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    Clinical Trial Results:
    A multicenter, randomized, double-blind, multiple dose, crossover study to evaluate the safety and equivalence of serum phosphate control of a new sevelamer carbonate tablet formulation in comparison with Renvela® in chronic kidney disease patients on hemodialysis

    Summary
    EudraCT number
    		 2011-006320-20
    Trial protocol
    		 BG  
    Global end of trial date
    03 Jan 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Jun 2016
    First version publication date
    10 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CT.SVL.PD.10.001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Synthon B.V.
    Sponsor organisation address
    Microweg 22, Nijmegen , Netherlands,
    Public contact
    clinical pharmacology , Synthon BV, +31 243727700, clinicalpharmacology@synthon.com
    Scientific contact
    clinical pharmacology , Synthon BV, +31 243727700, clinicalpharmacology@synthon.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
    04 Feb 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jan 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jan 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of Synthon sevelamer carbonate (SVL) compared to Renvela® (Genzyme) tablets in patients with CKD on hemodialysis based on the evaluation of the incidence of adverse events and serious adverse events as well as compliance.
    Protection of trial subjects
    The following parameters were defined as safety parameters in the trial: - general medical examination - vital signs (blood pressure, heart rate, body temperature) - 12 lead ECG - routine clinical laboratory tests - HIV and serum pregnancy test - adverse events monitoring
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Apr 2012
    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
    Bulgaria: 93
    Worldwide total number of subjects
    93
    EEA total number of subjects
    93
    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)
    81
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Planned for screening: 150, Screened: 124, Randomized: 93, Evaluated: 90

    Pre-assignment
    Screening details
    		 Planned for screening: 150, Screened: 124, Randomized: 93, Evaluated: 90

    Period 1
    Period 1 title
    Period 1 - Run-in
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    During the run-in period, the patient and the investigator were not blinded to the medication. All the patients received the reference product only in the period. This was to get familiar with the large size of the capsules. Besides this, this period was used to get the patients on a stable Sevelemer dosis.

    Arms
    Arm title
    		 Reference
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Renvela 800 mg film-coated tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received 1 to 5 800 mg tablets three times daily. The tablets had to be taken with meals and swallowed whole. All tablets were overencapsulated.

    Number of subjects in period 1
    		Reference
    Started
    93
    Completed
    93
    Period 2
    Period 2 title
    Period 2- Double blind treatment phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Test
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sevelamer carbonate 800 mg film-coated tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received 1 to 5 800 mg tablets three times daily. The tablets had to be taken with meals and swallowed whole. All tablets were overencapsulated.

    Arm title
    		 Reference
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Renvela 800 mg film-coated tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received 1 to 5 800 mg tablets three times daily. The tablets had to be taken with meals and swallowed whole. All tablets were overencapsulated.

    Number of subjects in period 2
    		Test Reference
    Started
    46
    47
    Completed
    45
    46
    Not completed
    1
    1
         Adverse event, non-fatal
    1
    1
    Period 3
    Period 3 title
    Period 3- Double blind treatment phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Test
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sevelamer carbonate 800 mg film-coated tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received 1 to 5 800 mg tablets three times daily. The tablets had to be taken with meals and swallowed whole. All tablets were overencapsulated.

    Arm title
    		 Reference
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Renvela 800 mg film-coated tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received 1 to 5 800 mg tablets three times daily. The tablets had to be taken with meals and swallowed whole. All tablets were overencapsulated.

    Number of subjects in period 3
    		Test Reference
    Started
    46
    45
    Completed
    46
    45

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Reference
    Reporting group description
    		 -

    Reporting group values
    		 Reference Total
    Number of subjects
    		 93 93
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 81 81
        From 65-84 years
    		 12 12
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 29 29
        Male
    		 64 64

    End points

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    End points reporting groups
    Reporting group title
    Reference
    Reporting group description
    		 -
    Reporting group title
    Test
    Reporting group description
    		 -

    Reporting group title
    Reference
    Reporting group description
    		 -
    Reporting group title
    Test
    Reporting group description
    		 -

