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    Clinical Trial Results:
    COMbination therapy for PulmonAry hypertension using RacEcadotril (COMPARE).

    Summary
    EudraCT number
    		 2012-003921-13
    Trial protocol
    		 GB  
    Global end of trial date
    05 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jun 2019
    First version publication date
    13 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    12/0368
    Additional study identifiers
    ISRCTN number
    		 ISRCTN96717546
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Comprehensive Clinical Trials Unit at UCL
    Sponsor organisation address
    Institute of Clinical Trials and Methodology, 90 High Holborn, London, United Kingdom, WC1V 6LJ
    Public contact
    CCTU Enquiry Desk, Comprehensive Clinical Trials Unit at UCL, CCTU-enquiries@ucl.ac.uk
    Scientific contact
    CCTU Enquiry Desk, Comprehensive Clinical Trials Unit at UCL, CCTU-enquiries@ucl.ac.uk
    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
    01 Feb 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This trial aims to generate data on the efficacy and safety of racecadotril in patients with pulmonary hypertension (PH) taking sildenafil or tadalafil. Step 1 (Step 1A and 1B) was carried out to identify a safe dose of racecadotril on pulmonary and systemic haemodynamics. The aim was to confirm that a single dose of racecadotril effectively inhibits the enzyme neutral endopeptidase (NEP) without causing unacceptable adverse effects. The aim of Step 2 was to investigate the safety and pharmacological effects of racecadotril on the six minute walk test, haemodynamics and biomarkers over a 12-14 day repeat-dosing study. The hypothesis to be tested: racecadotril, administered in single and repeat dosing, will increase plasma atrial natriuretic peptide (ANP) concentration in patients with PH.
    Protection of trial subjects
    The trial was conducted in compliance with the approved protocol, UCL CCTU Standard Operating Procedures, the Declaration of Helsinki (2008), the principles of Good Clinical Practice (GCP) as laid down by the Commission Directive 2005/28/EC with implementation in national legislation in the UK by Statutory Instrument 2004/1031 and subsequent amendments, the UK Data Protection Act and the National Health Service (NHS) Research Governance Framework for Health and Social Care (RGF). Protocol pre-defined reasons for discontinuation of trial medication were in place in the event of participants experiencing: unacceptable toxicity or adverse event; inter-current illness that prevents further treatment; any change in the patient’s condition that justifies the discontinuation of treatment in the clinician’s opinion; inadequate compliance with the protocol treatment in the judgement of the treating physician; withdrawal of consent for treatment by the patient; complications of right heart catheterisation (step 1 only) or pregnancy. All participants could choose to discontinue trial treatment at any time, without giving a reason and without medical care or legal rights being affected. Investigation and treatment of adverse events were as per NHS standard of care. Specific clinical measures that were put in place to protect trial subjects: During the extension to the routine Right Heart Catheterisation in step 1 to minimise the risk of thrombosis formation, the access sheath placed during the routine catheterisation was left in situ for approximately 2 hours and a small bolus of heparin (or another anti-thrombin agent) administered to ensure that no thrombus formation occurs. Patients with PH have higher concentrations of NP in their plasma. It is possible that they might be more sensitive to the vasodilator effects of racecadotril and might experience a fall in systemic blood pressure.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Feb 2014
    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: 21
    Worldwide total number of subjects
    21
    EEA total number of subjects
    21
    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)
    10
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 21
    Number of subjects completed
    		 21

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    All trial medication dispensed will have identical outer packaging to preserve the blind. The outer packaging will be labelled in compliance with clinical trial regulations, and will also contain a patient identification code which is given when the patient is randomised. On completion of the trial prescription, only the patient trial identification code will be used to identify the medication.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Racecadotril repeat dose
    Arm description
    		 Step 2 will be 12-14 day repeat-dosing. Patients will receive a dose of racecadotril either 100 mg or 200mg p.o. t.i.d. concurrently with sildenafil (20-100 mg; p.o.; t.i.d.), or tadalafil (20-40 mg; p.o./o.d.), for 12 or 13 or 14 days. The dose of racecadotril for step 2 will be determined by the IDMC following step 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Racecadotril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Step 2 will be 12-14 day repeat-dosing. Patients will receive a dose of racecadotril either 100 mg or 200mg p.o. t.i.d. concurrently with sildenafil (20-100 mg; p.o.; t.i.d.), or tadalafil (20-40 mg; p.o./o.d.), for 12 or 13 or 14 days. The dose of racecadotril for step 2 will be determined by the IDMC following step 1. 42 or 84 capsules will be dispensed either directly to the patient or to a member of the trial team to then pass on to the patient. The number of capsules dispensed per patient will depend on the dosing recommendation of the IDMC.

