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    Clinical Trial Results:
    A Double-blind, Randomised, Comparative Pharmacokinetic, Pharmacodynamic, Efficacy and Safety Evaluation of RGB-03 and MabThera® Combined with Methotrexate in Rheumatoid Arthritis Patients

    Summary
    EudraCT number
    		 2014-003255-54
    Trial protocol
    		 CZ  
    Global end of trial date
    24 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jul 2020
    First version publication date
    25 Jul 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RGB-03-104
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gedeon Richter Plc
    Sponsor organisation address
    Gyömrői út 19-21, Budapest, Hungary, H-1103
    Public contact
    Gedeon Richter Plc, Gedeon Richter Plc, RA.ctaRichter@richter.hu
    Scientific contact
    Gedeon Richter Plc, Gedeon Richter Plc, jelineki@richter.hu
    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 May 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the PK of RGB-03 and its reference product (MabThera) in a comparative manner in RA patients to establish biosimilarity.
    Protection of trial subjects
    The investigators and all designees involved in the study conducted the study in adherence to the ethical principles based on the Declaration of Helsinki, International Council for Harmonisation (ICH) Good Clinical Practice guidelines, and the applicable national and local laws and regulatory requirements. All safety parameters were being assessed during the whole study until last patient last visit. Safety was assessed by adverse events (AEs), serum laboratory tests, vital signs, physical examination, 12-lead electrocardiogram, body weight, body mass index and immunogenicity.
    Background therapy
    		 Methotrexate and folic acid
    Evidence for comparator
    		 RGB-03 is being developed as a biosimilar rituximab to MabThera. The study population reflects the approved indication for MabThera and the posology is based on the SmPC of MabThera.
    Actual start date of recruitment
    18 Mar 2015
    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
    Poland: 47
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Israel: 5
    Country: Number of subjects enrolled
    Ukraine: 45
    Worldwide total number of subjects
    129
    EEA total number of subjects
    79
    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)
    110
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 A total of 60 study centres were initiated in Europe and Middle East. There were a total of 129 participants randomly assigned in this study: 66 in the RGB-03 arm and 63 in the MabThera arm.

    Pre-assignment
    Screening details
    		 During the up to 4-week Screening Period assessments were performed to evaluate patient’s eligibility, and informed consent was obtained before any study-related assessment was performed. The patient’s eligibility was evaluated based on the Screening results and randomisation occurred before the Baseline Visit.

    Period 1
    Period 1 title
    Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    The patient, the Investigator, the study coordinator, the Sponsor, and the entire study processing team except the dedicated unblinded team member remained blinded to treatment assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RGB-03
    Arm description
    		 RGB-03 (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).
    Arm type
    		 Experimental

    Investigational medicinal product name
    RGB-03
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose of RGB-03 was 1000 mg for i.v. administration.

    Arm title
    		 MabThera
    Arm description
    		 MabThera (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    MabThera
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose of MabThera was 1000 mg for i.v. administration.

    Number of subjects in period 1 [1]
    		RGB-03 MabThera
    Started
    64
    58
    Completed
    62
    55
    Not completed
    2
    3
         Physician decision
    1
    -
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    1
    1
         Pregnancy
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Not applicable.
    Period 2
    Period 2 title
    1st Retreatment Course
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Subject, Assessor
    Blinding implementation details
    The patient, the Investigator, the study coordinator, the Sponsor, and the entire study processing team except the dedicated unblinded team member remained blinded to treatment assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RGB-03
    Arm description
    		 RGB-03 (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).
    Arm type
    		 Experimental

    Investigational medicinal product name
    RGB-03
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose of RGB-03 was 1000 mg for i.v. administration.

    Arm title
    		 MabThera
    Arm description
    		 MabThera (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    MabThera
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose of MabThera was 1000 mg for i.v. administration.

    Number of subjects in period 2
    		RGB-03 MabThera
    Started
    62
    55
    Completed
    58
    53
    Not completed
    4
    2
         Consent withdrawn by subject
    3
    1
         Physician decision
    1
    -
         Adverse event, non-fatal
    -
    1
    Period 3
    Period 3 title
    Open-label (2nd and 3rd Retreatment Cour
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    From the 2nd Retreatment Course all patients received MabThera were switched to receive RGB-03 treatment, from this time point the study was open-label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 RGB-03
    Arm description
    		 RGB-03 (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).
    Arm type
    		 Experimental

    Investigational medicinal product name
    RGB-03
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose of RGB-03 was 1000 mg for i.v. administration.

    Arm title
    		 MabThera
    Arm description
    		 Patients who were assigned to receive MabThera for the Treatment period and 1st Retreatment Course were switched from MabThera group and received RGB-03 for the 2nd and 3rd Retreatment Courses. RGB-03 (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).
    Arm type
    		 Experimental

    Investigational medicinal product name
    RGB-03
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose of RGB-03 was 1000 mg for i.v. administration.

