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    Clinical Trial Results:
    Single-center, randomized, double-blind, placebo-controlled clinical trial for the safety, tolerability and efficacy of ularitide in cirrhosis patients with refractory ascites.

    Summary
    EudraCT number
    		 2019-002268-28
    Trial protocol
    		 DK  
    Global end of trial date
    14 Dec 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jul 2024
    First version publication date
    15 Jul 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ULA04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04311489
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark, 8200
    Public contact
    Clinical Trials Information, Department of Hepatology and Gastroenterology, Aarhus University Hospital, henngroe@rm.dk
    Scientific contact
    Clinical Trials Information, Department of Hepatology and Gastroenterology, Aarhus University Hospital, henngroe@rm.dk
    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
    Interim
    Date of interim/final analysis
    28 Nov 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Nov 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To investigate the safety, tolerability and efficacy of ularitide on the renal response in patients with liver cirrhosis and refractory ascites (as defined in this protocol) for a maximum exposure duration of 48 hours, through a randomized, placebo-controlled, double-blind, single-center clinical trial.
    Protection of trial subjects
    Standard of care and treatment during hospitalization at a highly specialized hepatology department.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2020
    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
    Denmark: 17
    Worldwide total number of subjects
    17
    EEA total number of subjects
    17
    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)
    7
    From 65 to 84 years
    9
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Single-center study at the Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark. Participants were recruited from August 2020 to November 2022.

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 19 [1]
    Intermediate milestone: Number of subjects
    Included: 19
    Intermediate milestone: Number of subjects
    Randomized: 17
    Number of subjects completed
    		 17

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Adverse event, serious fatal: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 2 patients were included but failed to reach the stage of randomization.
    Period 1
    Period 1 title
    Hospitalization for treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ularitide
    Arm description
    		 Active treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ularitide
    Investigational medicinal product code
    Other name
    Urodilatin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The first eight participants were treated with a starting dose of 30 ng/kg/min with a possibility for a dose increase to 45 ng/kg/min or a reduction to 15 ng/kg/min. The last nine participants were treated with a dosing regimen reduced by one-third compared with the original regimen, i.e., a starting dose of 20 ng/kg/min, a possible dose increase to 30 ng/kg/min, and a safety dose reduction to 10 ng/kg/min.

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Ularitide
    Investigational medicinal product code
    Other name
    Urodilatin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The first eight participants were treated with a starting dose of 30 ng/kg/min with a possibility for a dose increase to 45 ng/kg/min or a reduction to 15 ng/kg/min. The last nine participants were treated with a dosing regimen reduced by one-third compared with the original regimen, i.e., a starting dose of 20 ng/kg/min, a possible dose increase to 30 ng/kg/min, and a safety dose reduction to 10 ng/kg/min.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo consists of mannitol and is supplied as a lyophilized powder. Reconstitution and dissolution in sterile saline is identical to the active treatment.

    Number of subjects in period 1
    		Ularitide Placebo
    Started
    11
    6
    Baseline
    11
    6
    2 hours treatment
    11
    6
    4 hours treatment
    11
    6
    24 hours treatment
    10 [2]
    6
    48 hours treatment
    1 [3]
    3 [4]
    4 hours post-treatment follow-up
    11
    6
    Completed
    11
    6
    Notes
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not an issue.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not an issue.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Not an issue.
    Period 2
    Period 2 title
    30 day follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ularitide
    Arm description
    		 Active treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ularitide
    Investigational medicinal product code
    Other name
    Urodilatin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The first eight participants were treated with a starting dose of 30 ng/kg/min with a possibility for a dose increase to 45 ng/kg/min or a reduction to 15 ng/kg/min. The last nine participants were treated with a dosing regimen reduced by one-third compared with the original regimen, i.e., a starting dose of 20 ng/kg/min, a possible dose increase to 30 ng/kg/min, and a safety dose reduction to 10 ng/kg/min.

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Ularitide
    Investigational medicinal product code
    Other name
    Urodilatin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The first eight participants were treated with a starting dose of 30 ng/kg/min with a possibility for a dose increase to 45 ng/kg/min or a reduction to 15 ng/kg/min. The last nine participants were treated with a dosing regimen reduced by one-third compared with the original regimen, i.e., a starting dose of 20 ng/kg/min, a possible dose increase to 30 ng/kg/min, and a safety dose reduction to 10 ng/kg/min.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo consists of mannitol and is supplied as a lyophilized powder. Reconstitution and dissolution in sterile saline is identical to the active treatment.