    Arm title
    		 Placebo repeat dose
    Arm description
    		 Step 2 will be 12-14 day repeat-dosing. Patients will receive a dose of Placebo concurrently with sildenafil (20-100 mg; p.o.; t.i.d.), or tadalafil (20-40 mg; p.o./o.d.), for 12 or 13 or 14 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Step 2 will be 12-14 day repeat-dosing. Patients will receive a dose of Placebo concurrently with sildenafil (20-100 mg; p.o.; t.i.d.), or tadalafil (20-40 mg; p.o./o.d.), for 12 or 13 or 14 days. 42 or 84 capsules will be dispensed either directly to the patient or to a member of the trial team to then pass on to the patient. The number of capsules dispensed per patient will depend on the dosing recommendation of the IDMC.

    Arm title
    		 Racecadotril single dose
    Arm description
    		 Six patients will be randomised 2:1 100mg racecadotril to placebo, concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.). After six patients have been recruited to and completed step 1a data will be reviewed by the IDMC to determine the dose to be used in step 1b. Six patients will be randomised 2:1 to either 100 mg or 200 mg p.o. racecadotril to placebo, concurrently with sildenafil (20-100mg; p.o) or tadalafil (20-40 mg; p.o./o.d.). The dose will depend on the results of the IDMC review in step 1a.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Racecadotril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    In Step1a patients will receive a single dose of racecadotril 100 mg p.o. Racecadotril will be co-administered concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.). After 6 patients have been randomised and completed step 1a, the IDMC will review their results and decide if the dose can be escalated to 200 mg. In Step1b patients will receive a single dose of racecadotril, either 100 mg or 200mg p.o. Racecadotril will be co-administered concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.).

    Arm title
    		 Placebo single dose
    Arm description
    		 Six patients will be randomised 2:1 100mg racecadotril to placebo, concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.). After six patients have been recruited to and completed step 1a data will be reviewed by the IDMC to determine the dose to be used in step 1b. Six patients will be randomised 2:1 to either 100 mg or 200 mg p.o. racecadotril to placebo, concurrently with sildenafil (20-100mg; p.o) or tadalafil (20-40 mg; p.o./o.d.). The dose will depend on the results of the IDMC review in step 1a.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    In Step1a patients will receive a single dose of Placebo. Placebo will be co-administered concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.). After 6 patients have been randomised and completed step 1a, the IDMC will review their results. In Step1b patients will receive a single dose of Placebo. Placebo will be co-administered concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.).

    Number of subjects in period 1
    		Racecadotril repeat dose Placebo repeat dose Racecadotril single dose Placebo single dose
    Started
    5
    3
    9
    4
    Completed
    5
    3
    9
    4
    Period 2
    Period 2 title
    End points
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor
    Blinding implementation details
    Blinding will be maintained using a placebo matched in appearance to racecadotril. All trial medication dispensed will have identical outer packaging to preserve the blind. The outer packaging will be labelled in compliance with clinical trial regulations, and will also contain a patient identification code which is given when the patient is randomised. On completion of the trial prescription, only the patient trial identification code will be used to identify the medication.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Racecadotril repeat dose
    Arm description
    		 This step will be 12-14 day repeat-dosing. Patients will receive a dose of racecadotril either 100 mg or 200mg p.o. t.i.d. concurrently with sildenafil (20-100 mg; p.o.; t.i.d.), or tadalafil (20-40 mg; p.o./o.d.), for 12 or 13 or 14 days. The dose of racecadotril for step 2 will be determined by the IDMC following step 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Racecadotril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    This step will be 12-14 day repeat-dosing. Patients will receive a dose of racecadotril either 100 mg or 200mg p.o. t.i.d. concurrently with sildenafil (20-100 mg; p.o.; t.i.d.), or tadalafil (20-40 mg; p.o./o.d.), for 12 or 13 or 14 days. The dose of racecadotril for step 2 will be determined by the IDMC following step 1. 42 or 84 capsules will be dispensed either directly to the patient or to a member of the trial team to then pass on to the patient. The number of capsules dispensed per patient will depend on the dosing recommendation of the IDMC.

