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    Clinical Trial Results:
    Study to investigate the therapeutic equivalence of OsvaRen® tablets and OsvaRen® granules

    Summary
    EudraCT number
    		 2012-004178-24
    Trial protocol
    		 DE  
    Global end of trial date
    30 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions
    Summary report(s)
    		 RP-OSV_02D_Final-Study-Report-OsvarenNEW_Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    RP-OSV-02-D
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02027662
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fresenius Medical Care Deutschland GmbH
    Sponsor organisation address
    Else-Kroener-Straße 1 , Bad Homburg, Germany, 61352
    Public contact
    Clinical Research, Fresenius Medical Care Deutschland GmbH, 49 6172 609 5248, Manuela.Stauss-Grabo@fmc-ag.com
    Scientific contact
    Clinical Research, Fresenius Medical Care Deutschland GmbH, 49 6172 609 5248, Manuela.Stauss-Grabo@fmc-ag.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
    18 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate the therapeutic equivalence of OsvaRen® granules and tablets. Adult patients on chronic haemodialysis or haemodiafiltration treatment with a diagnosis of hyperphosphataemia were randomised to receive either the study drug (OsvaRen® granules) or the control drug (OsvaRen® tablets) for a period of 4 weeks following a three-week run-in phase. Thereafter, patients on study drug received the control drug and vice versa. The primary parameter to test this was the serum phosphate level at the end of each treatment period.
    Protection of trial subjects
    Every reasonable precaution has been taken to protect the health and safety of subjects.
    Background therapy
    		 Extracorporeal renal replacement therapy for end stage renal failure
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Jan 2014
    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
    Germany: 61
    Worldwide total number of subjects
    61
    EEA total number of subjects
    61
    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)
    19
    From 65 to 84 years
    42
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Selection of eligible patients: Adults on three-times weekly chronic haemodialysis or haemodiafiltration treatment with a diagnosis of hyperphosphataemiawere included.

    Pre-assignment
    Screening details
    		 Eligible patients were adults on chronic haemodialysis or haemodiafiltration treatment with a diagnosis of hyperphosphataemia inluded according the defined inclusion criteria.

    Pre-assignment period milestones
    Number of subjects started
    		 61
    Number of subjects completed
    		 61

    Period 1
    Period 1 title
    Run-in-phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Run-in-phase: Baseline Population
    Arm description
    		 The main purpose of the run-in phase was to ensure that the patient’s serum phosphate level was sufficiently stable under the anti-hyperphosphataemic treatment with OsvaRen® tablets in order to commence the actual study (constant lower than or equal to 1.00 mmol/L).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    OsvaRen® tablets
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    12 DF dosage form per day

    Number of subjects in period 1
    		Run-in-phase: Baseline Population
    Started
    61
    Completed
    58
    Not completed
    3
         Phosphat levels too variable
    2
         Consent withdrawn by subject
    1
    Period 2
    Period 2 title
    Treatment 1
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OsvaRen® tablets
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    OsvaRen® tablets
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    12 DF dosage form per day

    Arm title
    		 OsvaRen® granules
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    OsvaRen® granules
    Investigational medicinal product code
    PR2
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    12 DF dosage form per day

    Number of subjects in period 2
    		OsvaRen® tablets OsvaRen® granules
    Started
    29
    29
    Completed
    29
    26
    Not completed
    0
    3
         Adverse event, non-fatal
    -
    2
         Taste intolerable
    -
    1
    Period 3
    Period 3 title
    Treatment 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OsvaRen® granules
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    OsvaRen® granules
    Investigational medicinal product code
    PR2
    Other name
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    12 DF dosage form per day

    Arm title
    		 OsvaRen® tablets
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    OsvaRen® tablets
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    12 DF dosage form per day

    Number of subjects in period 3
    		OsvaRen® granules OsvaRen® tablets
    Started
    29
    26
    Completed
    27
    24
    Not completed
    2
    2
         Adverse event, serious fatal
    -
    1
         Adverse event, non-fatal
    1
    1
         Taste intolerable
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Run-in-phase
    Reporting group description
    		 The main purpose of the 3 week run-in phase was to ensure that the patient’s serum phosphate levels are constant lower than or equal to 1.00 mmol/L.

