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    Clinical Trial Results:
    A Study of the Efficacy and Safety of Bardoxolone Methyl in Patients With Connective Tissue Disease-associated Pulmonary Arterial Hypertension

    Summary
    EudraCT number
    		 2016-000196-24
    Trial protocol
    		 ES   DE   BE   NL   CZ   GB  
    Global end of trial date
    07 May 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 Nov 2021
    First version publication date
    10 Jul 2021
    Other versions
    		 v1
    Version creation reason
    • Changes to summary attachments
    Updates on Trial information

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    402-C-1504
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02657356
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 RTA 402-C-1504: Catalyst
    Sponsors
    Sponsor organisation name
    Reata Pharmaceuticals, Inc.
    Sponsor organisation address
    5320 Legacy Drive, Plano, United States, 75024
    Public contact
    Kris Loerwald, Reata Pharmaceuticals, Inc., 1 972 865-2219, MedicalAffairs-Team@reatapharma.com
    Scientific contact
    Kris Loerwald, Reata Pharmaceuticals, Inc., 1 972 865-2219, MedicalAffairs-Team@reatapharma.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
    07 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    07 May 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the efficacy of bardoxolone methyl relative to placebo.
    Protection of trial subjects
    IDMC reviewed unblinded safety data throughout the study and made recommendations regarding study continuation, modification or termination as appropriate to protect patient safety.
    Background therapy
    		 Bardoxolone methyl or placebo was administered orally once a day at 2.5, 5, or 10 mg, using 2.5 and 5.0 mg capsules up to 24 weeks.
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    04 Oct 2016
    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
    Brazil: 9
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Argentina: 26
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Japan: 16
    Country: Number of subjects enrolled
    Mexico: 12
    Country: Number of subjects enrolled
    Philippines: 5
    Country: Number of subjects enrolled
    United States: 80
    Country: Number of subjects enrolled
    Austria: 15
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Czechia: 3
    Country: Number of subjects enrolled
    United Kingdom: 3
    Worldwide total number of subjects
    202
    EEA total number of subjects
    37
    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)
    134
    From 65 to 84 years
    68
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruited patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH).

    Pre-assignment
    Screening details
    		 Qualified patients with WHO Group I CTD-PAH were screened and enrolled per protocol inclusion/exclusion criteria.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    All patients, investigators, site personnel, laboratories, and central readers with direct involvement in the conduct of the study or their designees were blinded to treatment assignments throughout the trial. To maintain the blind, An IWRS system managed treatment assignments and distributed blinded study drug treatment kits. Investigators and patients were not blinded to dose level, but were be blinded to treatment assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo capsules
    Arm description
    		 Placebo capsules administered orally once a day for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo Capsules
    Investigational medicinal product code
    Placebo
    Other name
    Placebo
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administered orally once a day at 2.5, 5, or 10 mg, using 2.5 and 5.0 mg capsules up to 24 weeks.

    Arm title
    		 Bardoxolone methyl capsules
    Arm description
    		 Bardoxolone methyl capsules administered orally once a day for 24 weeks. Starting dosage is 5 mg with dose-escalation to 10 mg at week 4
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bardoxolone methyl capsules
    Investigational medicinal product code
    RTA 402
    Other name
    BARDOXOLONE METHYL, CDDO-Me, CDDO-Methyl Ester, NSC 713200, Chemical Name: Oleana-1,9(11)-dien-28-oic acid, 2-cyano-3,12-dioxo-, methyl ester
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Bardoxolone methyl administered orally once a day at 2.5, 5, or 10 mg, using 2.5 and 5.0 mg capsules up to 24 weeks.

    Number of subjects in period 1
    		Placebo capsules Bardoxolone methyl capsules
    Started
    102
    100
    Completed
    90
    93
    Not completed
    12
    7
         Adverse event, not serious
    5
    6
         Consent withdrawn by subject
    1
    1
         Study terminated by Sponsor
    5
    -
         Protocol-specified withdrawal criterion met
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo capsules
    Reporting group description
    		 Placebo capsules administered orally once a day for 24 weeks.

    Reporting group title
    Bardoxolone methyl capsules
    Reporting group description
    		 Bardoxolone methyl capsules administered orally once a day for 24 weeks. Starting dosage is 5 mg with dose-escalation to 10 mg at week 4

    Reporting group values
    		 Placebo capsules Bardoxolone methyl capsules Total
    Number of subjects
    		 102 100 202
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.5 ( 13.17 ) 55 ( 13.57 ) -
    Gender categorical
    Units: Subjects
        Female
    		 91 88 179
        Male
    		 11 12 23
    Subject analysis sets

    Subject analysis set title
    Intent-to-treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients categorized by their assigned treatment group regardless of treatment exposure. Analyses of both the primary and secondary efficacy outcomes will use the ITT population.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received at least one dose of randomized study drug.