    Arm title
    		 Placebo repeat dose
    Arm description
    		 This step will be 12-14 day repeat-dosing. Patients will receive a dose of Placebo concurrently with sildenafil (20-100 mg; p.o.; t.i.d.), or tadalafil (20-40 mg; p.o./o.d.), for 12 or 13 or 14 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    This step will be 12-14 day repeat-dosing. Patients will receive a dose of Placebo concurrently with sildenafil (20-100 mg; p.o.; t.i.d.), or tadalafil (20-40 mg; p.o./o.d.), for 12 or 13 or 14 days. 42 or 84 capsules will be dispensed either directly to the patient or to a member of the trial team to then pass on to the patient. The number of capsules dispensed per patient will depend on the dosing recommendation of the IDMC.

    Arm title
    		 Racecadotril single dose
    Arm description
    		 Six patients will be randomised 2:1 100mg racecadotril to placebo, concurrently with sildenafil (20-100mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.). After six patients have been recruited to and completed step 1a data will be reviewed by the IDMC to determine the dose to be used in step 1b. Six patients will be randomised 2:1 to either 100 mg or 200 mg p.o. racecadotril to placebo, concurrently with sildenafil (20-100mg; p.o) or tadalafil (20-40 mg; p.o./o.d.). The dose will depend on the results of the IDMC review in step 1a.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Racecadotril
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    In Step1a patients will receive a single dose of racecadotril 100 mg p.o. Racecadotril will be co-administered concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.). After 6 patients have been randomised and completed step 1a, the IDMC will review their results and decide if the dose can be escalated to 200 mg. In Step1b patients will receive a single dose of racecadotril, either 100 mg or 200mg p.o. Racecadotril will be co-administered concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.).

    Arm title
    		 Placebo single dose
    Arm description
    		 Six patients will be randomised 2:1 100mg racecadotril to placebo, concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.). After six patients have been recruited to and completed step 1a data will be reviewed by the IDMC to determine the dose to be used in step 1b. Six patients will be randomised 2:1 to either 100 mg or 200 mg p.o. racecadotril to placebo, concurrently with sildenafil (20-100mg; p.o) or tadalafil (20-40 mg; p.o./o.d.). The dose will depend on the results of the IDMC review in step 1a.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    In Step1a patients will receive a single dose of Placebo. Placebo will be co-administered concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.). After 6 patients have been randomised and completed step 1a, the IDMC will review their results. In Step1b patients will receive a single dose of Placebo. Placebo will be co-administered concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.).

    Number of subjects in period 2
    		Racecadotril repeat dose Placebo repeat dose Racecadotril single dose Placebo single dose
    Started
    5
    3
    9
    4
    Completed
    5
    3
    9
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Racecadotril repeat dose
    Reporting group description
    		 Step 2 will be 12-14 day repeat-dosing. Patients will receive a dose of racecadotril either 100 mg or 200mg p.o. t.i.d. concurrently with sildenafil (20-100 mg; p.o.; t.i.d.), or tadalafil (20-40 mg; p.o./o.d.), for 12 or 13 or 14 days. The dose of racecadotril for step 2 will be determined by the IDMC following step 1.

    Reporting group title
    Placebo repeat dose
    Reporting group description
    		 Step 2 will be 12-14 day repeat-dosing. Patients will receive a dose of Placebo concurrently with sildenafil (20-100 mg; p.o.; t.i.d.), or tadalafil (20-40 mg; p.o./o.d.), for 12 or 13 or 14 days.

    Reporting group title
    Racecadotril single dose
    Reporting group description
    		 Six patients will be randomised 2:1 100mg racecadotril to placebo, concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.). After six patients have been recruited to and completed step 1a data will be reviewed by the IDMC to determine the dose to be used in step 1b. Six patients will be randomised 2:1 to either 100 mg or 200 mg p.o. racecadotril to placebo, concurrently with sildenafil (20-100mg; p.o) or tadalafil (20-40 mg; p.o./o.d.). The dose will depend on the results of the IDMC review in step 1a.

    Reporting group title
    Placebo single dose
    Reporting group description
    		 Six patients will be randomised 2:1 100mg racecadotril to placebo, concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.). After six patients have been recruited to and completed step 1a data will be reviewed by the IDMC to determine the dose to be used in step 1b. Six patients will be randomised 2:1 to either 100 mg or 200 mg p.o. racecadotril to placebo, concurrently with sildenafil (20-100mg; p.o) or tadalafil (20-40 mg; p.o./o.d.). The dose will depend on the results of the IDMC review in step 1a.

