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    Clinical Trial Results:
    An Open-label Extension Study of UT-15C in Subjects with Pulmonary Arterial Hypertension - A Long-term Follow-up to Protocol TDE PH-310

    Summary
    EudraCT number
    		 2012-000098-21
    Trial protocol
    		 GB   DE   NL   AT   FR   IT   SE   BE   DK   GR   PL  
    Global end of trial date
    12 Aug 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Jun 2022
    First version publication date
    08 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TDE-PH-311
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01560637
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    United Therapeutics Corporation
    Sponsor organisation address
    55 TW Alexander Dr, Research Triangle Park, United States, 27709
    Public contact
    Global Medical Information, United Therapeutics Global Medical Information, 1 919-485-8350, clinicaltrials@unither.com
    Scientific contact
    Regulatory Department, United Therapeutics Regulatory Department, 1 919-485-8350, RTPRegulatory@unither.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
    02 Feb 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Aug 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Aug 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to provide UT-15C extended-release tablets for eligible subjects who participated in TDE-PH-310 (A Phase III, International, Multi-center, Randomized, Double-blind, Placebo-controlled, Clinical Worsening Study of UT-15C in Subjects with Pulmonary Arterial Hypertension Receiving Background Oral Monotherapy).
    Protection of trial subjects
    The study protocol, protocol amendments, and Informed Consent Forms (ICFs) were submitted for review and approval to each site’s Institutional Review Board (IRB) or Independent Ethics Committee (IEC). The IRBs/IECs were organized and functioned in accordance with the US Code of Federal Regulations (CFR; Title 21 CFR, Part 56) and/or applicable local regulations. This study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and the International Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP) guidance. Each subject enrolled in the study was provided with information related to the clinical study, including specifics related to subject participation. This was documented in a written ICF that was approved by the same IRB/IEC responsible for approval of the protocol at the clinical study site. Each ICF included the elements required by the Food and Drug Administration regulations in 21 CFR Part 50. Informed consent was obtained from each subject prior to initiating any study-specific procedures in accordance with Title 21 CFR, Part 50 and ICH E6 GCP guidance. A copy of the signed ICF was given to the subject and the original was retained in the study site’s records.
    Background therapy
    		 Subjects could receive a PDE5-I or an sGC stimulator or an ERA as background PAH therapy.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    China: 128
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Brazil: 40
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Chile: 14
    Country: Number of subjects enrolled
    India: 31
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Mexico: 76
    Country: Number of subjects enrolled
    Singapore: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Country: Number of subjects enrolled
    Taiwan: 20
    Country: Number of subjects enrolled
    United States: 48
    Worldwide total number of subjects
    470
    EEA total number of subjects
    44
    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)
    398
    From 65 to 84 years
    72
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects participated in the parent study, TDE-PH-310, and met the definition of clinical worsening (as specified in TDE-PH-310), remained on study drug, was compliant with study procedures and assessments during TDE-PH-310, or was currently enrolled in that study at the time the study was discontinued by the Sponsor.

    Pre-assignment
    Screening details
    		 To have been eligible for the present TDE-PH-311, participants in TDE-PH-310 either 1) met the definition of clinical worsening (as specified in the TDE PH 310 protocol), and remained on study drug while compliant with study procedures and assessments during TDE PH 310, or 2) were enrolled in that study at the time it was discontinued

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 UT-15C
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Treprostinil diolamine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once all entry criteria were met, placebo- or oral treprostinil-treated subjects from TDE PH 310 were administered oral treprostinil as follows. For subjects who received placebo in TDE-PH-310, dosing of oral treprostinil in TDE-PH-311 was initiated and optimized as in that study, including all safety monitoring and telephone contact. That is, the first dose of oral treprostinil (0.125 mg) was taken at the site by the subject immediately (~10 minutes) after consuming food. Oral dosing of treprostinil continued at 0.125 mg TID (every 6 to 8 hours) immediately after consuming food. Subjects were instructed to take the appropriate number of tablets based upon their prescribed dose. During the first 4 weeks, each dose of oral treprostinil was adjusted in 0.125-mg increments no more than every 24 hours as clinically indicated. Subsequent doses could be adjusted in 0.125- or 0.25-mg increments every 24 hours as necessary to achieve the optimal clinical response. No maximum dose.