    Number of subjects in period 2
    		Ularitide Placebo
    Started
    11
    6
    Completed
    11
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ularitide
    Reporting group description
    		 Active treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 Ularitide Placebo Total
    Number of subjects
    		 11 6 17
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 70 (60 to 77) 55 (53 to 68) -
    Gender categorical
    Units: Subjects
        Female
    		 4 2 6
        Male
    		 7 4 11
    Cirrhosis etiologies
    Units: Subjects
        Alcohol
    		 6 4 10
        MAFLD
    		 1 0 1
        Alcohol + MAFLD
    		 1 1 2
        PSC
    		 1 0 1
        Toxic
    		 1 0 1
        Budd-Chiari
    		 0 1 1
        Cryptogenic
    		 1 0 1
    Refractory ascites characteristics
    Units: Subjects
        Diuretic-intractable
    		 8 4 12
        Diuretic-resistant
    		 3 2 5
    Height
    Units: centimetre
        median (inter-quartile range (Q1-Q3))
    		 174 (163 to 178) 174 (170 to 174) -
    Body weight
    Units: kilogram(s)
        median (inter-quartile range (Q1-Q3))
    		 78 (63 to 85) 73 (68 to 83) -
    Cirrhosis debut
    Time since debut of cirrhosis
    Units: months
        median (inter-quartile range (Q1-Q3))
    		 25 (9 to 47) 24 (9 to 65) -
    Ascites debut
    Time since debut of ascites
    Units: months
        median (inter-quartile range (Q1-Q3))
    		 20 (4 to 47) 27 (9 to 65) -
    Refractory ascites debut
    Time since debut of refractory ascites
    Units: months
        median (inter-quartile range (Q1-Q3))
    		 5 (2 to 6) 7 (6 to 12) -
    Systolic blood pressure
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 116 (106 to 135) 111 (102 to 123) -
    Diastolic blood pressure
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 66 (54 to 79) 69 (62 to 78) -
    Heart rate
    Units: beats/min
        median (inter-quartile range (Q1-Q3))
    		 85 (66 to 93) 82 (76 to 94) -
    P-albumin
    Units: gram(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 30 (29 to 30) 27 (22 to 30) -
    P-bilirubin
    Units: micromole(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 23 (16 to 60) 22 (14 to 33) -
    P-ALAT
    alanine aminotransferase
    Units: U/l
        median (inter-quartile range (Q1-Q3))
    		 24 (18 to 62) 30 (14 to 45) -
    P-alkaline phosphatase
    Units: U/l
        median (inter-quartile range (Q1-Q3))
    		 154 (102 to 256) 135 (115 to 220) -
    INR
    international normalized ratio
    Units: ratio
        median (inter-quartile range (Q1-Q3))
    		 1.3 (1.3 to 1.5) 1.3 (1.2 to 1.6) -
    P-sodium
    Units: millimole(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 133 (129 to 135) 130 (123 to 132) -
    P-potassium
    Units: millimole(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 4.2 (3.9 to 4.4) 4.6 (3.8 to 5.2) -
    P-creatinine
    Units: micromole(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 103 (77 to 118) 100 (61 to 117) -
    B-platelets
    Units: x10^9
        median (inter-quartile range (Q1-Q3))
    		 97 (85 to 186) 227 (74 to 326) -
    B-hemoglobin
    Units: millimole(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 6.9 (6.2 to 8.1) 6.8 (6.4 to 7.0) -
    Child-Pugh score
    Units: points
        median (inter-quartile range (Q1-Q3))
    		 8 (8 to 10) 9 (8 to 10) -
    MELD-Na
    Model for end-stage liver disease with sodium
    Units: points
        median (inter-quartile range (Q1-Q3))
    		 21 (14 to 26) 23 (21 to 29) -
    MELD 3.0
    model for end-stage liver disease version 3.0
    Units: points
        median (inter-quartile range (Q1-Q3))
    		 18 (14 to 21) 21 (17 to 22) -
    P-renin
    Units: x10^-3 IU/l
        median (inter-quartile range (Q1-Q3))
    		 550 (183 to 550) 550 (240 to 550) -
    P-aldosterone
    Units: pmol/l
        median (inter-quartile range (Q1-Q3))
    		 3432 (2388 to 9777) 8532 (3533 to 9781) -
    U-sodium
    urine
    Units: millimole(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 16 (10 to 27) 13 (9 to 17) -
    U-sodium excretion rate
    urine
    Units: mmol/day
        median (inter-quartile range (Q1-Q3))
    		 24 (9 to 37) 11 (9 to 35) -
    U-potassium
    urine
    Units: millimole(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 32 (23 to 46) 32 (24 to 41) -
    U-potassium excretion rate
    urine
    Units: mmol/day
        median (inter-quartile range (Q1-Q3))
    		 32 (26 to 44) 39 (12 to 57) -
    U-creatinine
    urine
    Units: millimole(s)/litre
        median (inter-quartile range (Q1-Q3))
    		 6.7 (4.4 to 9.2) 7.5 (6.4 to 10.3) -
    U-creatinine excretion rate
    urine
    Units: mmol/day
        median (inter-quartile range (Q1-Q3))
    		 7.1 (4.6 to 8.3) 7.0 (6.2 to 7.7) -
    GFR-24h-creatinine-clearance
    Units: millilitre(s)/minute
        median (inter-quartile range (Q1-Q3))
    		 40 (27 to 69) 49 (39 to 75) -
    U-albumin
    urine
    Units: mg/day
        median (inter-quartile range (Q1-Q3))
    		 3 (2 to 7) 3 (2 to 4) -
    P-copeptin
    Precursor of vasopressin
    Units: pmol/l
        median (inter-quartile range (Q1-Q3))
    		 27.1 (14.1 to 35.6) 24.4 (19.6 to 52.5) -