    Reporting group values
    		 Racecadotril repeat dose Placebo repeat dose Racecadotril single dose Placebo single dose Total
    Number of subjects
    		 5 3 9 4 21
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 2 0 6 2 10
        From 65-84 years
    		 3 3 3 2 11
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69 ( 7 ) 67 ( 3 ) 57 ( 14 ) 58 ( 10 ) -
    Gender categorical
    Units: Subjects
        Female
    		 5 2 6 4 17
        Male
    		 0 1 3 0 4
    Plasma atrial natriuretic peptide (ANP)(nM)
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: nM
        geometric mean (standard deviation)
    		 0.16 ( 1.79 ) 0.2 ( 1.08 ) 0.076 ( 1.90 ) 0.114 ( 1.45 ) -
    Diastolic blood pressure (DBP)
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: mmHg
        geometric mean (standard deviation)
    		 70 ( 1.22 ) 73 ( 1.36 ) 72 ( 1.17 ) 76 ( 1.15 ) -
    Systolic blood pressure (SBP)
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: mmHg
        geometric mean (standard deviation)
    		 121 ( 1.13 ) 115 ( 1.17 ) 122 ( 1.13 ) 133 ( 1.12 ) -
    Mean arterial pressure (MAP)
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: mmHg
        geometric mean (standard deviation)
    		 88 ( 1.17 ) 87 ( 1.27 ) 89 ( 1.13 ) 96 ( 1.13 ) -
    Pulmonary vascular resistance (PVR)
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: dynes.sec/cm^5
        geometric mean (standard deviation)
    		 0 ( 0 ) 0 ( 0 ) 469 ( 1.38 ) 550 ( 1.39 ) -
    Mean Pulmonary artery wedge pressure (PAWP)
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: mmHg
        geometric mean (standard deviation)
    		 0 ( 0 ) 0 ( 0 ) 11.2 ( 1.17 ) 10.2 ( 1.46 ) -
    Cyclic guanosine-3',5'-monophosphate (cGMP)
    Here we report the geometric standard deviation, the exponent of the estimated standard deviation of the log-quantity, as the confidence intervals reported for this study were based on the assumption that the quantity was log-normally distributed.
    Units: nM
        geometric mean (standard deviation)
    		 13 ( 4.55 ) 58 ( 1.62 ) 16.8 ( 2.66 ) 41.3 ( 1.93 ) -

    End points

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    End points reporting groups
    Reporting group title
    Racecadotril repeat dose
    Reporting group description
    		 Step 2 will be 12-14 day repeat-dosing. Patients will receive a dose of racecadotril either 100 mg or 200mg p.o. t.i.d. concurrently with sildenafil (20-100 mg; p.o.; t.i.d.), or tadalafil (20-40 mg; p.o./o.d.), for 12 or 13 or 14 days. The dose of racecadotril for step 2 will be determined by the IDMC following step 1.

    Reporting group title
    Placebo repeat dose
    Reporting group description
    		 Step 2 will be 12-14 day repeat-dosing. Patients will receive a dose of Placebo concurrently with sildenafil (20-100 mg; p.o.; t.i.d.), or tadalafil (20-40 mg; p.o./o.d.), for 12 or 13 or 14 days.

    Reporting group title
    Racecadotril single dose
    Reporting group description
    		 Six patients will be randomised 2:1 100mg racecadotril to placebo, concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.). After six patients have been recruited to and completed step 1a data will be reviewed by the IDMC to determine the dose to be used in step 1b. Six patients will be randomised 2:1 to either 100 mg or 200 mg p.o. racecadotril to placebo, concurrently with sildenafil (20-100mg; p.o) or tadalafil (20-40 mg; p.o./o.d.). The dose will depend on the results of the IDMC review in step 1a.

    Reporting group title
    Placebo single dose
    Reporting group description
    		 Six patients will be randomised 2:1 100mg racecadotril to placebo, concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.). After six patients have been recruited to and completed step 1a data will be reviewed by the IDMC to determine the dose to be used in step 1b. Six patients will be randomised 2:1 to either 100 mg or 200 mg p.o. racecadotril to placebo, concurrently with sildenafil (20-100mg; p.o) or tadalafil (20-40 mg; p.o./o.d.). The dose will depend on the results of the IDMC review in step 1a.
    Reporting group title
    Racecadotril repeat dose
    Reporting group description
    		 This step will be 12-14 day repeat-dosing. Patients will receive a dose of racecadotril either 100 mg or 200mg p.o. t.i.d. concurrently with sildenafil (20-100 mg; p.o.; t.i.d.), or tadalafil (20-40 mg; p.o./o.d.), for 12 or 13 or 14 days. The dose of racecadotril for step 2 will be determined by the IDMC following step 1.