    Number of subjects in period 3 [2]
    		RGB-03 MabThera
    Started
    58
    52
    Completed
    57
    47
    Not completed
    1
    5
         Physician decision
    1
    2
         Consent withdrawn by subject
    -
    2
         INCOMPLIANCE WITH REQUIREMENTS FOR RETREATMENT 3
    -
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RGB-03
    Reporting group description
    		 RGB-03 (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).

    Reporting group title
    MabThera
    Reporting group description
    		 MabThera (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).

    Reporting group values
    		 RGB-03 MabThera Total
    Number of subjects
    		 64 58 122
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 56 47 103
        From 65-84 years
    		 8 11 19
    Gender categorical
    Units: Subjects
        Female
    		 51 47 98
        Male
    		 13 11 24

    End points

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    End points reporting groups
    Reporting group title
    RGB-03
    Reporting group description
    		 RGB-03 (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).

    Reporting group title
    MabThera
    Reporting group description
    		 MabThera (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).
    Reporting group title
    RGB-03
    Reporting group description
    		 RGB-03 (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).

    Reporting group title
    MabThera
    Reporting group description
    		 MabThera (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).
    Reporting group title
    RGB-03
    Reporting group description
    		 RGB-03 (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).

    Reporting group title
    MabThera
    Reporting group description
    		 Patients who were assigned to receive MabThera for the Treatment period and 1st Retreatment Course were switched from MabThera group and received RGB-03 for the 2nd and 3rd Retreatment Courses. RGB-03 (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).

    Primary: AUC0-tlast

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    End point title
    		 AUC0-tlast
    End point description
    AUC0-tlast: The area under the serum concentration versus time curve, from time 0 to last data point above the limit of quantitation during the Treatment Period, calculated by the linear trapezoidal method.
    End point type
    Primary
    End point timeframe
    over the first 24 weeks
    End point values
    		 RGB-03 MabThera
    Number of subjects analysed
    63
    54
    Units: h × μg/mL
        geometric mean (geometric coefficient of variation)
    183519.5 ( 29.2 )
    176994.4 ( 35.2 )
    Statistical analysis title
    		 Primary Pharmacokinetics Endpoints - AUC0-tlast
    Statistical analysis description
    Log-transformed AUC0-tlast values were compared by analysis of variance (ANOVA), with treatment allocation as the independent and individual ln(AUC0-tlast) as the dependent variable. Point estimates with 2-sided 90% confidence intervals for the ratios of geometric means of RGB-03 relative to MabThera® were constructed for AUC0-tlast. 90% CIs for the ratios were derived by exponentiation of the CIs obtained for the difference between treatment Least Square Means (LSMs) resulting from the ANOVA on
    Comparison groups
    RGB-03 v MabThera
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    Method
    Parameter type
    		 Ratio of geometric least square means
    Point estimate
    103.69
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 93.54
         upper limit
    		 114.94

    Secondary: Cmax

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    End point title
    		 Cmax
    End point description
    Maximum measured serum concentration over the Treatment Period (taken directly from the raw data).
    End point type
    Secondary
    End point timeframe
    over the first 24 weeks
    End point values
    		 RGB-03 MabThera
    Number of subjects analysed
    63
    54
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    380.1328 ( 19.6 )
    357.7597 ( 21.1 )
    No statistical analyses for this end point

    Secondary: AUC0-15d

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    End point title
    		 AUC0-15d
    End point description
    The area under the serum concentration versus time curve, from time 0 to Day 15 time point of the Treatment Period, calculated by the linear trapezoidal method.
    End point type
    Secondary
    End point timeframe
    over the first 24 weeks
    End point values
    		 RGB-03 MabThera
    Number of subjects analysed
    63
    54
    Units: h × μg/mL
        geometric mean (geometric coefficient of variation)
    44803.5 ( 24.2 )
    45148.7 ( 27.1 )
    No statistical analyses for this end point

    Secondary: AUC0-inf

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    End point title
    		 AUC0-inf
    End point description
    The area under the serum concentration versus time curve, from time 0 extrapolated to infinity.
    End point type
    Secondary
    End point timeframe
    over the first 24 weeks
    End point values
    		 RGB-03 MabThera
    Number of subjects analysed
    63
    54
    Units: h × μg/mL
        geometric mean (geometric coefficient of variation)
    191877.8 ( 26.7 )
    180405.4 ( 34.7 )
    No statistical analyses for this end point

    Secondary: Area Under CD19+ B-cell Count Versus Time Curve

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    End point title
    		 Area Under CD19+ B-cell Count Versus Time Curve
    End point description
    It refers to the CD19+ B-cell count from time 0 (before drug administration) to the last measured count at Day 169.
    End point type
    Secondary
    End point timeframe
    over the first 24 weeks
    End point values
    		 RGB-03 MabThera
    Number of subjects analysed
    60
    54
    Units: cells/μL/day
        geometric mean (standard deviation)
    3684.33 ( 891.312 )
    3448.45 ( 623.276 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in DAS28-ESR by Visit

