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    Clinical Trial Results:
    A Phase 2, Randomised, Double-Blind, Placebo-Controlled, Multicentre, Prospective Study to Assess Efficacy of Riociguat in Patients With Operable CTEPH Prior to Pulmonary Endarterectomy With High Preoperative Pulmonary Vascular Resistance

    Summary
    EudraCT number
    2017-001121-40
    Trial protocol
    GB   DE   FR  
    Global end of trial date
    05 May 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    21 May 2021
    First version publication date
    21 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PEA Bridging Study
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03273257
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    International CTEPH Association (ICA)
    Sponsor organisation address
    c/o artax Fide Consult AG, Gartenstrasse 95, Basel, Switzerland,
    Public contact
    Gérald Simonneau, International CTEPH Association (ICA), info@cteph-association.org
    Scientific contact
    David Jenkins, International CTEPH Association (ICA), 041 413797970, info@cteph-association.org
    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
    20 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the efficacy of riociguat on preoperative PVR in patients with operable CTEPH.
    Protection of trial subjects
    Patients were treated at expert centres with many years of experience in the management of CTEPH, and all patients were to receive the recommended gold standard treatment for operable CTEPH, i.e. PEA surgery. As per the protocol, surgery was to be performed by the principal surgeon of the site. Moreover, an unblinded, independent data safety monitoring board periodically reviewed safety data.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Aug 2018
    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
    United Kingdom: 7
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    France: 1
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    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)
    6
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Eligible patients were recruited at 3 expert centres for CTEPH in France, Germany and the UK between August 2018 and May 2020.

    Pre-assignment
    Screening details
    Patients could undergo a screening period of up to 90 days prior to the baseline visit in order to assess eligibility of patients and to allow for the washout of prohibited medications. A total of 17 patients were screened; of those, 14 were enrolled into the study.

    Period 1
    Period 1 title
    Randomisation (no drug treatment yet)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment arm
    Arm description
    Patients were randomised to receive riociguat for 90 days prior to surgery
    Arm type
    Active comparator

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.

    Arm title
    Placebo
    Arm description
    Patients were randomised to receive placebo for 90 days prior to surgery
    Arm type
    Placebo

    Investigational medicinal product name
    Matching placebo to riociguat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was given tid, mimicking the dosing scheme for riociguat

    Number of subjects in period 1
    Treatment arm Placebo
    Started
    7
    7
    Completed
    7
    7
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment arm
    Arm description
    Patients received riociguat for 90 days prior to surgery.
    Arm type
    Active comparator

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.

    Arm title
    Placebo
    Arm description
    Patients received placebo for 90 days prior to surgery.
    Arm type
    Placebo

    Investigational medicinal product name
    Matching placebo to riociguat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was given tid, mimicking the dosing scheme for riociguat

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: One patient died after randomisation, but before starting study treatment. As per the SAP, baseline characteristics are reported for the ITT population, which is defined as patients having received at least one dose of IMP. Therefore, the patient who died before starting treatment was not included in the analysis of baseline characteristics, and a new period had to be defined to account for this.
    Number of subjects in period 2 [2] [3]
    Treatment arm Placebo
    Started
    7
    6
    Completed
    6
    5
    Not completed
    1
    1
         Inability to schedule PEA according to protocol
    1
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One patient died after randomisation, but before starting study treatment. As per the SAP, baseline characteristics are reported for the ITT population, which is defined as patients having received at least one dose of IMP. Therefore, the patient who died before starting treatment was not included in the analysis of baseline characteristics; however, he is considered to have enrolled in the trial.
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: One patient in the placebo arm died after randomisation, but before starting study treatment.
    Period 3
    Period 3 title
    PEA (no more drug treatment)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment arm
    Arm description
    Patients had received riociguat for 90 days prior to surgery and underwent PEA surgery during this period
    Arm type
    Active comparator

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.

