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    Clinical Trial Results:
    PROTOCOL RET-D-001: EFFICACY AND SAFETY OF SPARSENTAN (RE-021), A DUAL ENDOTHELIN RECEPTOR AND ANGIOTENSIN RECEPTOR BLOCKER, IN PATIENTS WITH FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS): A RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROL, DOSE-ESCALATION STUDY

    Summary
    EudraCT number
    		 2014-002358-38
    Trial protocol
    		 CZ   IT   BE  
    Global end of trial date
    25 Mar 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Sep 2024
    First version publication date
    25 Sep 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RET-D-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01613118
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Travere Therapeutics, Inc.
    Sponsor organisation address
    3611 Valley Centre Drive, Suite 300, San Diego, United States, 92130
    Public contact
    Medical Information, Travere Call Center, 001 877.659.5518, medinfo@travere.com
    Scientific contact
    Medical Information, Travere Call Center, 001 877.659.5518, medinfo@travere.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001984-PIP02-20
    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
    Interim
    Date of interim/final analysis
    08 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the change in urine protein/creatinine (Up/C) after 8 weeks of treatment in FSGS patients receiving Sparsentan, a novel dual endothelin receptor and angiotensin receptor blocker, over a range of dose levels (200 mg, 400 mg, and 800 mg) compared to treatment with Irbesartan as active control.
    Protection of trial subjects
    Independent Ethics Committee (IEC) or Institutional Review Board (IRB) The Institutional Review Board (IRB) or Independent Ethics Committee (IEC) at each investigational site reviewed and approved the protocol and informed consent form (ICF)/assent form for the study prior to site initiation in accordance with ethical principles of Good Clinical Practice (GCP) as required by the major regulatory authorities, and in accordance with the Declaration of Helsinki. Ethical Conduct of the Study The study was conducted and monitored in accordance with the individual vendor/contractor procedures and SOPs. All procedures and SOPs comply with the ethical principles of GCP, as required by regulatory authorities, and are in accordance with the Declaration of Helsinki. Subject Information and Consent The Investigator was responsible for documenting the consent process within the source documents, and for obtaining consent using an IRB/IEC approved consent form. Subjects and/or their parent/legal guardian signed informed consent/assent at Visit 1 (beginning of the Screening period) prior to undergoing any protocol-related procedures. A signed and dated copy of the consent/assent form(s) was given to the subject.
    Background therapy
    		 None
    Evidence for comparator
    		 While there are currently no approved medicinal products indicated for the treatment of FSGS, an important part of treatment is rigorous blood pressure control using renin-angiotensin-aldosterone system (RAAS) inhibitor therapy (angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers [ARBs]) to target blood pressure values <130/80 mmHg in order to reduce hemodynamic stress and proteinuria and, thereby, slow the progression of renal disease. Randomized, placebo-controlled trials have shown long-term benefit of RAAS inhibitor treatment, which is universally considered to be first-line standard-of-care, as outlined in the KDIGO Clinical Practice Guideline.
    Actual start date of recruitment
    07 Mar 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 10 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 89
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    Italy: 16
    Worldwide total number of subjects
    109
    EEA total number of subjects
    20
    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)
    6
    Adolescents (12-17 years)
    12
    Adults (18-64 years)
    85
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 185 patients screened, 76 excluded, 109 enrolled

    Pre-assignment
    Screening details
    		 Screening was performed between 2 to 4 weeks before Washout began. Patients who failed screening for any reason were allowed to re-screen up to two times. In addition to confirming inclusion and exclusion criteria and repeating any necessary assessment, the following procedures were required: blood pressure, S-potassium, eGFR, and urine Up/C.

