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    Clinical Trial Results:
    A multicentre, open-label, non-inferiority sequential study, evaluating the efficacy, safety, tolerability and acceptability of ADV7103 compared to standard of care in distal renal tubular acidosis patients.

    Summary
    EudraCT number
    		 2013-002988-25
    Trial protocol
    		 SK  
    Global end of trial date
    20 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Jul 2021
    First version publication date
    21 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B21CS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Advicenne SA
    Sponsor organisation address
    2 rue Briconnet, Nimes, France, 30000
    Public contact
    Director of Clinical Affairs, Advicenne Pharma, 33 466 05 54 23, cguittet@advicenne.com
    Scientific contact
    Director of Clinical Affairs, Advicenne Pharma, 33 466 05 54 23, cguittet@advicenne.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001357-PIP01-12
    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
    26 Jun 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the relative efficacy of ADV7103 and standard of care on correcting metabolic acidosis as measured on pre-morning dose blood bicarbonate levels during 3 days of treatment at steady state (Day 2 to Day 4)
    Protection of trial subjects
    A Data Safety Monitoring Board, DSMB, will be constituted and will get together when at least 4 subjects of a defined sub-set of age, according to the planned inclusion’s staggered approach, will have completed the study. Two meetings will be organised in order to review data of at least 4 subjects of Sub-set 1 and Sub-set 2 then data of at least 4 subjects of Sub-set 3. Additional meetings may be organised at any time if any intolerable safety issue related to the study drug occurs during the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Slovakia: 1
    Country: Number of subjects enrolled
    France: 35
    Country: Number of subjects enrolled
    Serbia: 1
    Worldwide total number of subjects
    37
    EEA total number of subjects
    36
    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)
    2
    Children (2-11 years)
    18
    Adolescents (12-17 years)
    10
    Adults (18-64 years)
    7
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 the screening/inclusion visit will be planned in the investigator site (Visit 1) on Day-1 to perform the baseline evaluations.

    Period 1
    Period 1 title
    Study period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Standard of care (SoC)
    Arm description
    		 SP I is a steady phase with SoC at the therapeutic dose
    Arm type
    		 Active comparator

    Investigational medicinal product name
    SoC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The daily dose of standard of care (usual alkalising treatment) will be taken as usual by the subject. This dose should be determined at inclusion and the dose regimen should be the same all along the study period, with at least a dose in the morning.

    Number of subjects in period 1
    		Standard of care (SoC)
    Started
    37
    Completed
    35
    Not completed
    2
         Consent withdrawn by subject
    1
         difficulty in swallowing ADV7103
    1
    Period 2
    Period 2 title
    Study period 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 ADV7103 Titration
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    ADV7103
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release granules
    Routes of administration
    Oral use
    Dosage and administration details
    The daily dose will be provided in 2 doses a day in the morning and in the evening, to be taken orally before the meal or with some semi-liquid foods for the youngest children. The morning dose will be taken approximately between 7 and 8 am and the evening dose will be taken approximately between 7 and 9 pm. The granules must not be chewed.

    Number of subjects in period 2
    		ADV7103 Titration
    Started
    35
    Completed
    32
    Not completed
    3
         Consent withdrawn by subject
    2
         Lack of efficacy
    1
    Period 3
    Period 3 title
    Study period 3
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 ADV7103
    Arm description
    		 SPIII is a steady phase with ADV7103 at the optimal dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    ADV7103
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release granules
    Routes of administration
    Oral use
    Dosage and administration details
    The daily dose will be provided in 2 doses a day in the morning and in the evening, to be taken orally before the meal or with some semi-liquid foods for the youngest children. The morning dose will be taken approximately between 7 and 8 am and the evening dose will be taken approximately between 7 and 9 pm. The granules must not be chewed.

    Number of subjects in period 3
    		ADV7103
    Started
    32
    Completed
    32

    Baseline characteristics

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    End points

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    End points reporting groups
    Reporting group title
    Standard of care (SoC)
    Reporting group description
    		 SP I is a steady phase with SoC at the therapeutic dose
    Reporting group title
    ADV7103 Titration
    Reporting group description
    		 -
    Reporting group title
    ADV7103
    Reporting group description
    		 SPIII is a steady phase with ADV7103 at the optimal dose

    Primary: Average bicarbonate blood level

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    End point title
    		 Average bicarbonate blood level
    End point description
    End point type
    Primary
    End point timeframe
    during 3 days of treatment at steady state with ADV7103 and SoC (Day 2 to Day 4).
    End point values
    		 Standard of care (SoC) ADV7103
    Number of subjects analysed
    29
    30
    Units: mmol/L
        arithmetic mean (standard deviation)
    21.7 ± 3.06
    23.1 ± 1.62
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    Standard of care (SoC) v ADV7103
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 < 0.0001
    Method
    		 t-test, 1-sided
    Confidence interval
    Notes
    [1] - Analysis performed on 30 subjects as subjects switched from Study period 1 to Study period 3

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    during the course of the study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Standard of care steady state
    Reporting group description
    		 -

    Reporting group title
    ADV7103 titration
    Reporting group description
    		 -

    Reporting group title
    ADV7103 steady state
    Reporting group description
    		 -

    Serious adverse events
    		 Standard of care steady state ADV7103 titration ADV7103 steady state
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 34 (2.94%)
    0 / 32 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 34 (2.94%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Standard of care steady state ADV7103 titration ADV7103 steady state
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 37 (8.11%)
    19 / 34 (55.88%)
    0 / 32 (0.00%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 34 (8.82%)
    0 / 32 (0.00%)
         occurrences all number
    0
    3
    0
    pyrexia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 34 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 37 (8.11%)
    6 / 34 (17.65%)
    0 / 32 (0.00%)
         occurrences all number
    3
    7
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 34 (14.71%)
    0 / 32 (0.00%)
         occurrences all number
    0
    6
    0
    Vomiting
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 34 (8.82%)
    0 / 32 (0.00%)
         occurrences all number
    0
    3
    0
    Diarrhoea
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 34 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0
    Nausea
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 34 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    0
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jun 2014
    i. Bicarbonataemia analysis no longer performed in a centralised laboratory but taken directly to the nearest local laboratory. ii. Additional urinary and blood parameters added without change of number or volume of samples. iii. Patients presenting a moderate renal impairment excluded in addition to those presenting severe renal impairment. iv. Ethnic origins removed from demographic data to be collected. v. Volume of blood to be drawn modified to allow 4 samples for participation in the fluctuation evaluation. Samples planned to be 1 ml will be 2 ml for adolescents and adults. vi. New version of the IMPDs established for ADV7103-CK and ADV7103-BK. Loading rates of ADV7103-CK and ADV7103-BK slightly different to ones in previous batches. Error regarding alkalising power of ADV7103 corrected. Expiry period of ADV7103 modified in protocol following stability study. vii. Secondary packaging introduced for ADV7103. viii. Pharmacovigilance and data management activities delegated to external organisations.

    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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