    Reporting group title
    Placebo repeat dose
    Reporting group description
    		 This step will be 12-14 day repeat-dosing. Patients will receive a dose of Placebo concurrently with sildenafil (20-100 mg; p.o.; t.i.d.), or tadalafil (20-40 mg; p.o./o.d.), for 12 or 13 or 14 days.

    Reporting group title
    Racecadotril single dose
    Reporting group description
    		 Six patients will be randomised 2:1 100mg racecadotril to placebo, concurrently with sildenafil (20-100mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.). After six patients have been recruited to and completed step 1a data will be reviewed by the IDMC to determine the dose to be used in step 1b. Six patients will be randomised 2:1 to either 100 mg or 200 mg p.o. racecadotril to placebo, concurrently with sildenafil (20-100mg; p.o) or tadalafil (20-40 mg; p.o./o.d.). The dose will depend on the results of the IDMC review in step 1a.

    Reporting group title
    Placebo single dose
    Reporting group description
    		 Six patients will be randomised 2:1 100mg racecadotril to placebo, concurrently with sildenafil (20-100 mg; p.o.) or tadalafil (20-40 mg; p.o./o.d.). After six patients have been recruited to and completed step 1a data will be reviewed by the IDMC to determine the dose to be used in step 1b. Six patients will be randomised 2:1 to either 100 mg or 200 mg p.o. racecadotril to placebo, concurrently with sildenafil (20-100mg; p.o) or tadalafil (20-40 mg; p.o./o.d.). The dose will depend on the results of the IDMC review in step 1a.

    Primary: Step 1 - Maximum percentage change from baseline in ANP

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    End point title
    		 Step 1 - Maximum percentage change from baseline in ANP
    End point description
    The maximum percentage change in the log transformed ANP post baseline between the two treatments (racecadotril - placebo).
    End point type
    Primary
    End point timeframe
    Value at the time of the maximum change from baseline
    End point values
    		 Racecadotril repeat dose Placebo repeat dose Racecadotril single dose Placebo single dose Racecadotril single dose Placebo single dose
    Number of subjects analysed
    0 [1]
    0 [2]
    9
    4
    0 [3]
    0 [4]
    Units: nM
        geometric mean (confidence interval 95%)
    ( to )
    ( to )
    79 (6 to 203)
    -9 (-63 to 121)
    ( to )
    ( to )
    Notes
    [1] - N/A
    [2] - N/A
    [3] - N/A
    [4] - N/A
    Statistical analysis title
    		 Primary outcome analysis
    Statistical analysis description
    The maximum percentage change in the log transformed ANP post baseline between the two treatments (racecadotril - placebo) together with a two-sided 95% CI was estimated using a linear regression model adjusted for baseline values.
    Comparison groups
    Racecadotril single dose v Placebo single dose
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.26
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric Mean Difference
    Point estimate
    52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31
         upper limit
    		 235

    Primary: Step 2 - Percentage change in ANP from baseline

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    End point title
    		 Step 2 - Percentage change in ANP from baseline
    End point description
    The percentage change in log transformed ANP at end of treatment.
    End point type
    Primary
    End point timeframe
    14 days from baseline.
    End point values
    		 Racecadotril repeat dose Placebo repeat dose
    Number of subjects analysed
    5
    3
    Units: nM
        geometric mean (confidence interval 95%)
    19 (-18 to 73)
    -15 (-69 to 128)
    Statistical analysis title
    		 Primary outcome analysis
    Statistical analysis description
    Linear regression model is used to estimate the difference in percentage change in ANP between the two treatments (Racecadotril - placebo) at the end of treatment, adjusting for baseline values.
    Comparison groups
    Racecadotril repeat dose v Placebo repeat dose
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric Mean Difference
    Point estimate
    48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23
         upper limit
    		 187