    Period 1
    Period 1 title
    Double-blind
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Irbesartan 150 mg tablets were over-encapsulated (blinded) with size 00 gray opaque hard gelatin capsules (Capsugel) and backfilled with Avicel. Patients randomized to the irbesartan active control may also have receive placebo capsules, to maintain the blind by keeping the number of capsules taken consistent with that of sparsentan-treated patients in the same cohort. The placebo product used was a size 00 gray opaque capsule (Capsugel) containing microcrystalline cellulose.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Investigational medicinal product
    Arm description
    		 Investigational medicinal product
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sparsentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The doses to be administered in the double-blind period (200, 400, or 800 mg) were dispensed as 100 mg size 00 sparsentan capsules. In the open-label period, doses were dispensed as either 100 mg (size 00 or 0) sparsentan capsules or as 400 mg scored sparsentan tablets. Patients were instructed to take the appropriate quantity of capsules or tablets for the assigned cohort, orally once daily prior to the morning meal, with the exception of the day of a study visit as the patient took their study medication in the clinic.

    Arm title
    		 Active Control
    Arm description
    		 Active control
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Irbesartan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The irbesartan doses administered in the study (150 and 300 mg ) were supplied as double-blinded over-encapsulated tablets. Patients were instructed to take the appropriate quantity of capsules or tablets for the assigned cohort, orally once daily prior to the morning meal, with the exception of the day of a study visit as the patient took their study medication in the clinic.

    Number of subjects in period 1
    		Investigational medicinal product Active Control
    Started
    73
    36
    Completed
    68
    35
    Not completed
    5
    1
         Adverse event, non-fatal
    3
    1
         Discontinued
    1
    -
         Protocol deviation
    1
    -
    Period 2
    Period 2 title
    Open-label Extension
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Investigational medicinal product
    Arm description
    		 Investigational medicinal product
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sparsentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    In the open-label period, doses may be dispensed as either 100 mg (size 00 or 0) sparsentan capsules or as 400 mg scored sparsentan tablets. Patients were instructed to take the appropriate quantity of capsules or tablets for the assigned cohort, orally once daily prior to the morning meal, with the exception of the day of a study visit as the patient took their study medication in the clinic.

    Number of subjects in period 2
    		Investigational medicinal product
    Started
    103
    Completed
    34
    Not completed
    69
         Consent withdrawn by subject
    18
         Physician decision
    16
         Adverse event, non-fatal
    19
         Other
    5
         Pregnancy
    4
         Non-compliance with study intervention
    2
         Lost to follow-up
    4
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Investigational medicinal product
    Reporting group description
    		 Investigational medicinal product

    Reporting group title
    Active Control
    Reporting group description
    		 Active control

    Reporting group values
    		 Investigational medicinal product Active Control Total
    Number of subjects
    		 73 36 109
    Age categorical
    Age (years) at screening
    Units: Subjects
        Children (2-11 years)
    		 4 2 6
        Adolescents (12-17 years)
    		 7 5 12
        Adults (18-64 years)
    		 57 28 85
        From 65-84 years
    		 5 1 6
    Gender categorical
    Male or Female
    Units: Subjects
        Female
    		 32 17 49
        Male
    		 41 19 60
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 14 6 20
        Not Hispanic or Latino
    		 59 30 89
    Race
    Race
    Units: Subjects
        Asian
    		 5 1 6
        Black
    		 8 7 15
        White
    		 57 26 83
        Other
    		 3 2 5
    Weight
    Weight in kilograms
    Units: Kilograms
        arithmetic mean (standard deviation)
    		 81 ( 22.48 ) 82 ( 22.19 ) -
    Height
    Height in centimeters
    Units: centimetre
        arithmetic mean (standard deviation)
    		 168 ( 12.77 ) 168 ( 14.22 ) -
    BMI
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 28 ( 6.139 ) 29 ( 6.404 ) -
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects who received at least 1 dose of investigational product (ie, sparsentan or irbesartan) and have at least 1 postbaseline efficacy evaluation. Subjects were analyzed based on their randomized treatment.

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Defined as all subjects in the EES who completed the 8-week double-blind treatment period without major protocol deviations and who were 80% to 120% compliant with investigational product. Specific disallowed medications and other protocol deviations that excluded subjects from the PP analysis set were identified prior to unblinding the database for the primary analysis. Subjects were analyzed based on their randomized treatment.

    Subject analysis set title
    Efficacy Evaluable Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Defined as all subjects who received at least 1 dose of double-blind investigational product and have both baseline and Week 8 UP/C values. This population does not include subjects that were replaced due to missing a UP/C value. This analysis set was used for the analysis of the primary efficacy endpoint. Subjects were analyzed based on their randomized treatment.

