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    Clinical Trial Results:
    A multinational, multicentre, randomized, double-blind study to assess the efficacy and safety of oral sildenafil 20mg TID or placebo dosed concomitantly with Bosentan in the treatement of subjects , aged 18 years and above, with pulmonary arterial hypertension (PAH)

    Summary
    EudraCT number
    		 2006-001464-23
    Trial protocol
    		 CZ   DE   GB   IT   GR  
    Global end of trial date
    20 Aug 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 May 2016
    First version publication date
    05 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A1481243
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00323297
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc, 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc, 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Mar 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect on exercise capacity (as measured by the 6 Minute Walk Distance) after 12 weeks of treatment of sildenafil (20 milligram [mg] three times a day [TID]) or placebo when dosed concomitantly to subjects with PAH who are stabilized on bosentan therapy.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Sep 2006
    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
    Czech Republic: 13
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Taiwan: 5
    Worldwide total number of subjects
    103
    EEA total number of subjects
    71
    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)
    65
    From 65 to 84 years
    38
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 29 active centers in 10 countries (10 centers in Germany, 5 centers in the United States of America [USA], 3 centers in France, 2 centers in Australia, Czech Republic, Italy, and Israel, and 1 center in Greece, Taiwan and United Kingdom [UK]).

    Pre-assignment
    Screening details
    		 Subjects were on bosentan therapy for 3 months prior. Subjects were randomized to sildenafil or placebo. Part A study was double-blind phase (12 weeks) and Part B was 12 months open-label phase. 53 and 51 subjects were randomized to placebo and sildenafil arm respectively. One subject in sildenafil arm did not receive any treatment.

    Period 1
    Period 1 title
    Part A (Double Blind Randomized)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 In Part A of the study: the subjects received placebo, dosed concomitantly with their existing stable bosentan treatment, for Double-Blind Phase of the study. In Part B of the study: All the subjects received sildenafil.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo TID, dosed concomitantly with their existing stable bosentan treatment (62.5 mg two times a day (BID) or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study.

    Arm title
    		 Sildenafil
    Arm description
    		 In Part A of the study: the subjects received sildenafil, dosed concomitantly with their existing stable bosentan treatment, for Double-Blind Phase of the study. In Part B of the study: All the subjects received sildenafil.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sildenafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received sildenafil 20 mg TID, dosed concomitantly with their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study.

    Number of subjects in period 1
    		Placebo Sildenafil
    Started
    53
    50
    Completed
    48
    43
    Not completed
    5
    7
         Related and Unrelated adverse event
    1
    -
         Death
    -
    1
         Related adverse event
    2
    2
         Reason unspecified
    -
    1
         Protocol Violation
    1
    3
         Unrelated adverse event
    1
    -
    Period 2
    Period 2 title
    Part B (Open-label)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 In Part A of the study: the subjects received placebo, dosed concomitantly with their existing stable bosentan treatment, for Double-Blind Phase of the study. In Part B of the study: All the subjects received sildenafil.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo TID, dosed concomitantly with their existing stable bosentan treatment (62.5 mg BID or 125 mg BID for minimum 3 months prior to randomization), for 12-Week Double-Blind Phase of the study.

    Arm title
    		 Sildenafil
    Arm description
    		 In Part A of the study: the subjects received sildenafil, dosed concomitantly with their existing stable bosentan treatment, for Double-Blind Phase of the study. In Part B of the study: All the subjects received sildenafil.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sildenafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All the subjects received sildenafil 20 mg TID for 12 months.

    Number of subjects in period 2
    		Placebo Sildenafil
    Started
    48
    43
    Completed
    39
    31
    Not completed
    9
    12
         Consent withdrawn by subject
    1
    3
         Adverse Event
    5
    5
         Death
    -
    1
         Reason unspecified
    -
    1
         Protocol Violation
    -
    1
         Lack of efficacy
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 In Part A of the study: the subjects received placebo, dosed concomitantly with their existing stable bosentan treatment, for Double-Blind Phase of the study. In Part B of the study: All the subjects received sildenafil.