    Number of subjects in period 1
    		UT-15C
    Started
    470
    Completed
    272
    Not completed
    198
         Adverse event, serious fatal
    69
         Consent withdrawn by subject
    24
         Adverse event, non-fatal
    63
         Progressive Disease
    20
         Lost to follow-up
    8
         Reason not Specified
    6
         Protocol deviation
    8

    Baseline characteristics

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

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 470 470
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 398 398
        From 65-84 years
    		 72 72
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.2 ( 15.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 374 374
        Male
    		 96 96
    Etiology of PAH
    Units: Subjects
        Idiopathic/Heritable PAH
    		 299 299
        Collagen Vascular Disease
    		 114 114
        HIV Infection
    		 8 8
        Congenital Heart Defect
    		 38 38
        Other
    		 11 11
    Background PAH Therapy at Randomization in Parent Study
    Units: Subjects
        PDE5-I Alone or sGC Stimulator Alone
    		 348 348
        ERA Alone
    		 122 122
    6MWD Category at Baseline
    Units: Subjects
        ≤440 meters
    		 286 286
        >440 m
    		 176 176
        Not Applicable
    		 8 8
    WHO Functional Class at Baseline
    Units: Subjects
        WHO FC I
    		 41 41
        WHO FC II
    		 226 226
        WHO FC III
    		 182 182
        WHO FC IV
    		 21 21
    6MWD at Baseline
    Units: meters
        arithmetic mean (standard deviation)
    		 392.0 ( 128.1 ) -
    Time since PAH Diagnosis
    Units: years
        arithmetic mean (standard deviation)
    		 3.16 ( 2.69 ) -
    Subject analysis sets

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received oral treprostinil in TDE-PH-311 are included in the Safety Population

    Subject analysis sets values
    		 Safety Population
    Number of subjects
    470
    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)
    398
        From 65-84 years
    72
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    47.2 ( 15.1 )
    Gender categorical
    Units: Subjects
        Female
    374
        Male
    96
    Etiology of PAH
    Units: Subjects
        Idiopathic/Heritable PAH
    299
        Collagen Vascular Disease
    114
        HIV Infection
    8
        Congenital Heart Defect
    38
        Other
    11
    Background PAH Therapy at Randomization in Parent Study
    Units: Subjects
        PDE5-I Alone or sGC Stimulator Alone
    348
        ERA Alone
    122
    6MWD Category at Baseline
    Units: Subjects
        ≤440 meters
    286
        >440 m
    176
        Not Applicable
    WHO Functional Class at Baseline
    Units: Subjects
        WHO FC I
    41
        WHO FC II
    226
        WHO FC III
    182
        WHO FC IV
    21
    6MWD at Baseline
    Units: meters
        arithmetic mean (standard deviation)
    392.0 ( 128.1 )
    Time since PAH Diagnosis
    Units: years
        arithmetic mean (standard deviation)
    3.16 ( 2.69 )

    End points

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    End points reporting groups
    Reporting group title
    UT-15C
    Reporting group description
    		 -

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received oral treprostinil in TDE-PH-311 are included in the Safety Population

    Primary: Continued access

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    End point title
    		 Continued access
    End point description
    The primary objective of this study was to provide or continue to provide oral treprostinil extended-release tablets for eligible subjects who participated in TDE-PH-310.
    End point type
    Primary
    End point timeframe
    From Baseline to EOS
    End point values
    		 UT-15C Safety Population
    Number of subjects analysed
    470
    470
    Units: n (%)
    number (not applicable)
        Received Oral Treprostinil in TDE-PH-310
    212
    212
        Received Placebo in TDE-PH-311
    258
    258
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    Data is summarized in tables and listings only.
    Comparison groups
    UT-15C v Safety Population
    Number of subjects included in analysis
    940
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0
    Method
    		 NA
    Parameter type
    		 NA
    Point estimate
    0
    Confidence interval
         level
    		 0%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 100
    Notes
    [1] - No statistical analyses were performed. Data summarized in tables and listings only.