    Secondary: Step 1 - Maximum percentage change from baseline in DBP

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    End point title
    		 Step 1 - Maximum percentage change from baseline in DBP [5]
    End point description
    The maximum percentage change in the log transformed DBP post baseline between the two treatments.
    End point type
    Secondary
    End point timeframe
    Value at the time of the maximum change from baseline.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For repeat dosing the end point is only measured at a single time hence no maximum percentage change.
    End point values
    		 Racecadotril repeat dose Placebo repeat dose Racecadotril single dose Placebo single dose
    Number of subjects analysed
    0 [6]
    0 [7]
    9
    4
    Units: mmHg
        geometric mean (confidence interval 95%)
    ( to )
    ( to )
    -24 (-37 to -9)
    -16 (-60 to 74)
    Notes
    [6] - N/A
    [7] - N/A
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    The maximum percentage change in the log transformed DBP post baseline between the two treatments (racecadotril - placebo) together with a two-sided 95% CI was estimated using a linear regression model adjusted for baseline values.
    Comparison groups
    Racecadotril single dose v Placebo single dose
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric Mean Difference
    Point estimate
    -13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -42
         upper limit
    		 29

    Secondary: Step 1 - Maximum percentage change from baseline in SBP

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    End point title
    		 Step 1 - Maximum percentage change from baseline in SBP [8]
    End point description
    The maximum change in the log transformed SBP post baseline between the two treatments.
    End point type
    Secondary
    End point timeframe
    Value at the time of the maximum change from baseline.
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For repeat dosing the end point is only measured at a single time hence no maximum percentage change.
    End point values
    		 Racecadotril repeat dose Placebo repeat dose Racecadotril single dose Placebo single dose
    Number of subjects analysed
    0 [9]
    0 [10]
    9
    4
    Units: mmHg
        geometric mean (confidence interval 95%)
    ( to )
    ( to )
    -15 (-25 to -3)
    -6 (-54 to 94)
    Notes
    [9] - N/A
    [10] - N/A
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    The maximum percentage change in the log transformed SBP post baseline between the two treatments (racecadotril - placebo) together with a two-sided 95% CI was estimated using a linear regression model adjusted for baseline values.
    Comparison groups
    Racecadotril single dose v Placebo single dose
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric Mean Difference
    Point estimate
    -20
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -43
         upper limit
    		 13

    Secondary: Step 1 - Maximum percentage change from baseline in MAP

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    End point title
    		 Step 1 - Maximum percentage change from baseline in MAP [11]
    End point description
    The maximum percentage change in the log transformed MAP post baseline between the two treatments.
    End point type
    Secondary
    End point timeframe
    Value at the time of the maximum change from baseline.
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For repeat dosing the end point is only measured at a single time hence no maximum percentage change.
    End point values
    		 Racecadotril repeat dose Placebo repeat dose Racecadotril single dose Placebo single dose
    Number of subjects analysed
    0 [12]
    0 [13]
    9
    4
    Units: mmHg
        geometric mean (confidence interval 95%)
    ( to )
    ( to )
    -20 (-29 to -10)
    -14 (-55 to 66)
    Notes
    [12] - N/A
    [13] - N/A
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    The maximum percentage change in the log transformed MAP post baseline between the two treatments (racecadotril - placebo) together with a two-sided 95% CI was estimated using a linear regression model adjusted for baseline values.
    Comparison groups
    Racecadotril single dose v Placebo single dose
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.39
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric Mean Difference
    Point estimate
    -12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37
         upper limit
    		 22

    Secondary: Step 1 - Maximum percentage change from baseline in PVR

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    End point title
    		 Step 1 - Maximum percentage change from baseline in PVR [14]
    End point description
    The maximum percentage change in the log transformed PVR post baseline between the two treatments.
    End point type
    Secondary
    End point timeframe
    Value at the time of the maximum change
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For repeat dosing the end point is only measured at a single time hence no maximum percentage change.
    End point values
    		 Racecadotril repeat dose Placebo repeat dose Racecadotril single dose Placebo single dose
    Number of subjects analysed
    0 [15]
    0 [16]
    9
    4
    Units: dynes.sec/cm5
        geometric mean (confidence interval 95%)
    ( to )
    ( to )
    -14 (-23 to -3)
    -7 (-31 to 24)
    Notes
    [15] - N/A
    [16] - N/A
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    The maximum percentage change in the log transformed PVR post baseline between the two treatments (racecadotril - placebo) together with a two-sided 95% CI was estimated using a linear regression model adjusted for baseline values.
    Comparison groups
    Racecadotril single dose v Placebo single dose
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric Mean Difference
    Point estimate
    -7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25
         upper limit
    		 17