    Reporting group title
    Sildenafil
    Reporting group description
    		 In Part A of the study: the subjects received sildenafil, dosed concomitantly with their existing stable bosentan treatment, for Double-Blind Phase of the study. In Part B of the study: All the subjects received sildenafil.

    Reporting group values
    		 Placebo Sildenafil Total
    Number of subjects
    		 53 50 103
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.9 ± 14.14 55.2 ± 15.1 -
    Gender categorical
    Units: Subjects
        Female
    		 41 37 78
        Male
    		 12 13 25
    World Health Organization Functional Class in Subjects with Pulmonary Arterial Hypertension
    Pulmonary Arterial Hypertension criteria for WHO Class: Class I (Subjects with no limitation of physical activity); Class II (Subjects with slight limitation of physical activity); Class III (Subjects with marked limitation of physical activity); Class IV (Subjects with inability to carry out any physical activity).
    Units: Subjects
        Class I
    		 0 0 0
        Class II
    		 15 20 35
        Class III
    		 38 29 67
        Class IV
    		 0 1 1
    Six Minute Walk Test (6MWT)
    6MWT is the distance that a subject could walk in 6 minutes. Subjects were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Continuous pulse oximetry was conducted during the test for safety.
    Units: meters
        arithmetic mean (standard deviation)
    		 350.38 ± 87.587 354.44 ± 73.121 -
    Mean Pulmonary Artery Pressure (mPAP)
    Units: Millimeter (mm) of mercury (Hg)
        arithmetic mean (standard deviation)
    		 44.9 ± 13.33 46.9 ± 12.47 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 In Part A of the study: the subjects received placebo, dosed concomitantly with their existing stable bosentan treatment, for Double-Blind Phase of the study. In Part B of the study: All the subjects received sildenafil.

    Reporting group title
    Sildenafil
    Reporting group description
    		 In Part A of the study: the subjects received sildenafil, dosed concomitantly with their existing stable bosentan treatment, for Double-Blind Phase of the study. In Part B of the study: All the subjects received sildenafil.
    Reporting group title
    Placebo
    Reporting group description
    		 In Part A of the study: the subjects received placebo, dosed concomitantly with their existing stable bosentan treatment, for Double-Blind Phase of the study. In Part B of the study: All the subjects received sildenafil.

    Reporting group title
    Sildenafil
    Reporting group description
    		 In Part A of the study: the subjects received sildenafil, dosed concomitantly with their existing stable bosentan treatment, for Double-Blind Phase of the study. In Part B of the study: All the subjects received sildenafil.

    Primary: Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12

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    End point title
    		 Change From Baseline in the Total Distance Walked During 6 Minute Walk Time (6MWT) at Week 12
    End point description
    6MWT is the distance that a subject could walk in 6 minutes. Subjects were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Continuous pulse oximetry was conducted during the test for safety. Intent-to-Treat (ITT) Population (Full Analysis Set [FAS]) consisted of all subjects who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward (LOCF) approach. Statistical analysis was carried out on LOCF values.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Placebo Sildenafil
    Number of subjects analysed
    53
    50
    Units: meters
    arithmetic mean (standard deviation)
        Change from baseline at Week 12 (n=46,44)
    17.42 ± 57.27
    14.08 ± 63.679
        Change from baseline at Week 12 LOCF (n=53,49)
    14.08 ± 57.557
    13.62 ± 60.95
    Statistical analysis title
    		 6MWT at Week 12
    Statistical analysis description
    The estimated sample size was based upon the primary endpoint. A sample size of 51 subjects per treatment group was required to detect a difference of 30 meters between treatments with 80% power at a one sided significance level of 0.05, assuming a standard deviation of 60 meters. The mean difference in method of estimation is the difference between Sildenafil - placebo.
    Comparison groups
    Placebo v Sildenafil
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5802 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.38
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -21.843
         upper limit
    		 17.087
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.722
    Notes
    [1] - Sequential closed-testing procedure was implemented for all secondary endpoints. If no statistically significant treatment effect was found for primary endpoint then statistical tests were not to be performed on the secondary endpoints.

