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    Clinical Trial Results:
    A Phase 2, Double-Blind, Randomized, Placebo Controlled Study to Evaluate the Efficacy and Safety of ASP8232 as Add-On Therapy to Angiotensin Converting Enzyme inhibitor (ACEi) or Angiotensin Receptor Blocker (ARB) in Reducing Albuminuria in Patients with Type 2 Diabetes and Chronic Kidney Disease

    Summary
    EudraCT number
    2014-002349-23
    Trial protocol
    DK   GB   HU   CZ   DE   BE   IT   NL   ES   PL  
    Global end of trial date
    15 Mar 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Mar 2018
    First version publication date
    21 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    8232-CL-0004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02358096
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe BV
    Sponsor organisation address
    Sylviusweg 62, BE Leiden, Netherlands, 2333
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Europe BV, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Europe BV, astellas.resultsdisclosure@astellas.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
    15 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the efficacy of ASP8232 in reducing urinary albumin to creatinine ratio (UACR) in participants with Type 2 Diabetes Mellitus (T2DM) and Chronic Kidney Disease (CKD) at 12 weeks compared to placebo.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 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
    Czech Republic: 20
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Hungary: 23
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    United Kingdom: 6
    Worldwide total number of subjects
    125
    EEA total number of subjects
    125
    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)
    32
    From 65 to 84 years
    93
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 64 contracted sites in a total of 10 countries and regions. The randomization schedule was stratified by country. Participants selected for the study were suffering from Type 2 Diabetes Mellitus (T2DM) and Chronic Kidney Disease (CKD).

    Pre-assignment
    Screening details
    Participants who met eligibility criteria were enrolled in the study. The study consisted of a screening period of 1 week, a 5-week pretreatment period, a 12-week treatment period and a 24-week follow-up period. Participants were randomized to 1 of the 2 treatments in a 1:1 ratio to ASP8232 or placebo.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Assessor
    Blinding implementation details
    Participants were randomly assigned to 1 of 2 treatment arms, ASP8232 or placebo in a double-blind fashion such that the investigator, sponsor’s study management team, CRO staff, site staff and the participant did not know which treatment was being administered.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ASP8232
    Arm description
    Participants received 40 mg ASP8232 orally once a day for 84 consecutive days.
    Arm type
    Experimental

    Investigational medicinal product name
    ASP8232
    Investigational medicinal product code
    ASP8232
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 40 mg of ASP8232 orally once a day. It was administered in the morning with or without food.

    Arm title
    Placebo
    Arm description
    Participants received 40 mg matching placebo orally once a day for 84 consecutive days.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 40 mg of matching placebo orally once a day. It was administered in the morning with or without food

    Number of subjects in period 1
    ASP8232 Placebo
    Started
    64
    61
    Received Treatment
    64
    61
    Completed
    58
    59
    Not completed
    6
    2
         Adverse event, serious fatal
    1
    -
         Participant Randomized in Error
    -
    1
         Consent withdrawn by subject
    5
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ASP8232
    Reporting group description
    Participants received 40 mg ASP8232 orally once a day for 84 consecutive days.

    Reporting group title
    Placebo
    Reporting group description
    Participants received 40 mg matching placebo orally once a day for 84 consecutive days.