    Secondary: Step 1 - Maximum percentage change from baseline in PAWP

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    End point title
    		 Step 1 - Maximum percentage change from baseline in PAWP [17]
    End point description
    The maximum percentage change in the log transformed PAWP post baseline between the two treatments.
    End point type
    Secondary
    End point timeframe
    Value at the time of maximum change from baseline.
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For repeat dosing the end point is only measured at a single time hence no maximum percentage change.
    End point values
    		 Racecadotril repeat dose Placebo repeat dose Racecadotril single dose Placebo single dose
    Number of subjects analysed
    0 [18]
    0 [19]
    9
    4
    Units: mmHg
        geometric mean (confidence interval 95%)
    ( to )
    ( to )
    -19 (-38 to 4)
    24 (-25 to 105)
    Notes
    [18] - N/A
    [19] - N/A
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    The maximum percentage change in the log transformed PAWP post baseline between the two treatments (racecadotril - placebo) together with a two-sided 95% CI was estimated using a linear regression model adjusted for baseline values.
    Comparison groups
    Racecadotril single dose v Placebo single dose
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric Mean Difference
    Point estimate
    -33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -55
         upper limit
    		 2

    Secondary: Step 2 - Percentage change in DBP from baseline

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    End point title
    		 Step 2 - Percentage change in DBP from baseline
    End point description
    The percentage change in log transformed DBP at end of treatment.
    End point type
    Secondary
    End point timeframe
    14 days from baseline.
    End point values
    		 Racecadotril repeat dose Placebo repeat dose
    Number of subjects analysed
    5
    3
    Units: mmHg
        geometric mean (confidence interval 95%)
    -4 (-19 to 13)
    -10 (-56 to 83)
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    Linear regression model is used to estimate the difference in the percentage change in DBP between the two treatments (Racecadotril - placebo) at the end of treatment, adjusting for baseline values.
    Comparison groups
    Racecadotril repeat dose v Placebo repeat dose
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric Mean Difference
    Point estimate
    4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17
         upper limit
    		 28

    Secondary: Step 2 - Percentage change in SBP from baseline

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    End point title
    		 Step 2 - Percentage change in SBP from baseline
    End point description
    The percentage change in log transformed SBP at end of treatment.
    End point type
    Secondary
    End point timeframe
    14 days from baseline.
    End point values
    		 Racecadotril repeat dose Placebo repeat dose
    Number of subjects analysed
    5
    3
    Units: mmHg
        geometric mean (confidence interval 95%)
    -4 (-24 to 19)
    -10 (-42 to 41)
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    Linear regression model is used to estimate the difference in the percentage change in SBP between the two treatments (Racecadotril - placebo) at the end of treatment, adjusting for baseline values.
    Comparison groups
    Racecadotril repeat dose v Placebo repeat dose
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.36
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric Mean Difference
    Point estimate
    11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15
         upper limit
    		 46

    Secondary: Step 2 - Percentage change in HR from baseline

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    End point title
    		 Step 2 - Percentage change in HR from baseline
    End point description
    The percentage change in log HR at end of treatment.
    End point type
    Secondary
    End point timeframe
    14 days from baseline.
    End point values
    		 Racecadotril repeat dose Placebo repeat dose
    Number of subjects analysed
    5
    3
    Units: BPM
        geometric mean (confidence interval 95%)
    24 (5 to 46)
    -7 (-38 to 40)
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    Linear regression model is used to estimate the difference in the percentage change in HR between the two treatments (Racecadotril - placebo) at the end of treatment, adjusting for baseline values.
    Comparison groups
    Racecadotril repeat dose v Placebo repeat dose
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric Mean Difference
    Point estimate
    32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 74

    Secondary: Step 2 - Percentage change in MAP from baseline

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    End point title
    		 Step 2 - Percentage change in MAP from baseline
    End point description
    The percentage change in log transformed MAP at end of treatment.
    End point type
    Secondary
    End point timeframe
    14 days from baseline.
    End point values
    		 Racecadotril repeat dose Placebo repeat dose
    Number of subjects analysed
    5
    3
    Units: mmHg
        geometric mean (confidence interval 95%)
    -4 (-21 to 16)
    -10 (-50 to 61)
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    Linear regression model is used to estimate the difference in the percentage change in MAP between the two treatments (Racecadotril - placebo) at the end of treatment, adjusting for baseline values.
    Comparison groups
    Racecadotril repeat dose v Placebo repeat dose
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.45
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric Mean Difference
    Point estimate
    7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13
         upper limit
    		 31