    Subject analysis sets values
    		 Full Analysis Set Per Protocol Set Efficacy Evaluable Set
    Number of subjects
    109
    87
    96
    Age categorical
    Age (years) at screening
    Units: Subjects
        Children (2-11 years)
    6
    6
    6
        Adolescents (12-17 years)
    12
    11
    11
        Adults (18-64 years)
    85
    64
    73
        From 65-84 years
    6
    6
    6
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    Gender categorical
    Male or Female
    Units: Subjects
        Female
    60
    36
    41
        Male
    49
    51
    55
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    20
    17
    18
        Not Hispanic or Latino
    89
    70
    78
    Race
    Race
    Units: Subjects
        Asian
    6
    3
    5
        Black
    15
    11
    12
        White
    83
    69
    74
        Other
    5
    4
    5
    Weight
    Weight in kilograms
    Units: Kilograms
        arithmetic mean (standard deviation)
    81.40 ( 22.288 )
    80.65 ( 22.045 )
    81.05 ( 22.070 )
    Height
    Height in centimeters
    Units: centimetre
        arithmetic mean (standard deviation)
    167.77 ( 13.201 )
    167.74 ( 13.550 )
    167.80 ( 3.501 )
    BMI
    Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    28.49 ( 6.199 )
    28.22 ( 6.225 )
    28.33 ( 6.085 )

    End points

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    End points reporting groups
    Reporting group title
    Investigational medicinal product
    Reporting group description
    		 Investigational medicinal product

    Reporting group title
    Active Control
    Reporting group description
    		 Active control
    Reporting group title
    Investigational medicinal product
    Reporting group description
    		 Investigational medicinal product

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects who received at least 1 dose of investigational product (ie, sparsentan or irbesartan) and have at least 1 postbaseline efficacy evaluation. Subjects were analyzed based on their randomized treatment.

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Defined as all subjects in the EES who completed the 8-week double-blind treatment period without major protocol deviations and who were 80% to 120% compliant with investigational product. Specific disallowed medications and other protocol deviations that excluded subjects from the PP analysis set were identified prior to unblinding the database for the primary analysis. Subjects were analyzed based on their randomized treatment.

    Subject analysis set title
    Efficacy Evaluable Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Defined as all subjects who received at least 1 dose of double-blind investigational product and have both baseline and Week 8 UP/C values. This population does not include subjects that were replaced due to missing a UP/C value. This analysis set was used for the analysis of the primary efficacy endpoint. Subjects were analyzed based on their randomized treatment.

    Primary: Primary Endpoint 1

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    End point title
    		 Primary Endpoint 1
    End point description
    Change from baseline to Week 8 in urine protein to creatinine ratio in the 200, 400 and 800 mg groups combined
    End point type
    Primary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Investigational medicinal product Active Control
    Number of subjects analysed
    64
    32
    Units: g/g
    arithmetic mean (standard deviation)
        Baseline
    4.707 ( 3.7810 )
    4.017 ( 2.6717 )
        Week 8
    3.300 ( 3.5719 )
    3.164 ( 2.2713 )
    Attachments
    		 primary Endpoint Chart
    Statistical analysis title
    		 Primary Endpoint
    Statistical analysis description
    A multiple-comparisons adjustment procedure (gated sequential testing) was used to evaluate sparsentan dose effects while controlling the Type 1 error rate at 5%. Specifically, the sparsentan doses were compared to irbesartan in a pre defined hierarchal order.
    Comparison groups
    Investigational medicinal product v Active Control
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 ANCOVA
    Confidence interval

    Primary: Primary Endpoint 2

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    End point title
    		 Primary Endpoint 2
    End point description
    Change from baseline to Week 8 in urine protein to creatinine ratio in the 400 and 800 mg groups combined
    End point type
    Primary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Investigational medicinal product Active Control
    Number of subjects analysed
    51
    25
    Units: g/g
    arithmetic mean (standard deviation)
        Baseline
    4.824 ( 4.0506 )
    3.816 ( 2.7160 )
        Week 8
    3.208 ( 3.4738 )
    2.990 ( 2.3598 )
    Statistical analysis title
    		 Primary Endpoint 2
    Comparison groups
    Investigational medicinal product v Active Control
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 ANCOVA
    Confidence interval