    Reporting group values
    ASP8232 Placebo Total
    Number of subjects
    64 61
    Age categorical
    Units: Subjects
    Age continuous
    The analysis population consisted of all participants who were randomized to receive study treatment.
    Units: years
        arithmetic mean (standard deviation)
    69.5 ± 7.4 68.6 ± 6.7 -
    Gender categorical
    The analysis population consisted of all participants who were randomized to receive study treatment.
    Units:
        Male
    45 51 96
        Female
    19 10 29
    Race
    The analysis population consisted of all participants who were randomized to receive study treatment.
    Units: Subjects
        White
    60 58 118
        Black or African American
    1 0 1
        Asian
    2 2 4
        Other
    1 1 2
    Weight
    The analysis population consisted of all participants who were randomized to receive study treatment.
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    92.84 ± 18.57 94.74 ± 20.32 -
    Height
    The analysis population consisted of all participants who were randomized to receive study treatment.
    Units: centimeters (cm)
        arithmetic mean (standard deviation)
    169.2 ± 9.0 171.3 ± 8.6 -
    Body Mass Index (BMI)
    The analysis population consisted of all participants who were randomized to receive study treatment.
    Units: kg/m^2
        arithmetic mean (standard deviation)
    32.43 ± 5.75 32.20 ± 6.40 -
    Duration of Chronic Kidney Disease (CKD)
    The analysis population was full analysis set (FAS), which consisted of all participants who were randomized and received at least one dose of study drug and had at least one post-baseline urinary albumin to creatinine ratio (UACR)/ albumin excretion rate (AER) measurement. The number of participants used for the analysis was ASP8232=60 and Placebo=60. Duration in years was calculated as: (randomization date - diagnosis date + 1) / 365.25.
    Units: Years
        arithmetic mean (standard deviation)
    4.98 ± 4.42 5.46 ± 4.20 -
    Duration of Type 2 Diabetes Mellitus (T2DM)
    The analysis population was the FAS. The number of participants used for the analysis was ASP8232=60 and Placebo=60. Duration in years was calculated as: (randomization date - diagnosis date + 1) / 365.25.
    Units: Years
        arithmetic mean (standard deviation)
    16.34 ± 7.73 16.24 ± 7.04 -
    Baseline for Percent Change in First Morning Void (FMV) Urinary Albumin to Creatinine Ratio (UACR)
    The analysis population was the FAS. Baseline was defined as the geometric mean (GM) of all UACR measurements corresponding to FMV urine samples returned on site at visits 4 and 5 during pretreatment period. The number of participants used for the analysis was ASP8232=60 and Placebo=60.
    Units: Year
        geometric mean (full range (min-max))
    745.237 (418.400 to 1229.835) 686.911 (388.400 to 1062.855) -

    End points

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    End points reporting groups
    Reporting group title
    ASP8232
    Reporting group description
    Participants received 40 mg ASP8232 orally once a day for 84 consecutive days.

    Reporting group title
    Placebo
    Reporting group description
    Participants received 40 mg matching placebo orally once a day for 84 consecutive days.

    Primary: Change From Baseline in Mean Change of Log-transformed Urinary Albumin to Creatinine Ratio (UACR) at Week 12 End of Treatment (EoT)

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    End point title
    Change From Baseline in Mean Change of Log-transformed Urinary Albumin to Creatinine Ratio (UACR) at Week 12 End of Treatment (EoT)
    End point description
    The UACR measured albumin and creatinine concentrations in urine across 3 samples of the first morning void (FMV) taken on three consecutive days prior to 11 study visits starting at visit 2 (Day -39) until visit 14 end of study (EoS) (Day 253). The mean was taken over the log transformed UACR measurements from FMV samples prior to the relevant visit (6 days samples for pretreatment as baseline and 3 days samples for treatment period). The post-baseline visits were defined as the geometric mean (GM) of the 3 UACR measurements corresponding to FMV urine samples collected for that visit. Only data from first morning void samples were used. The analysis population was the Full Analysis Set (FAS), which consisted of participants who were randomized and received at least one dose of study drug and had at least one post-baseline UACR measurement.
    End point type
    Primary
    End point timeframe
    Baseline and end of treatment (EoT) (week 12)
    End point values
    ASP8232 Placebo
    Number of subjects analysed
    55
    56
    Units: Percent Change
    number (not applicable)
        Change from Baseline to Week 12
    -17.65
    2.31
    Statistical analysis title
    ASP8232 vs Placebo
    Statistical analysis description
    Statistical analysis comparing change from baseline between ASP8232 vs Placebo. Estimates were obtained from a mixed model of repeated measures on the log-transformed UACR that includes treatment, visit, visit by treatment interaction and region as fixed class factors and baseline log transformed UACR as a continuous covariate. Least square mean (LSM) and the 95% CI were transformed back to the original scale and expressed as percentages. Only data from first morning void samples were used.
    Comparison groups
    ASP8232 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.033
    Method
    Mixed models analysis
    Parameter type
    Percent Change
    Point estimate
    -19.51
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -34.01
         upper limit
    -1.82

    Secondary: Percentage of Participants With > 30%/40%/50% Reduction in UACR From Baseline to Week 12 (EoT)