    Reporting group values
    		 Run-in-phase Total
    Number of subjects
    		 61 61
    Age categorical
    Units: Subjects
        Adults (18-80 years)
    		 61 61
    Age continuous
    Units: years
        median (full range (min-max))
    		 69.5 (33 to 80) -
    Gender categorical
    Units: Subjects
        Female
    		 43 43
        Male
    		 17 17
        missing
    		 1 1
    Ethnic group
    Units: Subjects
        Caucasian
    		 60 60
        missing
    		 1 1
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 173.0 ( 9.6 ) -
    Pre-Dialysis Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 87.4 ( 20.1 ) -
    Post-Dialysis Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 85.5 ( 19.9 ) -
    Body mass index BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 28.1 ( 6.8 ) -
    Subject analysis sets

    Subject analysis set title
    Safety Population (SP)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    SP: includes all subjects who were included in the study by giving informed consent

    Subject analysis set title
    Treatment (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT: includes all subjects who were randomized and for whom valid data is available for at least one post-baseline assessment of serum phosphorous.

    Subject analysis set title
    Per Protocol (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PP: includes all subjects who entered the study in accordance with both the inclusion / exclusion criteria without major protocol deviations, who were randomized and who finished the study in accordance with the study protocol

    Subject analysis sets values
    		 Safety Population (SP) Treatment (ITT) Per Protocol (PP)
    Number of subjects
    61
    55
    26
    Age categorical
    Units: Subjects
        Adults (18-80 years)
    61
    55
    26
    Age continuous
    Units: years
        median (full range (min-max))
    69.5 (33 to 80)
    70.0 (33 to 80)
    72 (33 to 79)
    Gender categorical
    Units: Subjects
        Female
    17
    13
    3
        Male
    43
    42
    23
        missing
    1
    0
    0
    Ethnic group
    Units: Subjects
        Caucasian
    60
    55
    26
        missing
    1
    0
    0
    Height
    Units: cm
        arithmetic mean (standard deviation)
    173.0 ( 9.6 )
    173.8 ( 9.0 )
    173.6 ( 8.7 )
    Pre-Dialysis Weight
    Units: kg
        arithmetic mean (standard deviation)
    87.4 ( 20.1 )
    88.1 ( 19.5 )
    86.5 ( 16.8 )
    Post-Dialysis Weight
    Units: kg
        arithmetic mean (standard deviation)
    85.5 ( 19.9 )
    86.1 ( 19.2 )
    84.3 ( 16.5 )
    Body mass index BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    28.7 ( 6.8 )
    28.6 ( 6.5 )
    28.3 ( 7.0 )

    End points

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    End points reporting groups
    Reporting group title
    Run-in-phase: Baseline Population
    Reporting group description
    		 The main purpose of the run-in phase was to ensure that the patient’s serum phosphate level was sufficiently stable under the anti-hyperphosphataemic treatment with OsvaRen® tablets in order to commence the actual study (constant lower than or equal to 1.00 mmol/L).
    Reporting group title
    OsvaRen® tablets
    Reporting group description
    		 -

    Reporting group title
    OsvaRen® granules
    Reporting group description
    		 -
    Reporting group title
    OsvaRen® granules
    Reporting group description
    		 -

    Reporting group title
    OsvaRen® tablets
    Reporting group description
    		 -

    Subject analysis set title
    Safety Population (SP)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    SP: includes all subjects who were included in the study by giving informed consent

    Subject analysis set title
    Treatment (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT: includes all subjects who were randomized and for whom valid data is available for at least one post-baseline assessment of serum phosphorous.