    Secondary: 6MWD

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    End point title
    		 6MWD
    End point description
    Change in 6MWD from Baseline to Week 48
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 UT-15C Safety Population
    Number of subjects analysed
    341
    341
    Units: meters
        arithmetic mean (standard deviation)
    20.1 ( 79.6 )
    20.1 ( 79.6 )
    No statistical analyses for this end point

    Secondary: Borg Dyspnea Score

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    End point title
    		 Borg Dyspnea Score
    End point description
    Change in Borg Dyspnea Score from Baseline to Week 48
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 UT-15C Safety Population
    Number of subjects analysed
    341
    341
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    -0.49 ( 1.92 )
    -0.49 ( 1.92 )
    No statistical analyses for this end point

    Secondary: WHO Functional Class

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    End point title
    		 WHO Functional Class
    End point description
    Change in WHO Functional Class from Baseline to Week 48
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 UT-15C Safety Population
    Number of subjects analysed
    362
    362
    Units: Units on a Scale
        arithmetic mean (standard deviation)
    -0.2 ( 0.6 )
    -0.2 ( 0.6 )
    No statistical analyses for this end point

    Secondary: Plasma NT-proBNP

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    End point title
    		 Plasma NT-proBNP
    End point description
    Change in plasma NT-proBNP from Baseline to Week 48
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 UT-15C Safety Population
    Number of subjects analysed
    322
    322
    Units: pg/mL
        arithmetic mean (standard deviation)
    -179.23 ( 1968.99 )
    -179.23 ( 1968.99 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs were captured from the time the ICF was signed. All AEs were followed until resolution, until they were judged by the Investigator to no longer be clinically significant, or for up to 30 days if the AE extended beyond the final visit.
    Adverse event reporting additional description
    Any AEs that were ongoing at the study termination visit from the parent study were recorded as continuing AEs in this open-label study. All SAEs were followed until resolution, death, or the subject was lost to follow-up, even if they were ongoing more than 30 days after completion of the final visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Adverse Events - Safety Population
    Reporting group description
    		 All subjects who received oral treprostinil in TDE-PH-311 are included in the Safety Population.