    End points

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    End points reporting groups
    Reporting group title
    Ularitide
    Reporting group description
    		 Active treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo
    Reporting group title
    Ularitide
    Reporting group description
    		 Active treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Primary: Absolute urine production

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    End point title
    		 Absolute urine production
    End point description
    Change in urine volume production at 24 hours post infusion start versus baseline
    End point type
    Primary
    End point timeframe
    24 hours
    End point values
    		 Ularitide Placebo
    Number of subjects analysed
    10
    6
    Units: ml/h
        arithmetic mean (confidence interval 95%)
    -24.7 (-52.3 to 3.0)
    6.2 (-17.6 to 30.0)
    Attachments
    		 Untitled (Filename: Figure 1 - paper.jpg)
    Statistical analysis title
    		 Between-group analyses
    Comparison groups
    Ularitide v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    30.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 68.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    17.5
    Statistical analysis title
    		 Within-group: Ularitide
    Comparison groups
    Ularitide v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    P-value
    		 = 0.04
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -24.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -52.3
         upper limit
    		 3
    Variability estimate
    Standard error of the mean
    Dispersion value
    12.2
    Notes
    [1] - paired t-test

    Primary: Absolute renal sodium excretion rate

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    End point title
    		 Absolute renal sodium excretion rate
    End point description
    Change in renal sodium excretion rate at 24 hours post infusion start versus baseline
    End point type
    Primary
    End point timeframe
    24 hours
    End point values
    		 Ularitide Placebo
    Number of subjects analysed
    10
    6
    Units: micromoles/min
        arithmetic mean (confidence interval 95%)
    -21.8 (-61.9 to 18.4)
    3.3 (-7.0 to 13.7)
    Statistical analysis title
    		 Between-group analyses
    Comparison groups
    Ularitide v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.1
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    25.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.5
         upper limit
    		 65.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.2
    Notes
    [2] - unequal variance
    Statistical analysis title
    		 Within-group: Ularitide
    Comparison groups
    Ularitide v Placebo
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    P-value
    		 = 0.13
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -21.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -61.9
         upper limit
    		 18.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    17.8
    Notes
    [3] - paired t-test

    Primary: Absolute body weight reduction

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    End point title
    		 Absolute body weight reduction
    End point description
    Change of absolute body weight at the end of treatment versus baseline
    End point type
    Primary
    End point timeframe
    End of treatment; most patients recieved 24 hours of treatment.
    End point values
    		 Ularitide Placebo
    Number of subjects analysed
    11
    6
    Units: kilogram(s)
        arithmetic mean (confidence interval 95%)
    -0.98 (-1.61 to -0.35)
    -1.28 (-2.74 to 0.17)
    Statistical analysis title
    		 Between-group analyses
    Comparison groups
    Ularitide v Placebo
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 1.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.56

