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    Clinical Trial Results:
    DP13 – A Phase II Study in Patients with Primary Aldosteronism to Evaluate the Efficacy, Safety and Tolerability of the Aldosterone Synthase Inhibitor, DP13, over an 8-week Treatment Period

    Summary
    EudraCT number
    		 2019-000919-85
    Trial protocol
    		 NL   IT  
    Global end of trial date
    02 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Dec 2023
    First version publication date
    21 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DP13C201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04007406
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    DAMIAN Pharma AG
    Sponsor organisation address
    Haltli 6, Walchwil, Switzerland, 6318
    Public contact
    Teresa Gerlock, DAMIAN Pharma AG, 041 0616010978, teresa.gerlock@damianpharma.com
    Scientific contact
    Christoph Schumacher, DAMIAN Pharma AG, 041 0616010978, christoph.schumacher@damianpharma.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
    11 Jan 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    02 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To determine the efficacy of daily oral dexfadrostat phosphate (DP13) treatment (all dose arms combined) to decrease the plasma aldosterone-to-renin ratio (ARR) from baseline in patients with primary aldosteronism (PA) following 8 weeks of treatment • To determine the efficacy of daily oral dexfadrostat phosphate (DP13) treatment (all dose arms combined) to reduce 24-hour ambulatory systolic blood pressure (aSBP) from baseline in patients with primary aldosteronism (PA) following 8 weeks of treatment
    Protection of trial subjects
    The study was conducted in compliance with the study protocol, the recommendations on biomedical research on human subjects of the Declaration of Helsinki, International Conference of Harmonization (ICH)--Good Clinical Practice (GCP) Guidelines (ICH E6 (R2)), and all applicable laws and regulations. Agreement to adhere to the protocol was established by Investigators signing and returning the protocol signature page. Patient identities were kept confidential by assigning each patient a unique identifier consisting of a patient-specific numeric code, which was used throughout the study instead of the patient's name. All study sites received the approval of the local Ethics Committee. Additionally, patients were treated to routine care by the site investigator/physician. All patients were explained the nature and purpose of the study, the participation conditions and the risks and benefits to the patients before signing and dating the informed consent form.
    Background therapy
    		 In order to prevent uncontrolled hypertension during the study, a fixed-dose regimen of doxazosin (1-8 mg QD), as first-line medication and, if necessary, verapamil slow release (40-120 mg BID) or diltiazem (slow release 90-360 mg daily) or amlodipine (2.5-10 mg QD) was implemented if clinically applicable 2 weeks prior to eligibility verification. Exceptionally, a calcium channel blocker could be used as first-line treatment if medically justified. Patients were not to take diagnosis-interfering medications as listed in the Endocrine Society Clinical Practice Guidelines (e.g., ACEi, ARB) for the duration of the study. Recently diagnosed patients on spironolactone were required to be washed out at least 8 weeks prior to study entry.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Sep 2019
    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
    Netherlands: 2
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Switzerland: 10
    Worldwide total number of subjects
    35
    EEA total number of subjects
    25
    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)
    35
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited as 'de novo' i.e., diagnosed with PA within 10 weeks of study entry or as 'recently diagnosed' i.e., diagnosed between 10 weeks and 1 year prior to study entry.

    Pre-assignment
    Screening details
    		 Patient screening ARR and blood pressure were reviewed and approved by the Eligibility Review Panel prior to enrolling in the study. A suppression test also needed to be performed prior to study entry to confirm diagnosis of PA. Patients underwent a 2-week placebo run-in prior to randomization.

    Pre-assignment period milestones
    Number of subjects started
    		 35
    Number of subjects completed
    		 35

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    IMP-containing jars were labeled/packed according to SOP based on the randomization list. The following controls were employed to maintain blinding: 1. Placebo capsules for the run-in period were identical in appearance to the DP13 capsules 2. The investigator and other members of staff involved in the study remained blinded to the treatment randomization code 3. Interim bioanalytical/hemodynamic data were provided to the central lab in a blinded manner Emergency unblinding was possible

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Baseline
    Arm description
    		 Prior to active treatment but following 2-weeks single-blind placebo run-in
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Active treatment
    Arm description
    		 Values after 8 weeks of dexfadrostat phosphate treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    dexfadrostat phosphate
    Investigational medicinal product code
    Other name
    DP13
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily, before meals

    Number of subjects in period 1
    		Baseline Active treatment
    Started
    35
    35
    Completed
    35
    35

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 35 35
    Age categorical
    adults
    Units: Subjects
        Adults (18-64 years)
    		 35 35
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52 ± 9 -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 26 26
    Race
    Units: Subjects
        White
    		 32 32
        Black or African American
    		 2 2
        Asian
    		 1 1
    Body mass index
    Vital signs at baseline all dose groups combined
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 28 ± 3.5 -
    Office systolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 148 ± 12 -
    Potassium
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 3.5 ± 0.4 -
    Office diastolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 92 ± 10 -
    24-hour ambulatory systolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 143 ± 14 -
    Aldosterone-to-renin ratio
    Units: ng*L/d?*mU
        arithmetic mean (standard deviation)
    		 17.6 ± 15 -
    24-hour ambulatory diastolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 88 ± 8 -
    Subject analysis sets

    Subject analysis set title
    Baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Baseline values after 2 weeks of placebo run-in