    Subject analysis sets values
    		 Intent-to-treat population Safety Population
    Number of subjects
    202
    202
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55.7 ( 13.36 )
    ( )
    Gender categorical
    Units: Subjects
        Female
    179
        Male
    23

    End points

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    End points reporting groups
    Reporting group title
    Placebo capsules
    Reporting group description
    		 Placebo capsules administered orally once a day for 24 weeks.

    Reporting group title
    Bardoxolone methyl capsules
    Reporting group description
    		 Bardoxolone methyl capsules administered orally once a day for 24 weeks. Starting dosage is 5 mg with dose-escalation to 10 mg at week 4

    Subject analysis set title
    Intent-to-treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomized patients categorized by their assigned treatment group regardless of treatment exposure. Analyses of both the primary and secondary efficacy outcomes will use the ITT population.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received at least one dose of randomized study drug.

    Primary: Change from baseline in six-minute-walk distance (6MWD)

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    End point title
    		 Change from baseline in six-minute-walk distance (6MWD)
    End point description
    The 6MWT is a core clinical measure in the management of PAH and has been used as the primary endpoint in most previous registrational studies for PAH therapy. This unencouraged hallway walking test evaluates the global and integrated responses of all the systems involved during exercise, including the pulmonary and cardiovascular systems, systemic circulation, peripheral circulation, blood, neuromuscular units, and muscle metabolism.
    End point type
    Primary
    End point timeframe
    24 weeks
    End point values
    		 Placebo capsules Bardoxolone methyl capsules
    Number of subjects analysed
    102 [1]
    100 [2]
    Units: Meters
        least squares mean (standard error)
    9.25 ( 4.954 )
    -3.61 ( 4.952 )
    Notes
    [1] - Placebo capsules administered orally once a day for 24 weeks.
    [2] - Bardoxolone methyl capsules administered orally once a day for 24 weeks.
    Statistical analysis title
    		 Change from baseline in 6MWT at Week 24
    Statistical analysis description
    A mixed model was fit with this outcome using Screening 6MWT, number of background PAH medications, and Day 1 hemoglobin as covariates, treatment group and visit as fixed factors, as well as the interaction of treatment group and visit, and Screening 6MWT and visit. Missing values were not imputed.
    Comparison groups
    Placebo capsules v Bardoxolone methyl capsules
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0683 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -12.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.69
         upper limit
    		 0.98
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.012
    Notes
    [3] - Primary efficacy analysis compares changes from baseline (6WMT) between patients on μ BARD to patients on μ placebo at the wk 24 visit according to: Null hypothesis,H0:(μ BARD)–(μ placebo)=0m; Alternative hypothesis H1: (μ BARD) – (μ placebo) ≠ 0 m

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time administration of the first dose at the Day 1 visit until the final visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo capsules administered orally once a day for 24 weeks

    Reporting group title
    Bardoxolone methyl capsules
    Reporting group description
    		 Bardoxolone methyl capsules administered orally once a day for 24 weeks. Starting dosage is 5 mg with dose-escalation to 10 mg at week 4