    Subject analysis set title
    Per Protocol (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PP: includes all subjects who entered the study in accordance with both the inclusion / exclusion criteria without major protocol deviations, who were randomized and who finished the study in accordance with the study protocol

    Primary: Serum phosphate ratio tablets/granules after 4 weeks treatment

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    End point title
    		 Serum phosphate ratio tablets/granules after 4 weeks treatment
    End point description
    The aim of primary analysis for this study is to show equivalence in serum phosphate concentrations after 4 weeks of treatment with OsvaRen® Tablets and OsvaRen® Granulate respectively.
    End point type
    Primary
    End point timeframe
    Phosphate ratio tablets/granules after 4 weeks treatment phase
    End point values
    		 Treatment (ITT) Per Protocol (PP)
    Number of subjects analysed
    55
    26
    Units: Phophate ratio
        log mean (confidence interval 95%)
    0.97 (0.91 to 1.05)
    0.94 (0.86 to 1.02)
    Statistical analysis title
    		 Primary endpoint
    Comparison groups
    Per Protocol (PP) v Treatment (ITT)
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.25

    Secondary: Serum phosphate ratio tablets/granules after 2 weeks of each treatment phase

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    End point title
    		 Serum phosphate ratio tablets/granules after 2 weeks of each treatment phase
    End point description
    Absolute serum phosphate ratio tablets/granules and 95% CI after 2 weeks of each treatment phase
    End point type
    Secondary
    End point timeframe
    Phosphate ratio tablets/granules after 2 weeks of each treatment phase
    End point values
    		 Treatment (ITT) Per Protocol (PP)
    Number of subjects analysed
    55
    26
    Units: Phosphate ratio
        log mean (confidence interval 95%)
    0.96 (0.89 to 1.02)
    0.98 (0.88 to 1.10)
    Statistical analysis title
    		 Secondary endpoint
    Comparison groups
    Treatment (ITT) v Per Protocol (PP)
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.25

    Secondary: Number of patients with serum phosphate levels <1.76 mmol/l (ITT)

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    End point title
    		 Number of patients with serum phosphate levels <1.76 mmol/l (ITT)
    End point description
    Number of patients with a serum phosphate level ≤1.76 mmol/L after 4 weeks treatment (subject analysis set: ITT)
    End point type
    Secondary
    End point timeframe
    Comparing quoted end point after 4 weeks of treatment with test drug (OsvaRen granules) and comparator drug (OsvaRen tablets)
    End point values
    		 OsvaRen® tablets OsvaRen® granules OsvaRen® granules OsvaRen® tablets
    Number of subjects analysed
    29
    27
    26
    24
    Units: numbers
    19
    15
    18
    20
    Statistical analysis title
    		 Secondary endpoint
    Statistical analysis description
    Number of patients with serum phosphate levels <1.76 mmol/l (ITT). For secondary analysis of the proportion of patients with serum phosphate < 1.76 mmol/l Prescott’s test will be employed.
    Comparison groups
    OsvaRen® tablets v OsvaRen® granules v OsvaRen® granules v OsvaRen® tablets
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.05
    Method
    		 Prescott’s test
    Parameter type
    		 Proportion
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.25

    Secondary: Number of patients with serum phosphate levels <1.76 mmol/l (PP)

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    End point title
    		 Number of patients with serum phosphate levels <1.76 mmol/l (PP)
    End point description
    Number of patients with a serum phosphate level ≤1.76 mmol/L after 4 weeks treatment (subject analysis set: PP)
    End point type
    Secondary
    End point timeframe
    Comparing quoted end point after 4 weeks of treatment with test drug (OsvaRen granules) and comparator drug (OsvaRen tablets)
    End point values
    		 OsvaRen® tablets OsvaRen® granules OsvaRen® granules OsvaRen® tablets
    Number of subjects analysed
    12
    12
    14
    14
    Units: numbers
    9
    7
    10
    11
    Statistical analysis title
    		 Secondary endpoint
    Statistical analysis description
    Number of patients with serum phosphate levels <1.76 mmol/l (PP). For secondary analysis of the proportion of patients with serum phosphate < 1.76 mmol/l Prescott’s test will be employed.
    Comparison groups
    OsvaRen® tablets v OsvaRen® granules v OsvaRen® granules v OsvaRen® tablets
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.05
    Method
    		 Prescott’s test
    Parameter type
    		 Proportion
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.25

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The documentation of AEs started after the patient signed the informed consent and continued until end of study.
    Adverse event reporting additional description
    All AEs occurring during the study were documented by the investigator on the AE page of the CRF.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Safety Population
    Reporting group description
    		 All recruited patients were exposed to the study drug and were included in the safety population (N=61).