    Subject analysis set title
    DP13 active treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Values following 8 weeks of once daily treatment with dexfadrostat phosphate

    Subject analysis sets values
    		 Baseline DP13 active treatment
    Number of subjects
    35
    35
    Age categorical
    adults
    Units: Subjects
        Adults (18-64 years)
    35
    35
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    52 ± 9
    52 ± 9
    Gender categorical
    Units: Subjects
        Female
    9
    9
        Male
    26
    26
    Race
    Units: Subjects
        White
    32
    32
        Black or African American
    2
    2
        Asian
    1
    1
    Body mass index
    Vital signs at baseline all dose groups combined
    Units: kg/m2
        arithmetic mean (standard deviation)
    28 ± 3.5
    28 ± 3.5
    Office systolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    148 ± 12
    148 ± 12
    Potassium
    Units: mmol/L
        arithmetic mean (standard deviation)
    3.5 ± 0.4
    3.5 ± 0.4
    Office diastolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    92 ± 10
    92 ± 10
    24-hour ambulatory systolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    143 ± 14
    143 ± 14
    Aldosterone-to-renin ratio
    Units: ng*L/d?*mU
        arithmetic mean (standard deviation)
    17.6 ± 15
    17.6 ± 15
    24-hour ambulatory diastolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    88 ± 8
    88 ± 8

    End points

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    End points reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 Prior to active treatment but following 2-weeks single-blind placebo run-in

    Reporting group title
    Active treatment
    Reporting group description
    		 Values after 8 weeks of dexfadrostat phosphate treatment

    Subject analysis set title
    Baseline
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Baseline values after 2 weeks of placebo run-in

    Subject analysis set title
    DP13 active treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Values following 8 weeks of once daily treatment with dexfadrostat phosphate

    Primary: 24-hour ambulatory systolic blood pressure (SBP)

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    End point title
    		 24-hour ambulatory systolic blood pressure (SBP)
    End point description
    End point type
    Primary
    End point timeframe
    Change from baseline to end of active treatment (8 weeks) in ambulatory SBP
    End point values
    		 Baseline Active treatment Baseline DP13 active treatment
    Number of subjects analysed
    35
    35
    35
    35
    Units: mm Hg
        arithmetic mean (standard deviation)
    143 ± 14
    132 ± 13
    143 ± 14
    132 ± 13
    Statistical analysis title
    		 24-hour ambulatory SBP
    Statistical analysis description
    Change in mean 24-hour ambulatory systolic blood pressure (SBP) from baseline to the end of the 8-week DP13 treatment period for all dose arms combined
    Comparison groups
    Baseline v DP13 active treatment
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Primary: Aldosterone-to-renin ratio (ARR)

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    End point title
    		 Aldosterone-to-renin ratio (ARR)
    End point description
    End point type
    Primary
    End point timeframe
    Change from baseline to end of active treatment (8 weeks), all dose groups combined
    End point values
    		 Baseline Active treatment
    Number of subjects analysed
    35
    35
    Units: ng*L/dL*mU
        arithmetic mean (standard deviation)
    17.6 ± 15
    2.2 ± 3.3
    Statistical analysis title
    		 Aldosterone-to-renin ratio (ARR)
    Statistical analysis description
    Change in plasma ARR from baseline to the end of the 8-week DP13 treatment period for al dose arms combined
    Comparison groups
    Active treatment v Baseline
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Potassium

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    End point title
    		 Potassium
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to end of active treatment (8 weeks)
    End point values
    		 Baseline Active treatment Baseline DP13 active treatment
    Number of subjects analysed
    35
    35
    35
    35
    Units: mmol/L
        arithmetic mean (standard deviation)
    3.5 ± 0.4
    4.0 ± 0.3
    3.5 ± 0.4
    4.0 ± 0.3
    Statistical analysis title
    		 Plasma potassium
    Statistical analysis description
    Change in plasma potassium concentration from baseline to the end of the 8-week DP13 treatment period
    Comparison groups
    Baseline v DP13 active treatment
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Other pre-specified: 24-hour ambulatory diastolic blood pressure (aDBP)

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    End point title
    		 24-hour ambulatory diastolic blood pressure (aDBP)
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Change from baseline to the end of the 8-week DP13 treatment period, all dose groups combined
    End point values
    		 Baseline Active treatment
    Number of subjects analysed
    35
    35
    Units: mm Hg
        arithmetic mean (standard deviation)
    88 ± 8
    82 ± 7
    Statistical analysis title
    		 4-hour ambulatory diastolic blood pressure (aDBP)
    Statistical analysis description
    Change in mean 24-hour ambulatory DBP from baseline to the end of DP13 treatment period (8 weeks)
    Comparison groups
    Baseline v Active treatment
    Number of subjects included in analysis
    70
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected throughout the study including during the placebo run-in and withdrawal phases.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Safety analysis set
    Reporting group description
    		 All randomized patients who received at least one dose of active study drug

    Serious adverse events
    		 Safety analysis set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 35 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Safety analysis set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 35 (45.71%)
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Blood pressure diastolic increased
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Blood pressure increased
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 35 (11.43%)
         occurrences all number
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Dental caries
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    2 / 35 (5.71%)
         occurrences all number
    2
    Duodenitis
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Gastroesophageal reflux
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Breast tenderness
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Polymenorrhoea
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Renal and urinary disorders
    Cystitis
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Renal colic
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 35 (2.86%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36914591
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