    Secondary: Number of Subjects With Change From Baseline in World Health Organization (WHO) Functional Class in Subjects With PAH at Week 12 LOCF

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    End point title
    		 Number of Subjects With Change From Baseline in World Health Organization (WHO) Functional Class in Subjects With PAH at Week 12 LOCF
    End point description
    WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity) to Class IV (can not perform a physical activity without any symptoms, dyspnea at rest). Improvement=reduction in functional class; deterioration = increase in functional class, no change = no change in functional class. ITT Population (FAS) consisted of all subjects who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the LOCF approach.
    End point type
    Secondary
    End point timeframe
    week 12
    End point values
    		 Placebo Sildenafil
    Number of subjects analysed
    53
    50
    Units: subjects
        Worsened 2 Classes
    0
    0
        Worsened 1 Class
    1
    0
        No Change
    45
    39
        Improved 1 Class
    7
    10
        Improved 2 Classes
    0
    0
        Discontinued
    0
    0
        Died
    0
    1
        Missing
    0
    0
    No statistical analyses for this end point

    Secondary: Clinical Worsening Events

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    End point title
    		 Clinical Worsening Events
    End point description
    No survival analysis was carried out for the study due to very few events of clinical worsening. Hence, we present a summary of clinical worsening events instead. Events of clinical worsening were categorized as (A). Death, (B). Heart/lung transplantation, (C). Hospitalization due to pulmonary arterial hypertension (PAH), and (D). Clinical deterioration of PAH requiring additional therapy. ITT Population (FAS) consisted of all subjects who had been randomly assigned to study drug and received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Sildenafil
    Number of subjects analysed
    53
    50
    Units: subjects
        None
    51
    47
        (A)
    0
    1
        (B)
    0
    0
        (C)
    2
    2
        (D)
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Borg Dyspnea Score at Week 12

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    End point title
    		 Change From Baseline in Borg Dyspnea Score at Week 12
    End point description
    Borg dyspnea scale is a 10-point scale where following scores stands for severity of dyspnea: 0 (no breathlessness at all); 0.5 (very very slight [just noticeable]); 1.(very slight); 2.(slight breathlessness); 3.(moderate); 4 (some what severe); 5 (severe breathlessness); 7 (very severe breathlessness); 9 (very very severe [almost maximum]); and 10 (maximum). ITT Population (FAS) consisted of all subjects who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward LOCF approach.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Placebo Sildenafil
    Number of subjects analysed
    53
    50
    Units: units on a scale
    arithmetic mean (standard deviation)
        Change from Baseline at Week 12 (n=46,43)
    0.16 ± 1.637
    -0.73 ± 1.656
        Change from Baseline at Week 12 LOCF (n=53,49)
    0.24 ± 1.709
    -0.62 ± 1.583
    No statistical analyses for this end point

    Secondary: One Year Survival Probability From the Start of Sildenafil Treatment

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    End point title
    		 One Year Survival Probability From the Start of Sildenafil Treatment
    End point description
    The survival probability of all subjects up to 1-year post start of Sildenafil treatment; for subjects who were randomized to Sildenafil, this was the week 52 from randomization, and for subjects who were originally randomized to Placebo group, this was the Week 64 from Baseline (Week 52 from Week 12, when the first dose of Sildenafil was administered to these subjects).Subjects who discontinued from the study prior to 1 year after start of sildenafil were considered as censored at time of discontinuation and those who discontinued from study post 1-year after start of sildenafil were considered as censored at the time of 1-year post start of sildenafil. ITT Population (FAS) consisted of all subjects who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward LOCF approach. The subjects in placebo arm have received Sildenafil on or after Week 12.
    End point type
    Secondary
    End point timeframe
    One year from the time of starting sildenafil
    End point values
    		 Placebo Sildenafil
    Number of subjects analysed
    48
    50
    Units: Probability of death
        number (confidence interval 90%)
    0.042 (0.013 to 0.127)
    0.04 (0.013 to 0.124)
    No statistical analyses for this end point