    Serious adverse events
    		 Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 61 (19.67%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Investigations
    Colonoscopy
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Angiogram
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Shunt occlusion
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Head trauma with contusion
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Sudden cardiac death
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 61 (85.25%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Neoplasm skin
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Vascular disorders
    Bleeding varicose vein
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Haematoma
         subjects affected / exposed
    3 / 61 (4.92%)
         occurrences all number
    3
    Hypertension
         subjects affected / exposed
    3 / 61 (4.92%)
         occurrences all number
    5
    Hypotension
         subjects affected / exposed
    8 / 61 (13.11%)
         occurrences all number
    18
    Surgical and medical procedures
    Fracture reduction
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    General disorders and administration site conditions
    Contusion
    Additional description: SOCS: Gastrointestinal disorders; Injury, poisoning and procedural complications
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Asthenia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Chest pain
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Chills
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    2
    Device connection issue
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Impaired healing
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    2
    Injection site bruising
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Instillation site pain
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Oedema
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Thrombosis in device
         subjects affected / exposed
    3 / 61 (4.92%)
         occurrences all number
    3
    Ulcer
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Vessel puncture site haematoma
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    2
    Application site haematoma
    Additional description: Abdominal pain upper Diarrhoea
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    6 / 61 (9.84%)
         occurrences all number
    12
    Cough
         subjects affected / exposed
    4 / 61 (6.56%)
         occurrences all number
    5
    Dysphonia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    2
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Throat irritation
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Investigations
    Blood pressure decreased
         subjects affected / exposed
    5 / 61 (8.20%)
         occurrences all number
    6
    Blood pressure increased
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    2
    Body temperature increased
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    C-reactive protein increased
         subjects affected / exposed
    3 / 61 (4.92%)
         occurrences all number
    3
    Weight increased
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    3
    Injury, poisoning and procedural complications
    Arteriovenous fistula site complication
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Fall
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    2
    Head injury
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Muscle strain
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Post procedural haematoma
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Post procedural haemorrhage
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    2
    Procedural hypertension
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    6
    Shunt blood flow excessive
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Shunt stenosis
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    2
    Skin abrasion
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Venous injury
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Wound secretion
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    2
    Headache
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    2
    Hypotonia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Phantom pain
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    6 / 61 (9.84%)
         occurrences all number
    6
    Gastritis
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    2
    Gastritis erosive
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Large intestine polyp
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    8 / 61 (13.11%)
         occurrences all number
    10
    Vomiting
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Dermatitis contact
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Erythema
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    4 / 61 (6.56%)
         occurrences all number
    4
    Skin ulcer
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Haematuria
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    2
    Back pain
         subjects affected / exposed
    4 / 61 (6.56%)
         occurrences all number
    4
    Muscle spasms
         subjects affected / exposed
    3 / 61 (4.92%)
         occurrences all number
    5
    Musculoskeletal pain
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Pathological fracture
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Soft tissue mass
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    3
    Diabetic gangrene
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Infected skin ulcer
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Injection site abscess
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    4 / 61 (6.56%)
         occurrences all number
    4
    Postoperative wound infection
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Pulpitis dental
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Renal cyst infection
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Hypercalcaemia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Hyperkalaemia
         subjects affected / exposed
    2 / 61 (3.28%)
         occurrences all number
    2
    Hypocalcaemia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1
    Malnutrition
         subjects affected / exposed
    1 / 61 (1.64%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Aug 2013
    Modifications to inclusion criteria
    20 Jun 2014
    Extension of the clinical phase until Dec 26, 2014
    09 Oct 2014
    Extension of the clinical phase until April 30, 2015

    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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