    Serious adverse events
    		 Placebo Bardoxolone methyl capsules
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 102 (17.65%)
    16 / 100 (16.00%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         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
    2 / 102 (1.96%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriospasm coronary
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Food poisoning
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal hypomotility
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis ulcerative
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 102 (0.98%)
    4 / 100 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephritis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 102 (2.94%)
    2 / 100 (2.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         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
    0 / 102 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo Bardoxolone methyl capsules
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    85 / 102 (83.33%)
    91 / 100 (91.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Headache
         subjects affected / exposed
    21 / 102 (20.59%)
    14 / 100 (14.00%)
         occurrences all number
    28
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 102 (12.75%)
    9 / 100 (9.00%)
         occurrences all number
    13
    9
    Oedema peripheral
         subjects affected / exposed
    12 / 102 (11.76%)
    9 / 100 (9.00%)
         occurrences all number
    14
    9
    Non-cardiac chest pain
         subjects affected / exposed
    6 / 102 (5.88%)
    3 / 100 (3.00%)
         occurrences all number
    7
    3
    Pyrexia
         subjects affected / exposed
    3 / 102 (2.94%)
    3 / 100 (3.00%)
         occurrences all number
    3
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    12 / 102 (11.76%)
    9 / 100 (9.00%)
         occurrences all number
    12
    9
    Cough
         subjects affected / exposed
    10 / 102 (9.80%)
    6 / 100 (6.00%)
         occurrences all number
    12
    6
    Dyspnoea exertional
         subjects affected / exposed
    3 / 102 (2.94%)
    4 / 100 (4.00%)
         occurrences all number
    3
    4
    Epistaxis
         subjects affected / exposed
    1 / 102 (0.98%)
    4 / 100 (4.00%)
         occurrences all number
    1
    4
    Rales
         subjects affected / exposed
    3 / 102 (2.94%)
    3 / 100 (3.00%)
         occurrences all number
    4
    3
    Nasal congestion
         subjects affected / exposed
    3 / 102 (2.94%)
    2 / 100 (2.00%)
         occurrences all number
    3
    2
    Oropharyngeal pain
         subjects affected / exposed
    6 / 102 (5.88%)
    1 / 100 (1.00%)
         occurrences all number
    6
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 102 (5.88%)
    3 / 100 (3.00%)
         occurrences all number
    6
    3
    Depression
         subjects affected / exposed
    3 / 102 (2.94%)
    1 / 100 (1.00%)
         occurrences all number
    3
    1
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 102 (1.96%)
    8 / 100 (8.00%)
         occurrences all number
    2
    8
    Weight decreased
         subjects affected / exposed
    2 / 102 (1.96%)
    7 / 100 (7.00%)
         occurrences all number
    2
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 102 (0.98%)
    6 / 100 (6.00%)
         occurrences all number
    1
    6
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 102 (0.00%)
    6 / 100 (6.00%)
         occurrences all number
    0
    6
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    1 / 102 (0.98%)
    5 / 100 (5.00%)
         occurrences all number
    1
    5
    Brain natriuretic peptide increased
         subjects affected / exposed
    2 / 102 (1.96%)
    3 / 100 (3.00%)
         occurrences all number
    2
    3
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 102 (0.98%)
    3 / 100 (3.00%)
         occurrences all number
    1
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 102 (1.96%)
    3 / 100 (3.00%)
         occurrences all number
    2
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 102 (11.76%)
    8 / 100 (8.00%)
         occurrences all number
    12
    10
    Presyncope
         subjects affected / exposed
    1 / 102 (0.98%)
    3 / 100 (3.00%)
         occurrences all number
    1
    4
    Dizziness postural
         subjects affected / exposed
    3 / 102 (2.94%)
    0 / 100 (0.00%)
         occurrences all number
    3
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 102 (1.96%)
    6 / 100 (6.00%)
         occurrences all number
    2
    6
    Eye disorders
    Dry eye
         subjects affected / exposed
    3 / 102 (2.94%)
    1 / 100 (1.00%)
         occurrences all number
    3
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    21 / 102 (20.59%)
    13 / 100 (13.00%)
         occurrences all number
    25
    15
    Nausea
         subjects affected / exposed
    11 / 102 (10.78%)
    12 / 100 (12.00%)
         occurrences all number
    13
    12
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 102 (3.92%)
    9 / 100 (9.00%)
         occurrences all number
    4
    10
    Vomiting
         subjects affected / exposed
    7 / 102 (6.86%)
    8 / 100 (8.00%)
         occurrences all number
    8
    8
    Constipation
         subjects affected / exposed
    6 / 102 (5.88%)
    5 / 100 (5.00%)
         occurrences all number
    6
    5
    Abdominal pain
         subjects affected / exposed
    3 / 102 (2.94%)
    3 / 100 (3.00%)
         occurrences all number
    3
    3