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    End point title
    Percentage of Participants With > 30%/40%/50% Reduction in UACR From Baseline to Week 12 (EoT)
    End point description
    The percentage of participants achieving a 30/40/50% reduction in GM of UACR from baseline to EoT were described using frequency tabulations. The FAS was used for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and end of treatment (EoT) (week 12)
    End point values
    ASP8232 Placebo
    Number of subjects analysed
    60
    60
    Units: Percentage of Participants
    number (not applicable)
        Reduction > 30%
    36.7
    21.7
        Reduction > 40%
    21.7
    20.0
        Reduction > 50%
    11.7
    11.7
    Statistical analysis title
    ASP8232 vs Placebo (Reduction > 30%)
    Statistical analysis description
    Statistical analysis comparing the percentage of reduction between ASP8232 vs Placebo. The percentage of participants with > 30% reduction in GM of UACR from baseline to EoT were analyzed using a logistic regression model including treatment as fixed factor and country and (mean) log transformed UACR at baseline as covariates.
    Comparison groups
    ASP8232 v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.109
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    4.94
    Statistical analysis title
    ASP8232 vs Placebo (Reduction > 40%)
    Statistical analysis description
    Statistical analysis comparing the percentage of reduction between ASP8232 vs Placebo. The percentage of participants with > 40% reduction in GM of UACR from baseline to EoT were analyzed using a logistic regression model including treatment as fixed factor and country and (mean) log transformed UACR at baseline as covariates.
    Comparison groups
    ASP8232 v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.993
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    2.56
    Statistical analysis title
    ASP8232 vs Placebo (Reduction > 50%)
    Statistical analysis description
    Statistical analysis comparing the percentage of reduction between ASP8232 vs Placebo. The percentage of participants with > 50% reduction in GM of UACR from baseline to EoT were analyzed using a logistic regression model including treatment as fixed factor and country and (mean) log transformed UACR at baseline as covariates.
    Comparison groups
    ASP8232 v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.887
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.28
         upper limit
    2.98

    Secondary: Mean Change of Log-transformed Albumin Excretion Rate (AER) From Baseline to Week 12 (EoT)

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    End point title
    Mean Change of Log-transformed Albumin Excretion Rate (AER) From Baseline to Week 12 (EoT)
    End point description
    The AER was measured from urine collected 24 hours (h) before visit 6 (baseline), visit 8 (Day 29) and visit 11 (Day 85). The 24 h urine collection started on Day 1 before the scheduled visit up to and including the FMV on the day of the scheduled visit. The FAS was used for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and end of treatment (EoT) (week 12)
    End point values
    ASP8232 Placebo
    Number of subjects analysed
    53
    53
    Units: Percent Change
    number (not applicable)
        Change from Baseline in 24h AER at Week 12 (EoT)
    -26.67
    -8.35
    Statistical analysis title
    ASP8232 vs Placebo
    Statistical analysis description
    Statistical analysis comparing the percent change in 24h AER at Week 12 (EoT) between ASP8232 vs Placebo. Estimates were obtained from a mixed model of repeated measures on the log-transformed UACR that includes treatment, visit, visit by treatment interaction and region as fixed class factors and baseline log transformed UACR as a continuous covariate.
    Comparison groups
    ASP8232 v Placebo
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.094
    Method
    Mixed models analysis
    Parameter type
    Percent Change
    Point estimate
    -20
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -38.45
         upper limit
    3.99

    Secondary: Percentage of Participants With > 30%/40%/50% Reduction in AER From Baseline to Week 12 (EoT)

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    End point title
    Percentage of Participants With > 30%/40%/50% Reduction in AER From Baseline to Week 12 (EoT)
    End point description
    The percentage of participants achieving a 30/40/50% reduction in AER from baseline to EoT were described using frequency tabulations. The FAS was used for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and end of treatment (EoT) (week 12)
    End point values
    ASP8232 Placebo
    Number of subjects analysed
    56
    56
    Units: Percentage of Participants
    number (not applicable)
        Reduction > 30%
    44.6
    28.6
        Reduction > 40%
    33.9
    23.2
        Reduction > 50%
    28.6
    14.3
    Statistical analysis title
    ASP8232 vs Placebo (Reduction > 30%)
    Statistical analysis description
    Statistical analysis depicts AER Reduction of > 30%. The model included treatment as fixed factor, and country and baseline log transformed AER as covariates.
    Comparison groups
    ASP8232 v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.072
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.93
         upper limit
    4.78
    Statistical analysis title
    ASP8232 vs Placebo (Reduction > 40%)
    Statistical analysis description
    Statistical analysis depicts AER Reduction of > 40%. The model included treatment as fixed factor, and country and baseline log transformed AER as covariates.
    Comparison groups
    ASP8232 v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.216
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.73
         upper limit
    4.04
    Statistical analysis title
    ASP8232 vs Placebo (Reduction > 50%)
    Statistical analysis description
    Statistical analysis depicts AER Reduction of > 50%. The model includes treatment as fixed factor, and country and baseline log transformed AER as covariates.
    Comparison groups
    ASP8232 v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.074
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.92
         upper limit
    6.44

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 28 days after last intake of study drug
    Adverse event reporting additional description
    The safety analysis set (SAF) was used for the analysis and consisted of all randomized participants who received at least 1 dose of study drug. The treatment emergent adverse events (TEAEs) were defined as adverse events (AEs) observed after start of the administration of the test drug until 28 days after last intake of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    ASP8232
    Reporting group description
    Participants received ASP8232 orally once a day for 84 consecutive days.