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    End point title
    		 Change from Baseline in DAS28-ESR by Visit
    End point description
    The DAS28-ESR was calculated from tender joints, swollen joints, ESR, and Patient’s Global Assessment of Disease Activity. Categorization of the DAS28-ESR scores: high disease activity - 5.1 < DAS28, moderate disease activity - 3.2 < DAS28 ≤ 5.1, low disease activity - DAS28 ≤ 3.2 and remission - DAS28 < 2.6.
    End point type
    Secondary
    End point timeframe
    over the first 24 weeks
    End point values
    		 RGB-03 MabThera
    Number of subjects analysed
    60
    54
    Units: change from baseline
        geometric mean (standard deviation)
    6.629 ( 0.8691 )
    6.530 ( 0.6885 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 48 weeks (Double-blind period)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    RGB-03
    Reporting group description
    		 RGB-03 (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).

    Reporting group title
    MabThera
    Reporting group description
    		 MabThera (1000mg) coadministered with MTX (10 to 25 mg weekly orally or parenterally) and folic acid (according to local standard of care).

    Serious adverse events
    		 RGB-03 MabThera
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 64 (10.94%)
    8 / 58 (13.79%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 64 (1.56%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diabetic foot infection
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroborreliosis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 RGB-03 MabThera
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 64 (70.31%)
    45 / 58 (77.59%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 64 (7.81%)
    2 / 58 (3.45%)
         occurrences all number
    6
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 64 (6.25%)
    2 / 58 (3.45%)
         occurrences all number
    4
    3
    Blood cholesterol increased
         subjects affected / exposed
    3 / 64 (4.69%)
    0 / 58 (0.00%)
         occurrences all number
    3
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    Transaminases increased
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    3
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    8 / 64 (12.50%)
    6 / 58 (10.34%)
         occurrences all number
    11
    12
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 64 (4.69%)
    4 / 58 (6.90%)
         occurrences all number
    4
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 64 (6.25%)
    2 / 58 (3.45%)
         occurrences all number
    4
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 64 (6.25%)
    1 / 58 (1.72%)
         occurrences all number
    4
    1
    Hypochromic anaemia
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    Leukopenia
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 58 (0.00%)
         occurrences all number
    4
    0
    Neutropenia
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 58 (1.72%)
         occurrences all number
    2
    1
    Pulmonary embolism
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    2
    Hepatobiliary disorders
    Hepatic steatosis
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Leukocyturia
         subjects affected / exposed
    2 / 64 (3.13%)
    2 / 58 (3.45%)
         occurrences all number
    2
    2
    Renal cyst
         subjects affected / exposed
    2 / 64 (3.13%)
    1 / 58 (1.72%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    2 / 64 (3.13%)
    2 / 58 (3.45%)
         occurrences all number
    2
    2
    Arthralgia
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 58 (3.45%)
         occurrences all number
    1
    2
    Back pain
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 64 (4.69%)
    9 / 58 (15.52%)
         occurrences all number
    4
    10
    Urinary tract infection
         subjects affected / exposed
    8 / 64 (12.50%)
    3 / 58 (5.17%)
         occurrences all number
    9
    4
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 64 (6.25%)
    3 / 58 (5.17%)
         occurrences all number
    4
    3
    Influenza
         subjects affected / exposed
    3 / 64 (4.69%)
    3 / 58 (5.17%)
         occurrences all number
    3
    4
    Bronchitis
         subjects affected / exposed
    3 / 64 (4.69%)
    1 / 58 (1.72%)
         occurrences all number
    3
    1
    Asymptomatic bacteriuria
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 58 (3.45%)
         occurrences all number
    1
    2
    Herpes zoster
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    Pharyngitis
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    Pyelonephritis
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    Respiratory tract infection
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0
    Tonsillitis
         subjects affected / exposed
    0 / 64 (0.00%)
    2 / 58 (3.45%)
         occurrences all number
    0
    2
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    3 / 64 (4.69%)
    1 / 58 (1.72%)
         occurrences all number
    5
    1
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    2 / 58 (3.45%)
         occurrences all number
    2
    2
    Hypocalcaemia
         subjects affected / exposed
    2 / 64 (3.13%)
    0 / 58 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Oct 2014
    The purpose of this amendment was • to include the contact details of the assigned Medical Monitor • to change the study design and harmonise the new study design in the document, • to correct the protocol title and typographical errors in the Protocol. • to clarify RGB-03 administration.
    01 Apr 2015
    The protocol was amended • with administrative changes, including corrections to typographical errors, Medical Support information, • to clarify weight measurement during Screening Visit, blinding and IMP handling/administration procedure, patient monitoring during IMP administration, • to complete missing measurements during Clinical Laboratory evaluation, • to reflect change in efficacy analysis.

    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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