    Arm title
    Placebo
    Arm description
    Patients had received placebo for 90 days prior to surgery and underwent PEA surgery during this period
    Arm type
    Placebo

    Investigational medicinal product name
    Matching placebo to riociguat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was given tid, mimicking the dosing scheme for riociguat

    Number of subjects in period 3
    Treatment arm Placebo
    Started
    6
    5
    Completed
    6
    5
    Period 4
    Period 4 title
    Post-surgery observation
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment arm
    Arm description
    Patients had received riociguat for 90 days prior to surgery and had undergone PEA surgery
    Arm type
    Active comparator

    Investigational medicinal product name
    Riociguat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Riociguat will be initiated at 1 mg tid. The dosage will be increased by 0.5 mg at 2 week intervals based on tolerability as assessed by systolic blood pressure up to a maximum dose of 2.5 mg tid. Downtitration to 0.5 mg tid is foreseen for patients with low optimal tolerability.

    Arm title
    Placebo
    Arm description
    Patients had received placebo for 90 days prior to surgery and had undergone PEA surgery
    Arm type
    Placebo

    Investigational medicinal product name
    Matching placebo to riociguat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was given tid, mimicking the dosing scheme for riociguat

    Number of subjects in period 4
    Treatment arm Placebo
    Started
    6
    5
    Completed
    3
    3
    Not completed
    3
    2
         Study terminated
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    Patients received riociguat for 90 days prior to surgery.

    Reporting group title
    Placebo
    Reporting group description
    Patients received placebo for 90 days prior to surgery.

    Reporting group values
    Treatment arm Placebo Total
    Number of subjects
    7 6 13
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    66 (48 to 75) 67 (52 to 74) -
    Gender categorical
    Units: Subjects
        Female
    4 1 5
        Male
    3 5 8
    Race
    Units: Subjects
        White
    6 6 12
        Black African
    1 0 1
    Received beta blockers between enrolment and PEA
    Units: Subjects
        Yes
    3 0 3
        No
    4 6 10
    Received vitamin K antagonists between enrolment and PEA
    Units: Subjects
        Yes
    1 2 3
        No
    6 4 10
    Received new/direct oral anticoagulants between enrolment and PEA
    Units: Subjects
        Yes
    6 4 10
        No
    1 2 3
    Body mass index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    31.2 ± 3.9 25.4 ± 1.7 -
    PVR at diagnosis
    Units: dyn*sec/cm^5
        arithmetic mean (standard deviation)
    944.0 ± 92.7 1007.5 ± 368.2 -
    mPAP at diagnosis
    Units: mmHg
        arithmetic mean (standard deviation)
    50.3 ± 8.4 53.2 ± 4.8 -

    End points

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    End points reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    Patients were randomised to receive riociguat for 90 days prior to surgery

    Reporting group title
    Placebo
    Reporting group description
    Patients were randomised to receive placebo for 90 days prior to surgery
    Reporting group title
    Treatment arm
    Reporting group description
    Patients received riociguat for 90 days prior to surgery.

    Reporting group title
    Placebo
    Reporting group description
    Patients received placebo for 90 days prior to surgery.
    Reporting group title
    Treatment arm
    Reporting group description
    Patients had received riociguat for 90 days prior to surgery and underwent PEA surgery during this period

    Reporting group title
    Placebo
    Reporting group description
    Patients had received placebo for 90 days prior to surgery and underwent PEA surgery during this period
    Reporting group title
    Treatment arm
    Reporting group description
    Patients had received riociguat for 90 days prior to surgery and had undergone PEA surgery

    Reporting group title
    Placebo
    Reporting group description
    Patients had received placebo for 90 days prior to surgery and had undergone PEA surgery