    Primary: Primary Endpoint 3

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    End point title
    		 Primary Endpoint 3
    End point description
    Change from baseline to Week 8 in urine protein to creatinine ratio in the 400 mg group
    End point type
    Primary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Investigational medicinal product Active Control
    Number of subjects analysed
    21
    17
    Units: g/g
    arithmetic mean (standard deviation)
        Baseline
    4.749 ( 4.1696 )
    3.482 ( 2.6074 )
        Week 8
    2.452 ( 2.6254 )
    2.795 ( 2.4581 )
    Statistical analysis title
    		 Primary Endpoint 3
    Comparison groups
    Investigational medicinal product v Active Control
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.056
    Method
    		 ANCOVA
    Confidence interval

    Primary: Primary Endpoint 4

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    End point title
    		 Primary Endpoint 4
    End point description
    Change from baseline to Week 8 in urine protein to creatinine ratio in the 800 mg group
    End point type
    Primary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Investigational medicinal product Active Control
    Number of subjects analysed
    30
    8
    Units: g/g
    arithmetic mean (standard deviation)
        Baseline
    4.876 ( 4.0362 )
    4.526 ( 2.9842 )
        Week 8
    3.737 ( 3.9177 )
    3.405 ( 2.2343 )
    Statistical analysis title
    		 Primary Endpoint 4
    Comparison groups
    Investigational medicinal product v Active Control
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.127
    Method
    		 ANCOVA
    Confidence interval

    Primary: Primary Endpoint 5

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    End point title
    		 Primary Endpoint 5
    End point description
    Change from baseline to Week 8 in urine protein to creatinine ratio in the 200 mg group
    End point type
    Primary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Investigational medicinal product Active Control
    Number of subjects analysed
    13
    7
    Units: g/g
    arithmetic mean (standard deviation)
        Baseline
    4.248 ( 2.5304 )
    4.734 ( 2.5701 )
        Week 8
    3.663 ( 4.0650 )
    3.786 ( 1.9501 )
    Statistical analysis title
    		 Primary Endpoint 5
    Comparison groups
    Investigational medicinal product v Active Control
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.298
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Secondary Endpoint 1

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    End point title
    		 Secondary Endpoint 1
    End point description
    Proportion of Subjects Achieving UP/C <1.5 g/g and >40% Reduction from Baseline in UP/C (FPRE) at Week 8 in the 200, 400, and 800 mg groups combined
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Investigational medicinal product Active Control
    Number of subjects analysed
    64
    32
    Units: Subjects
        Number of subjects achieving FPRE
    18
    3
    Statistical analysis title
    		 Secondary Endpoints
    Statistical analysis description
    Analyses of the secondary endpoints were conducted using a Fisher’s exact test to compare sparsentan doses (or combination of doses) with irbesartan
    Comparison groups
    Investigational medicinal product v Active Control
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Secondary Endpoint 1
    Comparison groups
    Investigational medicinal product v Active Control
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Secondary Endpoint 2

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    End point title
    		 Secondary Endpoint 2
    End point description
    Proportion of Subjects Achieving UP/C <1.5 g/g and >40% Reduction from Baseline in UP/C at Week 8 in the 400 and 800 mg groups combined
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Investigational medicinal product Active Control
    Number of subjects analysed
    51
    25
    Units: Subjects
        Number of subjects achieving FPRE
    16
    3
    Statistical analysis title
    		 Secondary Endpoint 2
    Comparison groups
    Investigational medicinal product v Active Control
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.092
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Secondary Endpoint 3

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    End point title
    		 Secondary Endpoint 3
    End point description
    Proportion of Subjects Achieving UP/C <1.5 g/g and >40% Reduction from Baseline in UP/C (FPRE) at Week 8 in the 400 mg group
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Investigational medicinal product Active Control
    Number of subjects analysed
    21
    17
    Units: Subjects
        Number of subjects achieving FPRE
    8
    3
    Statistical analysis title
    		 Secondary Endpoint 3
    Comparison groups
    Investigational medicinal product v Active Control
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.282
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Secondary Endpoint 4