    Abdominal distension
         subjects affected / exposed
    1 / 102 (0.98%)
    3 / 100 (3.00%)
         occurrences all number
    1
    3
    Abdominal pain upper
         subjects affected / exposed
    1 / 102 (0.98%)
    3 / 100 (3.00%)
         occurrences all number
    1
    3
    Dyspepsia
         subjects affected / exposed
    1 / 102 (0.98%)
    3 / 100 (3.00%)
         occurrences all number
    1
    3
    Abdominal tenderness
         subjects affected / exposed
    0 / 102 (0.00%)
    3 / 100 (3.00%)
         occurrences all number
    0
    3
    Gastritis
         subjects affected / exposed
    0 / 102 (0.00%)
    3 / 100 (3.00%)
         occurrences all number
    0
    3
    Dry mouth
         subjects affected / exposed
    3 / 102 (2.94%)
    0 / 100 (0.00%)
         occurrences all number
    3
    0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    2 / 102 (1.96%)
    3 / 100 (3.00%)
         occurrences all number
    2
    3
    Rash
         subjects affected / exposed
    3 / 102 (2.94%)
    1 / 100 (1.00%)
         occurrences all number
    3
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    6 / 102 (5.88%)
    17 / 100 (17.00%)
         occurrences all number
    7
    19
    Back pain
         subjects affected / exposed
    7 / 102 (6.86%)
    9 / 100 (9.00%)
         occurrences all number
    7
    10
    Pain in extremity
         subjects affected / exposed
    2 / 102 (1.96%)
    8 / 100 (8.00%)
         occurrences all number
    2
    9
    Myalgia
         subjects affected / exposed
    5 / 102 (4.90%)
    6 / 100 (6.00%)
         occurrences all number
    5
    6
    Arthralgia
         subjects affected / exposed
    12 / 102 (11.76%)
    3 / 100 (3.00%)
         occurrences all number
    13
    5
    Rheumatoid arthritis
         subjects affected / exposed
    3 / 102 (2.94%)
    1 / 100 (1.00%)
         occurrences all number
    5
    1
    Joint swelling
         subjects affected / exposed
    3 / 102 (2.94%)
    0 / 100 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 102 (10.78%)
    19 / 100 (19.00%)
         occurrences all number
    15
    27
    Nasopharyngitis
         subjects affected / exposed
    5 / 102 (4.90%)
    11 / 100 (11.00%)
         occurrences all number
    5
    13
    Urinary tract infection
         subjects affected / exposed
    6 / 102 (5.88%)
    8 / 100 (8.00%)
         occurrences all number
    11
    11
    Bronchitis
         subjects affected / exposed
    5 / 102 (4.90%)
    7 / 100 (7.00%)
         occurrences all number
    5
    7
    Sinusitis
         subjects affected / exposed
    4 / 102 (3.92%)
    4 / 100 (4.00%)
         occurrences all number
    4
    4
    Gastroenteritis
         subjects affected / exposed
    2 / 102 (1.96%)
    4 / 100 (4.00%)
         occurrences all number
    2
    4
    Pneumonia
         subjects affected / exposed
    3 / 102 (2.94%)
    3 / 100 (3.00%)
         occurrences all number
    3
    3
    Influenza
         subjects affected / exposed
    7 / 102 (6.86%)
    2 / 100 (2.00%)
         occurrences all number
    7
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 102 (0.98%)
    5 / 100 (5.00%)
         occurrences all number
    1
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 102 (2.94%)
    9 / 100 (9.00%)
         occurrences all number
    3
    9
    Gout
         subjects affected / exposed
    0 / 102 (0.00%)
    5 / 100 (5.00%)
         occurrences all number
    0
    7
    Fluid retention
         subjects affected / exposed
    1 / 102 (0.98%)
    4 / 100 (4.00%)
         occurrences all number
    1
    6
    Hypokalaemia
         subjects affected / exposed
    1 / 102 (0.98%)
    4 / 100 (4.00%)
         occurrences all number
    1
    4
    Hypomagnesaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    3 / 100 (3.00%)
         occurrences all number
    0
    3
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 102 (1.96%)
    4 / 100 (4.00%)
         occurrences all number
    2
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Oct 2016
    Version 2.0: Updated estimated study start and end dates, Clarified dose escalation and de-escalation rules, Updated Patient Inclusion Critera (Criteron 7, 9, 10, 16, 21, and 30); Clarified Patient discontinuation criteria and management of fluid status; Added guidelines on Anemia treatment; Removed unnecessary excluded medication; Added guidelines for additional medications that may affect PAH walking distance and clarified the requirements for use of background medications for the treatment of CTD; Removed use of home health vendor; Clarification to consider potential comorbidities; Procedural clarification regarding the Assessment of Digital Ulcers; Clarification for patients not participating in PK sub-study; Clarification AE documentation to continue 28 days after last dose and made procedural reporting clarifications; Added Borg Dyspnea Scale appendix

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    07 May 2020
    Exposure of these high-risk patients to clinic or in-person visits during the Covid-19 pandemic presented an unacceptable risk to their health, as such the trial was terminated.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the risk of severe adverse outcomes associated with COVID-19 among patients with respiratory and autoimmune diseases, and on recommendation from the study’s DSMB, the Sponsor terminated the trial due to unacceptable health risks to patients.
    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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