    Reporting group title
    Reference
    Reporting group description
    		 -

    Primary: Evaluation safety and tolerability of sevelamer carbonate

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    End point title
    		 Evaluation safety and tolerability of sevelamer carbonate
    End point description
    End point type
    Primary
    End point timeframe
    Entire study, so period 1 run-in phase and period 2 and 3 of the double blind treatment period
    End point values
    		 Reference Test Reference Test Reference
    Number of subjects analysed
    93
    46
    47
    46
    45
    Units: incidence of AEs and SAEs
    93
    45
    46
    46
    45
    Statistical analysis title
    		 Primary endpoint Safety
    Statistical analysis description
    Summary statistics on incidence of treatment emergent adverse events and percentage of subjects who withdrew due to adverse events. Values entered at "Parameter estimate" should not be taken in consideration. Only summary statistics were used for primary endpoint as described above.
    Comparison groups
    Test v Reference v Test v Reference
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Incidence of AEs
    Point estimate
    1.1
    Confidence interval
         level
    		 0%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 1.1
    Variability estimate
    Standard error of the mean
    Notes
    [1] - A total number of 26 AEs occurred during the double-blind phase: 12 AEs were reported under treatment with the test product and 14 AEs under treatment with ref. 5 AEs in 4 patients were reported as serious, all under treatment with the ref product. No AE was judged as related to study medication. One SAE (transplant) lead to a permanent withdraw of the study drug. In total, 2 patients were withdrawn due to an AE: The %of subjects withdrawn due to AEs is 1.1% for the test and 1.1% for Ref.

    Secondary: Bioequivalence Test and Reference

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    End point title
    		 Bioequivalence Test and Reference
    End point description
    End point type
    Secondary
    End point timeframe
    During period 2 and 3 (Double-blind treatment periods)
    End point values
    		 Reference Test Reference Test Reference
    Number of subjects analysed
    93
    46
    47
    46
    45
    Units: Mean serum concentration
    93
    45
    47
    46
    45
    Statistical analysis title
    		 T/R ratio for mean serum phosphorus concentration
    Comparison groups
    Test v Reference v Test v Reference
    Number of subjects included in analysis
    184
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    Method
    Parameter type
    		 T/R ratio serum concentration
    Point estimate
    98.36
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 95.22
         upper limit
    		 101.61
    Variability estimate
    Standard error of the mean
    Notes
    [2] - The number of subjects specified for this analysis is incorrect. It should state 90 instead of 184. Since this is a 2-way crossover bioequivalence study all 93 subjects have received test and reference and all the data was taken into account for the statistical analysis. 3 subjects were excluded from analysis. 93-3=90

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the entire study period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    unknown
    Reporting groups
    Reporting group title
    Test
    Reporting group description
    		 -

    Reporting group title
    Reference
    Reporting group description
    		 -

    Serious adverse events
    		 Test Reference
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 93 (0.00%)
    4 / 93 (4.30%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Blood and lymphatic system disorders
    neutrophilia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    coronary artery disease
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Immune system disorders
    Transplant
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure chronic
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 93 (1.08%)
         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
    arthropathy
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 93 (1.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Test Reference
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 93 (8.60%)
    12 / 93 (12.90%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 93 (1.08%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Neutrophilia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 93 (1.08%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 93 (1.08%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    constipation
         subjects affected / exposed
    0 / 93 (0.00%)
    2 / 93 (2.15%)
         occurrences all number
    0
    3
    nausea
         subjects affected / exposed
    0 / 93 (0.00%)
    2 / 93 (2.15%)
         occurrences all number
    0
    3
    vomitting
         subjects affected / exposed
    1 / 93 (1.08%)
    2 / 93 (2.15%)
         occurrences all number
    2
    3
    abdominal discomfort
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 93 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 93 (1.08%)
    1 / 93 (1.08%)
         occurrences all number
    1
    1
    Endocrine disorders
    Hyperparathyroidism secondary
         subjects affected / exposed
    1 / 93 (1.08%)
    0 / 93 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 93 (1.08%)
         occurrences all number
    0
    1
    Infections and infestations
    cytomegalovirus infection
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 93 (1.08%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 93 (0.00%)
    2 / 93 (2.15%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    hypoproteinamia
         subjects affected / exposed
    0 / 93 (0.00%)
    1 / 93 (1.08%)
         occurrences all number
    0
    1
    Decreased appetite
         subjects affected / exposed
    3 / 93 (3.23%)
    0 / 93 (0.00%)
         occurrences all number
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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