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    End point title
    		 Secondary Endpoint 4
    End point description
    Proportion of Subjects Achieving UP/C <1.5 g/g and >40% Reduction from Baseline in UP/C (FPRE) at Week 8 in the 800 mg group
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Investigational medicinal product Active Control
    Number of subjects analysed
    30
    8
    Units: Subjects
        Number of subjects achieving FPRE
    8
    0
    Statistical analysis title
    		 Secondary Endpoint 4
    Comparison groups
    Investigational medicinal product v Active Control
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.164
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Secondary Endpoint 5

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    End point title
    		 Secondary Endpoint 5
    End point description
    Proportion of Subjects Achieving UP/C <1.5 g/g and >40% Reduction from Baseline in UP/C (FPRE) at Week 8 in the 200 mg group
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8
    End point values
    		 Investigational medicinal product Active Control
    Number of subjects analysed
    13
    7
    Units: Subjects
        Number of subjects achieving FPRE
    2
    0
    Statistical analysis title
    		 Secondary Endpoint 5
    Comparison groups
    Investigational medicinal product v Active Control
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.521
    Method
    		 Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Period 1 + Period 2
    Adverse event reporting additional description
    Included all subjects who were randomized and took at least 1 dose of sparsentan during either the Double Blind Period (those randomized to sparsentan in Period 1) or OLE Period (all subjects who entered the OLE [Period 2]) were included in the All Sparsentan Analysis Set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    All Sparsentan Analysis Set
    Reporting group description
    		 The All Sparsentan Analysis Set was included all subjects who were randomized and took at least 1 dose of sparsentan during either the Double Blind Period (those randomized to sparsentan in Period 1) or OLE Period (all subjects who entered the OLE [Period 2]) were included in the All Sparsentan Analysis Set.