    Primary: Number of treatment responders

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    End point title
    		 Number of treatment responders [4]
    End point description
    Responder as predefined in the study protocol.
    End point type
    Primary
    End point timeframe
    During the whole treatment course
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: A statistical analysis is irrelevant here.
    End point values
    		 Ularitide Placebo
    Number of subjects analysed
    11
    6
    Units: number
        Responder
    3
    3
        Non-responder
    8
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to post-treatment follow-up (de facto while hospitalized). SAE's were collected from inclusion until the 30-day follow-up visit.
    Adverse event reporting additional description
    All adverse events were collected and reported by study investigators. The incidence of stopping criteria leading to a dose reduction was higher in ularitide than placebo (p = 0.043). The incidence rate of adverse reactions was higher in ularitide than placebo, with an IRR of 8.5 (95% CI: 2.0 – 35, p = 0.003).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Ularitide
    Reporting group description
    		 Active treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 Ularitide Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 11 (36.36%)
    5 / 6 (83.33%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Haemoconcentration
    Additional description: Hemoconcentration (10019479)
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
    Additional description: Hypotension (10021097)
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
    Additional description: Upper abdominal discomfort (10067000)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
    Additional description: Hemoptysis (10019523)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Decompensated cirrhosis
    Additional description: Decompensated cirrhosis (10064704)
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    Peritonitis bacterial
    Additional description: Spontaneous bacterial peritonitis (10061135)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Pneumonia (10035664)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
    Additional description: Infection (10021789)
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
    Additional description: Hyperkalaemia (10020646)
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Ularitide Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 11 (100.00%)
    3 / 6 (50.00%)
    Cardiac disorders
    Hypotension
    Additional description: Blood pressure systolic low (10005763)
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Tachycardia
    Additional description: Tachycardia (10043071)
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Presyncope
    Additional description: Pre-syncope (10036507)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Syncope
    Additional description: Syncope (10042772)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Headache
    Additional description: Headaches (10019231)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Haemoglobin decreased
    Additional description: Hemoglobin low (10055600)
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Dizziness
    Additional description: Dizziness (10013573)
         subjects affected / exposed
    6 / 11 (54.55%)
    0 / 6 (0.00%)
         occurrences all number
    7
    0
    Gastrointestinal disorders
    Vomiting
    Additional description: Vomiting (10047700)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 11 (54.55%)
    0 / 6 (0.00%)
         occurrences all number
    8
    0
    Nausea
    Additional description: Nausea and vomiting symptoms (10028817)
         subjects affected / exposed
    3 / 11 (27.27%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Appetite disorder
    Additional description: Appetite suppressed (10003030)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Diarrhoea
    Additional description: Diarrhoea (10012735)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatic enzyme increased
    Additional description: Hepatic enzyme increased (10060795)
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Albuminuria
    Additional description: Albuminuria (10001580)
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Creatinine renal clearance increased
    Additional description: Creatinine blood increased (10011361)
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Muscle pain
    Additional description: Muscle pains (10028323)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
    Additional description: Muscle spasms (10028334)
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hyperkalaemia
    Additional description: Hyperkalaemia (10020646)
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Sep 2021
    After treatment of the first eight participants: A high rate of hypotensive episodes was observed, likely influencing the renal efficacy measures. The overall treatment algorithm persisted but with all three dose steps reduced by one-third and incorporation of safety precautions at each status time point to supplement the efficacy criteria determining a dose increase.
    21 Nov 2022
    After treatment of the first 17 participants: The study investigators observed a persistent high level of adverse reactions and had a clinical impression of sparse renal effects regardless of the new dose regimen. Therefore, a hired external biostatistician performed an unblinded interim analysis to determine if further reduction of the dose scheme or trial termination should be performed.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    14 Dec 2022
    After completing 17 participants, the interim analysis demonstrated that ularitide was neither safe nor better than placebo as a treatment of refractory cirrhotic ascites with the setup and doses used. Therefore, the trial was terminated and unblinded to permit further investigations of the efficacy endpoints and safety measures, as well as subgroup analysis on the different dose regimens.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/38934679
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