    Secondary: One Year Survival From the Start of Sildenafil Treatment

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    End point title
    		 One Year Survival From the Start of Sildenafil Treatment
    End point description
    The survival status of all subjects who discontinued from the study, including those subjects who discontinued during the double-blind phase, was to be assessed at one year post their Week 12 visit/ End of treatment visit. ITT Population (FAS) consisted of all subjects who had been randomly assigned to study drug and received at least one dose of study medication. Missing values were replaced according to the last observation carried forward LOCF approach. The subjects in placebo arm have received Sildenafil on or after Week 12.
    End point type
    Secondary
    End point timeframe
    One year from the time of starting sildenafil
    End point values
    		 Placebo Sildenafil
    Number of subjects analysed
    48
    50
    Units: subjects who died
    2
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time that the subject provides informed consent through and including 28 calendar days after the last administration of the investigational product
    Adverse event reporting additional description
    The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Sildenafil
    Reporting group description
    		 In Part A of the study: the subjects received sildenafil, dosed concomitantly with their existing stable bosentan treatment, for Double-Blind Phase of the study. In Part B of the study: All the subjects received sildenafil.

    Reporting group title
    Placebo
    Reporting group description
    		 In Part A of the study: the subjects received placebo, dosed concomitantly with their existing stable bosentan treatment, for Double-Blind Phase of the study. In Part B of the study: All the subjects received sildenafil.

    Serious adverse events
    		 Sildenafil Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 50 (44.00%)
    23 / 53 (43.40%)
         number of deaths (all causes)
    4
    4
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic neoplasm
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Skin graft
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    2 / 50 (4.00%)
    6 / 53 (11.32%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Psychiatric disorders
    Mania
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Walking distance test abnormal
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haematoma
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Paresis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis viral
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sildenafil Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 50 (66.00%)
    38 / 53 (71.70%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    5 / 50 (10.00%)
    4 / 53 (7.55%)
         occurrences all number
    5
    4
    Hypertension
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 53 (5.66%)
         occurrences all number
    1
    3
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 53 (7.55%)
         occurrences all number
    0
    5
    Oedema peripheral
         subjects affected / exposed
    7 / 50 (14.00%)
    8 / 53 (15.09%)
         occurrences all number
    9
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 53 (5.66%)
         occurrences all number
    1
    3
    Dyspnoea
         subjects affected / exposed
    3 / 50 (6.00%)
    8 / 53 (15.09%)
         occurrences all number
    4
    12
    Pulmonary arterial hypertension
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 53 (7.55%)
         occurrences all number
    2
    5
    Pulmonary hypertension
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 53 (0.00%)
         occurrences all number
    4
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0
    Investigations
    Weight increased
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    5 / 50 (10.00%)
    3 / 53 (5.66%)
         occurrences all number
    5
    3
    Right ventricular failure
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 53 (7.55%)
         occurrences all number
    0
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 50 (14.00%)
    7 / 53 (13.21%)
         occurrences all number
    9
    8
    Presyncope
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 53 (5.66%)
         occurrences all number
    3
    3
    Syncope
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 50 (4.00%)
    4 / 53 (7.55%)
         occurrences all number
    2
    6
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    5 / 50 (10.00%)
    2 / 53 (3.77%)
         occurrences all number
    7
    2
    Eye disorders
    Vision blurred
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 53 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 50 (14.00%)
    5 / 53 (9.43%)
         occurrences all number
    8
    7
    Nausea
         subjects affected / exposed
    1 / 50 (2.00%)
    5 / 53 (9.43%)
         occurrences all number
    2
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 53 (7.55%)
         occurrences all number
    0
    6
    Back pain
         subjects affected / exposed
    1 / 50 (2.00%)
    5 / 53 (9.43%)
         occurrences all number
    1
    5
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 53 (9.43%)
         occurrences all number
    7
    9
    Nasopharyngitis
         subjects affected / exposed
    5 / 50 (10.00%)
    8 / 53 (15.09%)
         occurrences all number
    7
    9
    Respiratory tract infection
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 53 (1.89%)
         occurrences all number
    5
    1
    Sinusitis
         subjects affected / exposed
    1 / 50 (2.00%)
    5 / 53 (9.43%)
         occurrences all number
    1
    7
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 53 (9.43%)
         occurrences all number
    3
    9
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 53 (5.66%)
         occurrences all number
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Nov 2006
    The safety language has been revised to address new reporting requirements related to Exposure in Utero.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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