    Serious adverse events
    		 Adverse Events - Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    206 / 470 (43.83%)
         number of deaths (all causes)
    74
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Breast cancer
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hepatic cancer recurrent
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    POEMS syndrome
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    6 / 470 (1.28%)
         occurrences causally related to treatment / all
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    Shock
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Oedema
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Sudden death
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    Asthenia
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Reproductive system and breast disorders
    Breast mass
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fibrocystic breast disease
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intermenstrual bleeding
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic fluid collection
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary hypertension
         subjects affected / exposed
    57 / 470 (12.13%)
         occurrences causally related to treatment / all
    7 / 79
         deaths causally related to treatment / all
    1 / 1
    Respiratory failure
         subjects affected / exposed
    8 / 470 (1.70%)
         occurrences causally related to treatment / all
    1 / 8
         deaths causally related to treatment / all
    0 / 2
    Dyspnoea
         subjects affected / exposed
    7 / 470 (1.49%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    5 / 470 (1.06%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Haemoptysis
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Catheterisation cardiac
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coagulation time prolonged
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Hand fracture
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Arteriovenous fistula site haemorrhage
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Intentional overdose
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Splenic rupture
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Right ventricular failure
         subjects affected / exposed
    22 / 470 (4.68%)
         occurrences causally related to treatment / all
    1 / 27
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    19 / 470 (4.04%)
         occurrences causally related to treatment / all
    5 / 25
         deaths causally related to treatment / all
    2 / 9
    Cardiac arrest
         subjects affected / exposed
    4 / 470 (0.85%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    4 / 470 (0.85%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Atrial flutter
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Atrioventricular block complete
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Right ventricular dysfunction
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Acute right ventricular failure
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cor pulmonale acute
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    4 / 470 (0.85%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Brain injury
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coma
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 470 (1.06%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Anaemia of malignant disease
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erythropenia
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Amaurosis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine ophthalmopathy
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 470 (1.28%)
         occurrences causally related to treatment / all
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Vomiting
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute abdomen
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulum
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric polyps
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric varices haemorrhage
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal polyp haemorrhage
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal vascular malformation haemorrhagic
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Portal hypertensive gastropathy
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    5 / 470 (1.06%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute hepatic failure
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Biliary tract disorder
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congestive hepatopathy
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hepatitis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Subcapsular hepatic haematoma
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Purpura
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    7 / 470 (1.49%)
         occurrences causally related to treatment / all
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Chronic kidney disease
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Glomerulonephritis acute
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lupus nephritis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal vasculitis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Scleroderma renal crisis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    4 / 470 (0.85%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Adrenocortical insufficiency acute
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Systemic lupus erythematosus
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Sjogren's syndrome
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Muscle atrophy
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    32 / 470 (6.81%)
         occurrences causally related to treatment / all
    5 / 39
         deaths causally related to treatment / all
    1 / 1
    Septic shock
         subjects affected / exposed
    9 / 470 (1.91%)
         occurrences causally related to treatment / all
    1 / 9
         deaths causally related to treatment / all
    0 / 4
    Gastroenteritis
         subjects affected / exposed
    6 / 470 (1.28%)
         occurrences causally related to treatment / all
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    5 / 470 (1.06%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 470 (1.06%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    5 / 470 (1.06%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    COVID-19
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    COVID-19 pneumonia
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    Bronchitis
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacterial translocation
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis listeria
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sialoadenitis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    3 / 470 (0.64%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Gout
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Adverse Events - Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    450 / 470 (95.74%)
    Investigations
    Weight decreased
         subjects affected / exposed
    25 / 470 (5.32%)
         occurrences all number
    25
    Vascular disorders
    Flushing
         subjects affected / exposed
    201 / 470 (42.77%)
         occurrences all number
    204
    Hypotension
         subjects affected / exposed
    36 / 470 (7.66%)
         occurrences all number
    42
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    74 / 470 (15.74%)
         occurrences all number
    81
    Right ventricular failure
         subjects affected / exposed
    39 / 470 (8.30%)
         occurrences all number
    54
    Cardiac failure
         subjects affected / exposed
    26 / 470 (5.53%)
         occurrences all number
    34
    Nervous system disorders
    Headache
         subjects affected / exposed
    328 / 470 (69.79%)
         occurrences all number
    348
    Dizziness
         subjects affected / exposed
    120 / 470 (25.53%)
         occurrences all number
    131
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    51 / 470 (10.85%)
         occurrences all number
    55
    Thrombocytopenia
         subjects affected / exposed
    17 / 470 (3.62%)
         occurrences all number
    19
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    85 / 470 (18.09%)
         occurrences all number
    98
    Fatigue
         subjects affected / exposed
    64 / 470 (13.62%)
         occurrences all number
    68
    Chest pain
         subjects affected / exposed
    45 / 470 (9.57%)
         occurrences all number
    54
    Asthenia
         subjects affected / exposed
    34 / 470 (7.23%)
         occurrences all number
    38
    Pyrexia
         subjects affected / exposed
    24 / 470 (5.11%)
         occurrences all number
    24
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    35 / 470 (7.45%)
         occurrences all number
    38
    Diarrhoea
         subjects affected / exposed
    311 / 470 (66.17%)
         occurrences all number
    354
    Nausea
         subjects affected / exposed
    188 / 470 (40.00%)
         occurrences all number
    197
    Vomiting
         subjects affected / exposed
    147 / 470 (31.28%)
         occurrences all number
    161
    Abdominal pain
         subjects affected / exposed
    40 / 470 (8.51%)
         occurrences all number
    43
    Abdominal pain upper
         subjects affected / exposed
    38 / 470 (8.09%)
         occurrences all number
    40
    Gastrooesophageal reflux disease
         subjects affected / exposed
    36 / 470 (7.66%)
         occurrences all number
    37
    Abdominal discomfort
         subjects affected / exposed
    30 / 470 (6.38%)
         occurrences all number
    30
    Dyspepsia
         subjects affected / exposed
    28 / 470 (5.96%)
         occurrences all number
    30
    Colitis
         subjects affected / exposed
    25 / 470 (5.32%)
         occurrences all number
    29
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    113 / 470 (24.04%)
         occurrences all number
    131
    Pulmonary hypertension
         subjects affected / exposed
    103 / 470 (21.91%)
         occurrences all number
    147
    Cough
         subjects affected / exposed
    72 / 470 (15.32%)
         occurrences all number
    76
    Epistaxis
         subjects affected / exposed
    24 / 470 (5.11%)
         occurrences all number
    26
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    40 / 470 (8.51%)
         occurrences all number
    41
    Musculoskeletal and connective tissue disorders
    Pain in jaw
         subjects affected / exposed
    103 / 470 (21.91%)
         occurrences all number
    106
    Myalgia
         subjects affected / exposed
    78 / 470 (16.60%)
         occurrences all number
    82
    Pain in extremity
         subjects affected / exposed
    78 / 470 (16.60%)
         occurrences all number
    90
    Arthralgia
         subjects affected / exposed
    57 / 470 (12.13%)
         occurrences all number
    69
    Back pain
         subjects affected / exposed
    41 / 470 (8.72%)
         occurrences all number
    45
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    116 / 470 (24.68%)
         occurrences all number
    160
    Nasopharyngitis
         subjects affected / exposed
    61 / 470 (12.98%)
         occurrences all number
    85
    Pneumonia
         subjects affected / exposed
    50 / 470 (10.64%)
         occurrences all number
    59
    Bronchitis
         subjects affected / exposed
    31 / 470 (6.60%)
         occurrences all number
    41
    Urinary tract infection
         subjects affected / exposed
    30 / 470 (6.38%)
         occurrences all number
    37
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    50 / 470 (10.64%)
         occurrences all number
    56
    Decreased appetite
         subjects affected / exposed
    41 / 470 (8.72%)
         occurrences all number
    43