    Secondary: Step 2 - Percentage change in cGMP from baseline

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    End point title
    		 Step 2 - Percentage change in cGMP from baseline
    End point description
    The percentage change in log transformed cGMP at the end of treatment.
    End point type
    Secondary
    End point timeframe
    14 days from baseline.
    End point values
    		 Racecadotril repeat dose Placebo repeat dose
    Number of subjects analysed
    5
    3
    Units: nM
        geometric mean (confidence interval 95%)
    34 (-64 to 395)
    -51 (-92 to 193)
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    Linear regression model is used to estimate the difference in the percentage change in cGMP between the two treatments (Racecadotril - placebo) at the end of treatment, adjusting for baseline values.
    Comparison groups
    Racecadotril repeat dose v Placebo repeat dose
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.66
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric Mean Difference
    Point estimate
    42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -79
         upper limit
    		 871

    Secondary: Step 1 - Maximum percentage change from baseline in cGMP

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    End point title
    		 Step 1 - Maximum percentage change from baseline in cGMP [20]
    End point description
    The maximum percentage change in the log transformed cGMP post baseline between the two treatments.
    End point type
    Secondary
    End point timeframe
    Value at the time of the maximum change from baseline.
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For repeat dosing the end point is only measured at a single time hence no maximum percentage change.
    End point values
    		 Racecadotril repeat dose Placebo repeat dose Racecadotril single dose Placebo single dose
    Number of subjects analysed
    0 [21]
    0 [22]
    9
    4
    Units: nM
        geometric mean (confidence interval 95%)
    ( to )
    ( to )
    98 (-4 to 308)
    -53 (-89 to 110)
    Notes
    [21] - N/A
    [22] - N/A
    Statistical analysis title
    		 Secondary outcome analysis
    Statistical analysis description
    The maximum percentage change in the log transformed cGMP post baseline between the two treatments (racecadotril - placebo) together with a two-sided 95% CI was estimated using a linear regression model adjusted for baseline values.
    Comparison groups
    Racecadotril single dose v Placebo single dose
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Regression, Linear
    Parameter type
    		 Geometric Mean Difference
    Point estimate
    166
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26
         upper limit
    		 861

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to end of treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Racecadotril single dose
    Reporting group description
    		 -

    Reporting group title
    Racecadotril repeat dose
    Reporting group description
    		 -

    Reporting group title
    Placebo repeat dose
    Reporting group description
    		 -

    Reporting group title
    Placebo single dose
    Reporting group description
    		 -

    Serious adverse events
    		 Racecadotril single dose Racecadotril repeat dose Placebo repeat dose Placebo single dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Racecadotril single dose Racecadotril repeat dose Placebo repeat dose Placebo single dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 5 (80.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
    Vascular disorders
    Dizziness
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Headache
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 5 (40.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    General disorders and administration site conditions
    All over body cramps
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Stomach pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jul 2013
    Protocol updated to v3.0 with the following: Tiorfan (racecadotril) becoming licensed in the UK (doses added); addition of Patients taking ACE inhibitors to the exclusion criteria; update to how the placebo is matched to racecadotril to maintain the blind; the investigator being able to unblind without the involvement of the sponsor; updates to the processing of SUSARs; allowance for not all IMP and/or containers being returned; clarification of assessment schedules.
    15 Aug 2014
    Protocol updated to v4.0 with the following: inclusion of patients on tadalafil (addition) or sildenafil (original); time window for the right heart catheter measurements increase; allowance for replacement participants if needed; updated SmPC for Tiorfan 100mg capsule and Adcirca 20 mg film coated tablets; clarifications throughout.
    20 Jan 2015
    Protocol updated to v5.0 with clarifications to possible study processes following the step 1a IDMC data review and the transition from step 1b to step 2 with other clarifications throughout.
    27 May 2015
    Protocol updated to v6.0 with the following: recruitment stop for the IDMC to review step 1a and step 1b data at the end of step 1b; an update to data review criteria; allowance for IMP to be allocated (but not administered) before eligibility is confirmed; clarifications throughout.

    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.
    For repeat dosing the end point is only measured at a single time hence no maximum percentage change. Repeat dosing arms did not measure PVR and PAWP - '0' has been entered as summary measures.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30761523
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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