    Serious adverse events
    		 All Sparsentan Analysis Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 108 (40.74%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Renal cell carcinoma
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Angiopathy
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    4 / 108 (3.70%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Corona test positive
         subjects affected / exposed
    3 / 108 (2.78%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulse absent
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Jaw fracture
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Perirenal hematoma
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Aortic valve stenosis
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Conduction disorder
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    3 / 108 (2.78%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Anal fistula
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erosive oesophagitis
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Liver injury
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    9 / 108 (8.33%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    End stage renal disease
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Proteinuria
         subjects affected / exposed
    3 / 108 (2.78%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hyperaldosteronism
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone infarction
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Corona virus infection
         subjects affected / exposed
    7 / 108 (6.48%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 108 (2.78%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fluid overload
         subjects affected / exposed
    3 / 108 (2.78%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 108 (1.85%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All Sparsentan Analysis Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    104 / 108 (96.30%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 108 (16.67%)
         occurrences all number
    29
    Hypotension
         subjects affected / exposed
    22 / 108 (20.37%)
         occurrences all number
    37
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 108 (5.56%)
         occurrences all number
    8
    Chest pain
         subjects affected / exposed
    10 / 108 (9.26%)
         occurrences all number
    14
    Fatigue
         subjects affected / exposed
    12 / 108 (11.11%)
         occurrences all number
    15
    Oedema peripheral
         subjects affected / exposed
    29 / 108 (26.85%)
         occurrences all number
    44
    Pyrexia
         subjects affected / exposed
    16 / 108 (14.81%)
         occurrences all number
    19
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 108 (12.04%)
         occurrences all number
    18
    Dyspnoea
         subjects affected / exposed
    8 / 108 (7.41%)
         occurrences all number
    8
    Nasal congestion
         subjects affected / exposed
    10 / 108 (9.26%)
         occurrences all number
    15
    Oropharyngeal pain
         subjects affected / exposed
    11 / 108 (10.19%)
         occurrences all number
    18
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 108 (9.26%)
         occurrences all number
    10
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    17 / 108 (15.74%)
         occurrences all number
    21
    Blood creatine increased
         subjects affected / exposed
    15 / 108 (13.89%)
         occurrences all number
    22
    Coronavirus test positive
         subjects affected / exposed
    6 / 108 (5.56%)
         occurrences all number
    7
    Glomerular filtration rate decreased
         subjects affected / exposed
    11 / 108 (10.19%)
         occurrences all number
    14
    Haemoglobin decreased
         subjects affected / exposed
    7 / 108 (6.48%)
         occurrences all number
    7
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    6 / 108 (5.56%)
         occurrences all number
    8
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    7 / 108 (6.48%)
         occurrences all number
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 108 (16.67%)
         occurrences all number
    27
    Headache
         subjects affected / exposed
    32 / 108 (29.63%)
         occurrences all number
    43
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    18 / 108 (16.67%)
         occurrences all number
    20
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 108 (5.56%)
         occurrences all number
    9
    Abdominal pain upper
         subjects affected / exposed
    6 / 108 (5.56%)
         occurrences all number
    7
    Diarrhoea
         subjects affected / exposed
    25 / 108 (23.15%)
         occurrences all number
    31
    Nausea
         subjects affected / exposed
    25 / 108 (23.15%)
         occurrences all number
    35
    Vomiting
         subjects affected / exposed
    18 / 108 (16.67%)
         occurrences all number
    29
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    7 / 108 (6.48%)
         occurrences all number
    9
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    14 / 108 (12.96%)
         occurrences all number
    19
    Proteinuria
         subjects affected / exposed
    15 / 108 (13.89%)
         occurrences all number
    20
    Renal impairment
         subjects affected / exposed
    6 / 108 (5.56%)
         occurrences all number
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 108 (12.96%)
         occurrences all number
    21
    Back pain
         subjects affected / exposed
    13 / 108 (12.04%)
         occurrences all number
    14
    Flank pain
         subjects affected / exposed
    6 / 108 (5.56%)
         occurrences all number
    6
    Muscle spasms
         subjects affected / exposed
    11 / 108 (10.19%)
         occurrences all number
    13
    Musculoskeletal pain
         subjects affected / exposed
    6 / 108 (5.56%)
         occurrences all number
    7
    Myalgia
         subjects affected / exposed
    6 / 108 (5.56%)
         occurrences all number
    6
    Osteoarthritis
         subjects affected / exposed
    6 / 108 (5.56%)
         occurrences all number
    7
    Pain in extremity
         subjects affected / exposed
    10 / 108 (9.26%)
         occurrences all number
    15
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    7 / 108 (6.48%)
         occurrences all number
    10
    Cellulitis
         subjects affected / exposed
    6 / 108 (5.56%)
         occurrences all number
    6
    Corona virus infection
         subjects affected / exposed
    11 / 108 (10.19%)
         occurrences all number
    12
    Influenza
         subjects affected / exposed
    9 / 108 (8.33%)
         occurrences all number
    10
    Nasopharyngitis
         subjects affected / exposed
    12 / 108 (11.11%)
         occurrences all number
    21
    Sinusitis
         subjects affected / exposed
    9 / 108 (8.33%)
         occurrences all number
    12
    Upper respiratory tract infection
         subjects affected / exposed
    15 / 108 (13.89%)
         occurrences all number
    40
    Urinary tract infection
         subjects affected / exposed
    10 / 108 (9.26%)
         occurrences all number
    21
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    6 / 108 (5.56%)
         occurrences all number
    7
    Gout
         subjects affected / exposed
    11 / 108 (10.19%)
         occurrences all number
    22
    Hyperkalaemia
         subjects affected / exposed
    21 / 108 (19.44%)
         occurrences all number
    40
    Metabolic acidosis
         subjects affected / exposed
    10 / 108 (9.26%)
         occurrences all number
    11
    Vitamin D deficiency
         subjects affected / exposed
    6 / 108 (5.56%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jul 2012
    Amendment 1
    11 Jul 2013
    Amendment 2
    20 Sep 2013
    Amendment 3
    25 Nov 2013
    Amendment 4
    21 May 2014
    Amendment 5
    22 Dec 2014
    Amendment 6
    05 Dec 2016
    Amendment 7
    20 Dec 2017
    Amendment 8
    24 Oct 2018
    Amendment 9
    25 Jul 2019
    Amendment 10
    27 Feb 2020
    Amendment 11
    01 Nov 2021
    Amendment 12

    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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    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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