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Mar 2012
    • Added that AEs extending beyond the final visit were followed for up to 30 days. • Clarified timing of subject contact to assess death and/or AEs following the last study visit. • Updated Guidelines and Definitions for Recording AEs (Section 15.4) to reflect current data capture conventions for AEs.
    13 Jun 2012
    • Duration of contraceptive use for WOCBP following last dose of study drug was expanded to 30 days. • Pregnancy reporting procedures were updated. • Updated Guidelines and Definitions for Recording AEs (Section 15.4) to reflect current data capture conventions for AEs regarding action taken.
    05 Dec 2012
    • Dosing was changed from twice daily (BID) to TID. • Results of an additional open-label study were added to better understand TID dosing pharmacokinetics. • Clinical laboratory assessments updated to be assessed at all Follow-up Visits. • Timing of TID dosing following meals was updated. • Exercise capacity (6MWD and Borg dyspnea score) timing changed to following the last study dose. • Added that site personnel will be unblinded to treatment assignments following the Study Termination assessments for TDE-PH-310. • Removed caloric requirements for meals preceding the 6MWT.
    10 Mar 2014
    • Clarified the logistics of dosing every 6 to 8 hours TID, including the intake of only a partial meal prior to study drug administration. • Updated newly approved PAH therapies and background data for oral treprostinil. • Updated estimated study duration to 4 years. • Clarified abstinence in inclusion criterion to align with regulatory agency review. • Allowed subjects who temporarily used a prostacyclin (28 days or less) to be included in the study. • Method for recording and reporting AEs associated with progression of PAH was clarified. • Storage temperature of study drug updated to be consistent with study drug labels.
    09 Jan 2015
    • Reduced sample size based on the amendment to TDE-PH-310.
    29 Sep 2016
    • Increased the number of subjects enrolled from approximately 610 subjects to up to 850 subjects. • Added clarification that clinical worsening events in TDE-PH-310 include cases of morbidity or mortality. • Updated the number of subjects that have been treated with Remodulin from 7000 to 17,000. • Added Uptravi® (Actelion Pharmaceuticals US, Inc.) as an approved pharmacotherapy for PAH. • Information regarding TDE-PH-304 was revised to include data from the 01 September 2015 data cut.
    13 Jul 2018
    • Added exploratory objectives for optional evaluation of pharmacogenomics. • Increased the estimated study duration from 4 years to approximately 6 years.

    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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