    Reporting group title
    Placebo
    Reporting group description
    Participants received matching placebo orally once a day for 84 consecutive days.

    Serious adverse events
    ASP8232 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 64 (4.69%)
    3 / 61 (4.92%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Atrioventricular block complete
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemianopia homonymous
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 64 (0.00%)
    1 / 61 (1.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 61 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    ASP8232 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 64 (25.00%)
    11 / 61 (18.03%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 64 (3.13%)
    6 / 61 (9.84%)
         occurrences all number
    2
    6
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    6 / 64 (9.38%)
    1 / 61 (1.64%)
         occurrences all number
    6
    1
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    9 / 64 (14.06%)
    1 / 61 (1.64%)
         occurrences all number
    9
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 64 (3.13%)
    4 / 61 (6.56%)
         occurrences all number
    2
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jan 2015
    The changes include: Substantial Amendment 1 ● As the requirement for the mean UACR to be ≥ 200 mg/g at baseline ensured that participants were randomized with significant levels of albuminuria despite adequate treatment with angiotensin converting enzyme inhibitor (ACEi)/ARB, inclusion criterion 9 (FMV samples) was also to be met at visit 4 and 5. ● The criterion that prohibited sperm donation during the study period was a standard procedure in Astellas sponsored clinical trials and was deleted in error in the original protocol. It was re-introduced. ● As it was deemed important to repeat the electrocardiogram (ECG) during the 4-week follow-up visit, an ECG assessment was added to visit 12. ● There were no drug-related histopathological changes in the male reproductive organs in the 4-week and 13-week repeated dose studies in rats and monkeys. Therefore, it was concluded that the potential for effects on male fertility was low. Hence, the details of follow-up for pregnancy of partners of participating male patients were removed. ● Based on local requirements, certain events that occurred during a participant's participation in the clinical trial were to be reported as adverse events (AEs) or expedited as serious adverse events (SAEs).
    30 Mar 2015
    The changes include: Substantial Amendment 2 ● In order to further characterize the pharmacokinetic and pharmacodynamic profile and long-term pharmacodynamic and pharmacodynamic profile of the investigational product ASP8232, the follow-up period was extended up to approximately 24 weeks after the EoT visit to cover approximately 5 times the mean terminal elimination halflife of 760 hours. ● In inclusion criteria 10, 11 and 12, the use of contraception for female participants of childbearing potential was extended until 24 weeks after the final study drug administration
    24 Nov 2015
    The changes include: Substantial Amendment 3 ● In order to facilitate participants’ enrollment into the study, the eGFR entry criterion was extended. The participant must have an eGFR (based on the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) of ≥ 25 and < 75 mL/min/1.73 m2. ● Additional specification of study population for stable treatment for at least 3 months prior to screening was updated. ● Retesting of UACR measurement at visit 2 was allowed if value was between 100 and 200 mg/g. It was allowed to avoid the rejection of participants who were potentially valid candidates for the study, but appeared to be below 200 mg/g due to the day to day variability of albuminuria. ● Rescreening of the participants was allowed once per participant, if the participant was not randomized into this trial before. ● The previous criterion of at least 2 samples out of 3 per triplicate (at visit 4 and visit 5) was considered too strict, therefore this criterion was changed in order to facilitate enrollment. For a participant to be eligible, it is required that the geometric mean UACR of all visit 4 and visit 5 samples is ≥ 200 and ≤ 3000 mg/g AND in at least 3 FMV samples, and the UACR at visit 4 and visit 5 is ≥ 200 mg/g. ● Additional specifications of concomitant medication (and nonmedication therapies) were updated. Carvedilol was removed from the list of the prohibited drugs for pharmacokinetic interferences. ● Additional specification of previous and concomitant treatments was updated. ● Details of study completion date and number of patients participating in the study were updated.

    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.
    Seven isolated UACR data points and 1 AER datapoint below the lower limit of quantification (LLOQ) were detected after database softlock. Following database hardlock and study treatment unblinding, the team decided to exclude these values.
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