    Primary: Change in PVR from baseline to immediately before PEA

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    End point title
    Change in PVR from baseline to immediately before PEA
    End point description
    End point type
    Primary
    End point timeframe
    90 days
    End point values
    Treatment arm Placebo
    Number of subjects analysed
    6 [1]
    5 [2]
    Units: percent change from baseline
        arithmetic mean (standard deviation)
    -28.4 ± 16.2
    -6.9 ± 27.9
    Notes
    [1] - One subject was discontinued during the treatment phase
    [2] - One subject was discontinued during the treatment phase
    Statistical analysis title
    Statistical analysis of primary endpoint
    Comparison groups
    Treatment arm v Placebo
    Number of subjects included in analysis
    11
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.139
    Method
    2-sample Wilcoxon rank sum test
    Confidence interval

    Secondary: Change in PVR from baseline to 6 months post-PEA

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    End point title
    Change in PVR from baseline to 6 months post-PEA
    End point description
    End point type
    Secondary
    End point timeframe
    270 days
    End point values
    Treatment arm Placebo
    Number of subjects analysed
    3 [3]
    3 [4]
    Units: percent change from baseline
        arithmetic mean (standard deviation)
    -68.1 ± 9.8
    -83.0 ± 2.2
    Notes
    [3] - One subject was discontinued during the treatment phase and 3 during post-surgery follow-up
    [4] - One subject was discontinued during the treatment phase and 2 during post-surgery follow-up
    No statistical analyses for this end point

    Secondary: All-cause death, PH-related hospitalisation, need for PAH-targeted therapy or WHO functional class unchanged or worse between randomisation and 6 months post-PEA (composite endpoint)

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    End point title
    All-cause death, PH-related hospitalisation, need for PAH-targeted therapy or WHO functional class unchanged or worse between randomisation and 6 months post-PEA (composite endpoint)
    End point description
    End point type
    Secondary
    End point timeframe
    270 days
    End point values
    Treatment arm Placebo
    Number of subjects analysed
    6
    5
    Units: Number of patients
        Experienced endpoint event
    6
    5
        Did not experience endpoint event
    0
    0
    No statistical analyses for this end point

    Secondary: Intraoperative circulatory arrest time

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    End point title
    Intraoperative circulatory arrest time
    End point description
    End point type
    Secondary
    End point timeframe
    intraoperative
    End point values
    Treatment arm Placebo
    Number of subjects analysed
    6
    5
    Units: minutes
        arithmetic mean (standard deviation)
    32 ± 9
    40 ± 12
    No statistical analyses for this end point

    Secondary: Intraoperative surgery-related complications

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    End point title
    Intraoperative surgery-related complications
    End point description
    The occurence of any of the following complications will be assessed: - Bleeding and/or blood loss >1 L in 12 hours - Airway bleed with need for extracorporeal membrane oxygenation - Any use of extracorporeal membrane oxygenation for respiratory or haemodynamic support, specified as venovenous or veno-arterial - Prolonged ventilation >96 hours - Need for tracheostomy - Need for drainage of pericardial effusion - Neurological complications, ie, stroke, cerebral, subdural bleeding - Reintubation or noninvasive ventilation for reperfusion response - Haemoptysis requiring any intervention - Renal failure requiring dialysis - Wound infections - Pneumonia - Prolonged need for inotropic support (≥ 5 days)
    End point type
    Secondary
    End point timeframe
    intraoperative
    End point values
    Treatment arm Placebo
    Number of subjects analysed
    6
    5
    Units: Number of patients
        Experienced endpoint event
    0
    0
        Did not experience endpoint event
    6
    5
    No statistical analyses for this end point

    Secondary: Surgical evaluation of specimen: ease of dissection plane

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    End point title
    Surgical evaluation of specimen: ease of dissection plane
    End point description
    End point type
    Secondary
    End point timeframe
    intraoperative
    End point values
    Treatment arm Placebo
    Number of subjects analysed
    6
    5
    Units: Number of patients
        Easier than normal
    1
    1
        Normal
    3
    4
        More difficult than normal
    2
    0
    No statistical analyses for this end point

    Secondary: Surgical evaluation of specimen: completeness of disease clearance

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    End point title
    Surgical evaluation of specimen: completeness of disease clearance
    End point description
    End point type
    Secondary
    End point timeframe
    intraoperative
    End point values
    Treatment arm Placebo
    Number of subjects analysed
    6
    5
    Units: Number of patients
        Better than expected
    0
    0
        As expected
    6
    5
        Worse than expected
    0
    0
    No statistical analyses for this end point

