller meals of the day). All randomized subjects were considered.

    Reporting group title
    Sevelamer HCl
    Reporting group description
    		 Daily dose of 4.8 g sevelamer HCl (6 tablets of 800 mg: divided in 3 doses with meals). All randomized subjects were considered.

    Primary: Change from baseline in serum phosphorus levels at the end of treatment

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    End point title
    		 Change from baseline in serum phosphorus levels at the end of treatment
    End point description
    For this primary endpoint, data from the full analysis set (FAS) was used. The FAS consisted of all randomised subjects who received at least 1 dose of study treatment and had at least 1 post-baseline efficacy evaluation (while on treatment).
    End point type
    Primary
    End point timeframe
    Baseline and End of Treatment six weeks after.
    End point values
    		 1.25 g PA21 5.0 g PA21 7.5 g PA21 10.0 g PA21 12.5 g PA21 Sevelamer HCl
    Number of subjects analysed
    26
    26
    25
    25
    24
    24
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.042 ( 0.65 )
    -0.348 ( 0.684 )
    -0.404 ( 0.391 )
    -0.644 ( 0.551 )
    -0.547 ( 0.584 )
    -0.341 ( 0.436 )
    Statistical analysis title
    		 Analysis of serum phosphorus -5.0 g
    Statistical analysis description
    Analysis of serum phosphorus (mmol/L): absolute change from baseline at end of treatment. The absolute change from baseline in serum phosphorus levels at the end of treatment (i.e., value at Week 7, D1, or last observation carried forward (LOCF) for missing values (where a subject was withdrawn prior to Week 7)) was analysed within each of the 5 PA21 dose groups using a single sample paired t-test.
    Comparison groups
    5.0 g PA21 v 1.25 g PA21
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.078
    Method
    		 t-test, 2-sided
    Parameter type
    		 least squares mean
    Point estimate
    -0.341
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.07
         upper limit
    		 0.78
    Variability estimate
    Standard deviation
    Dispersion value
    0.684
    Notes
    [1] - To preserve the overall alpha, a hierarchical testing procedure was applied, testing from the highest PA21 dose (12.5 g/day) to the lowest dose (1.25 g/day) until all doses are tested or the first p-value above 0.05 is observed.
    Statistical analysis title
    		 Analysis of serum phosphorus - 7.5 g
    Statistical analysis description
    Analysis of serum phosphorus (mmol/L): absolute change from baseline at end of treatment. The absolute change from baseline in serum phosphorus levels at the end of treatment (i.e., value at Week 7, D1, or last observation carried forward (LOCF) for missing values (where a subject was withdrawn prior to Week 7)) was analysed within each of the 5 PA21 dose groups using a single sample paired t-test.
    Comparison groups
    7.5 g PA21 v 1.25 g PA21
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.063
    Method
    		 t-test, 2-sided
    Parameter type
    		 least squares mean
    Point estimate
    -0.357
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.26
         upper limit
    		 0.28
    Variability estimate
    Standard deviation
    Dispersion value
    0.391
    Notes
    [2] - To preserve the overall alpha, a hierarchical testing procedure was applied, testing from the highest PA21 dose (12.5 g/day) to the lowest dose (1.25 g/day) until all doses are tested or the first p-value above 0.05 is observed.
    Statistical analysis title
    		 Analysis of serum phosphorus - 10.0 g
    Statistical analysis description
    Analysis of serum phosphorus (mmol/L): absolute change from baseline at end of treatment. The absolute change from baseline in serum phosphorus levels at the end of treatment (i.e., value at Week 7, D1, or last observation carried forward (LOCF) for missing values (where a subject was withdrawn prior to Week 7)) was analysed within each of the 5 PA21 dose groups using a single sample paired t-test.
    Comparison groups
    10.0 g PA21 v 1.25 g PA21
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 least squares mean
    Point estimate
    -0.612
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.85
         upper limit
    		 0.68
    Variability estimate
    Standard deviation
    Dispersion value
    0.551
    Notes
    [3] - To preserve the overall alpha, a hierarchical testing procedure was applied, testing from the highest PA21 dose (12.5 g/day) to the lowest dose (1.25 g/day) until all doses are tested or the first p-value above 0.05 is observed.
    Statistical analysis title
    		 Analysis of serum phosphorus - 12.5 g
    Statistical analysis description
    Analysis of serum phosphorus (mmol/L): absolute change from baseline at end of treatment. The absolute change from baseline in serum phosphorus levels at the end of treatment (i.e., value at Week 7, D1, or last observation carried forward (LOCF) for missing values (where a subject was withdrawn prior to Week 7)) was analysed within each of the 5 PA21 dose groups using a single sample paired t-test.
    Comparison groups
    12.5 g PA21 v 1.25 g PA21
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 least squares mean
    Point estimate
    -0.564
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.85
         upper limit
    		 0.56
    Variability estimate
    Standard deviation
    Dispersion value
    0.584
    Notes
    [4] - To preserve the overall alpha, a hierarchical testing procedure was applied, testing from the highest PA21 dose (12.5 g/day) to the lowest dose (1.25 g/day) until all doses are tested or the first p-value above 0.05 is observed.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening to the end of trial.
    Adverse event reporting additional description
    The safety set was considered.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    1.25 g PA21
    Reporting group description
    		 Daily dose of 1.25 g PA21 (1 tablet)

    Reporting group title
    5.0 g PA21
    Reporting group description
    		 Daily dose of 5.0 g PA21 (4 tablets)

    Reporting group title
    7.5 g PA21
    Reporting group description
    		 Daily dose of 7.5 g PA21 (6 tablets)

    Reporting group title
    10.0 g PA21
    Reporting group description
    		 Daily dose of 10.0 g PA21 (8 tablets)

    Reporting group title
    12.5 g PA21
    Reporting group description
    		 Daily dose of 12.5 g PA21 (10 tablets)

    Reporting group title
    Sevelamer HCl
    Reporting group description
    		 Daily dose of 4.8 g Sevelamer hydrochloride (6 tablets)

    Serious adverse events
    		 1.25 g PA21 5.0 g PA21 7.5 g PA21 10.0 g PA21 12.5 g PA21 Sevelamer HCl
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 26 (7.69%)
    1 / 25 (4.00%)
    1 / 27 (3.70%)
    2 / 24 (8.33%)
    2 / 26 (7.69%)
         number of deaths (all causes)
    0
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Rib fracture
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous graft site haematoma
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 25 (4.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Eye disorders
    Diabetic retinopathy
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastrointestinal disorders
    Diverticular perforation
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous graft site abscess
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Peritoneal infection
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    1 / 24 (4.17%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 1.25 g PA21 5.0 g PA21 7.5 g PA21 10.0 g PA21 12.5 g PA21 Sevelamer HCl
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 26 (50.00%)
    15 / 26 (57.69%)
    13 / 25 (52.00%)
    18 / 27 (66.67%)
    17 / 24 (70.83%)
    14 / 26 (53.85%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    2 / 25 (8.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    2
    0
    3
    1
    Hypotension
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    1
    0
    0
    0
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    3 / 25 (12.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    Gastrointestinal disorders
    Faeces discoloured
         subjects affected / exposed
    2 / 26 (7.69%)
    3 / 26 (11.54%)
    3 / 25 (12.00%)
    4 / 27 (14.81%)
    3 / 24 (12.50%)
    0 / 26 (0.00%)
         occurrences all number
    2
    3
    3
    4
    3
    0
    Diarrhoea
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 26 (7.69%)
    2 / 25 (8.00%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    3 / 26 (11.54%)
         occurrences all number
    1
    8
    5
    1
    1
    3
    Constipation
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    1 / 25 (4.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    5
    1
    2
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 25 (0.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    6
    0
    1
    0
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 26 (3.85%)
    2 / 25 (8.00%)
    1 / 27 (3.70%)
    3 / 24 (12.50%)
    0 / 26 (0.00%)
         occurrences all number
    5
    1
    2
    1
    3
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    0 / 25 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    2 / 26 (7.69%)
    4 / 26 (15.38%)
    2 / 25 (8.00%)
    8 / 27 (29.63%)
    7 / 24 (29.17%)
    3 / 26 (11.54%)
         occurrences all number
    2
    6
    2
    8
    8
    3
    Hyperphosphataemia
         subjects affected / exposed
    5 / 26 (19.23%)
    3 / 26 (11.54%)
    1 / 25 (4.00%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    6
    3
    1
    1
    0
    2
    Hypercalcaemia
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 26 (7.69%)
    1 / 25 (4.00%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    1
    1
    1
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Nov 2008
    Amendment 1 was implemented before the first patient was randomised and included the following changes pertaining to conduct and interpretation of the study: • Clarification of the AE reporting procedures (eliciting and recording of AEs) • Addition of 2 bone markers (carboxyterminal cross-linking telopeptide of bone collagen (beta-CTX) and tartrate-resistant acid phosphatase 5b) • Clarification that the study treatment must not be taken on an empty stomach • The assessment of calcium and iPTH was made consistent with the risk-benefit analysis (measurement of calcium added to Visits Week -2, D1, and Week -1, D2, and D3, and clarification that the iPTH exclusion criterion applied only at screening) • Exclusion criteria 4, 10 and 13 were clarified to confirm that they referred to screening
    17 Mar 2009
    Amendment 2 included the following changes pertaining to conduct and interpretation of the study: • Text modified in risk-benefit assessment section on AEs seen with sevelamer (HCl) • Clarification that patients’ serum phosphate level assessed twice during Week -1 and patients could be randomised based on their serum phosphate level at either Week -1, D2 or Week -1, D3 • Inclusion criterion 9 modified to allow for small dose adjustments of erythropoietin therapy before and during the study • Exclusion criterion 10 modified to include a history of other iron storage disorders and removal of reference to ferritin level (>800mcg/L at screening) • Exclusion criterion 12 modified (split into 2 separate criteria) to allow for Investigator’s judgment (criterion 12) and to add the time window (5 years) for major gastrointestinal surgery (criterion 13) • Exclusion criterion 13 clarified (now exclusion criterion 14) to exclude patients with active hepatitis B or C infection • Exclusion criterion 24 modified (now exclusion criterion 25) to exclude patients taking medication specifically for moderate to severe arrhythmic and seizure disorders • Planned number of EU study centres and countries reduced from 65 to 60 and 10 to 8, respectively. Planned number of US centres increased from 10 to 15 • Permitted and prohibited medications was clarified that IV iron preparations were permitted until end of screening, and anti-arrhythmic and anti-seizure medications were not permitted during the study if prescribed for moderate to severe arrhythmic and seizure disorders • General considerations section of statistical methods was clarified that no adjustments for multiplicity unless specified otherwise in subsequent sections • Clarified that comparisons between PA21 and sevelamer (HCl) were not based on statistical tests • Text modified for determination of sample size • Protocol updated to reference Declaration of Helsinki, dated 2008 instead of 1996
    10 Jun 2009
    Amendment 3 included the following changes pertaining to conduct and interpretation of the study: • The sample size was reduced from 252 randomised patients to up to 132 randomised patients to obtain about 114 evaluable patients (i.e., who have at least 1 post-baseline efficacy measurement)

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/23124782
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