    Secondary: Surgical evaluation of specimen: appearance of clot

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    End point title
    Surgical evaluation of specimen: appearance of clot
    End point description
    End point type
    Secondary
    End point timeframe
    intraoperative
    End point values
    Treatment arm Placebo
    Number of subjects analysed
    6
    5
    Units: Number of patients
        More solid than usual
    0
    0
        Normal
    4
    5
        More friable than usual
    2
    0
    No statistical analyses for this end point

    Secondary: Surgical evaluation of specimen: appearance of vessel wall

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    End point title
    Surgical evaluation of specimen: appearance of vessel wall
    End point description
    End point type
    Secondary
    End point timeframe
    intraoperative
    End point values
    Treatment arm Placebo
    Number of subjects analysed
    6
    5
    Units: Number of patients
        More solid than usual
    0
    0
        Normal
    4
    5
        More friable than ususal
    2
    0
    No statistical analyses for this end point

    Secondary: All-cause death

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    End point title
    All-cause death
    End point description
    End point type
    Secondary
    End point timeframe
    270 days
    End point values
    Treatment arm Placebo
    Number of subjects analysed
    6
    5
    Units: Number of patients
        Died
    0
    0
        Did not die
    6
    5
    No statistical analyses for this end point

    Secondary: Withdrawal during randomised treatment phase

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    End point title
    Withdrawal during randomised treatment phase
    End point description
    Only withdrawals after randomisation but before PEA are included
    End point type
    Secondary
    End point timeframe
    90 days
    End point values
    Treatment arm Placebo
    Number of subjects analysed
    7
    6
    Units: Number of patients
        Withdrew
    1
    1
        Did not withdraw
    6
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From informed consent until study completion (270-360 days) or early termination
    Adverse event reporting additional description
    Events reported are treatment-emergent adverse events, i.e. any event not present before exposure to study drug or any event already present that worsened in either intensity or frequency after exposure to study drug, in patients who actually received any study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    Patients received riociguat for 90 days prior to surgery, then underwent PEA surgery and were subsequently followed up for 6 months

    Reporting group title
    Placebo
    Reporting group description
    Patients received placebo for 90 days prior to surgery, then underwent PEA surgery and were subsequently followed up for 6 months

    Serious adverse events
    Treatment arm Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 6 (33.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary hypertension
    Additional description: Worsening symptoms of CTEPH, including increased NT-proBNP, peripheral oedema and breathlessness
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Mediastinitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment arm Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    5 / 6 (83.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Hypotension
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Surgical and medical procedures
    Drug therapy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Discomfort
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 6 (50.00%)
         occurrences all number
    2
    4
    Feeling cold
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Pyrexia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Anxiety disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Confusional state
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Delirium
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Restlessness
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Procedural haemorrhage
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Vaccination complication
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Inflammatory marker increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Bradycardia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Cardiac failure
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    Tachyarrhythmia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    Dyspnoea
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 6 (33.33%)
         occurrences all number
    2
    4
    Dyspnoea exertional
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Hypoxia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Productive cough
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 6 (33.33%)
         occurrences all number
    4
    2
    Lethargy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Memory impairment
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Retinal artery occlusion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    1
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Constipation
         subjects affected / exposed
    4 / 7 (57.14%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Diarrhoea
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Dyspepsia
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Eructation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Flatulence
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    Toothache
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Back pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Chest wall haematoma
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Joint swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 6 (50.00%)
         occurrences all number
    0
    4
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Dyslipidaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Hypomagnesaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Post procedural infection
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0

    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.
    The study was terminated after enrolling only 14 out of 88 planned patients due to slow recruitment and further limitations imposed by the COVID-19 pandemic. No firm conclusions can be drawn based on the study data due to the limited sample size.
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