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    Clinical Trial Results:
    OPuS-2 A multicentre, randomised, double blind, placebo controlled, parallel group study to evaluate the efficacy and safety of two dose levels of BCX4161 for 12 weeks as an oral prophylaxis treatment for attacks of hereditary angioedema.

    Summary
    EudraCT number
    		 2014-002655-26
    Trial protocol
    		 GB   DE   HU   BE   FR   IT  
    Global end of trial date
    08 Jan 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Mar 2021
    First version publication date
    24 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BCX4161-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02303626
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    BioCryst Pharmaceuticals, Inc
    Sponsor organisation address
    4505 Emperor Blvd, Suite 200, Durham, United States, 27703
    Public contact
    Study Director, BioCryst Pharmaceuticals Inc, 001 919-859-1302, clinicaltrials@biocryst.com
    Scientific contact
    Study Director, BioCryst Pharmaceuticals Inc, 001 919-859-1302, clinicaltrials@biocryst.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
    27 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy of prophylactic Avoralstat (BCX4161) 300 mg and 500 mg administered three times daily for 12 weeks compared to placebo
    Protection of trial subjects
    This trial was conducted in compliance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines for conducting, recording, and reporting trials, and in accordance with the Declaration of Helsinki. The informed consent form (ICF), protocol and amendments for this trial were submitted to and approved by an appropriate Independent Ethics Committee (IEC). Routine monitoring was performed to verify that rights and well-being of subjects were protected. Emergency equipment and medications were available within the clinical unit as per current standard procedures. Any medication considered necessary for the subject’s safety and well-being was given at the discretion of the Investigator. A signed informed consent form (ICF) was obtained from each subject prior to performing any study-related procedures. The informed consent process took place under conditions where the subject had adequate time to consider the risks and benefits associated with his/her participation in the study. The Investigator explained to potential subjects the aims, methods, reasonably anticipated benefits, and potential hazards of the trial and any discomfort it may entail.
    Background therapy
    		 Subjects used their prescribed standard of care medication to treat any breakthrough HAE attacks on study
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 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: 14
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    United States: 54
    Worldwide total number of subjects
    110
    EEA total number of subjects
    50
    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)
    103
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 110 subjects were randomized/enrolled into 1 of 3 parts.

    Pre-assignment
    Screening details
    		 A total of 137 subjects were screened for the study and 110 subjects were randomized and dosed. 27 subjects were screening failures due to one of the following reasons: did not meet inclusion criteria (15), Investigator discretion (1), met exclusion criteria (5), subject consent withdrawn (4), and/or lost to follow-up (2).

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    This was a double-blind study; as such, the treatment assignment in each part was blinded to the PI, study subjects, staff involved in the clinical evaluation of the subjects and the analysis of data, and the Biometrics team. The PI or designee(s) confirmed subject eligibility.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Avoralstat 500mg
    Arm description
    		 5x 100 mg Avoralstat capsules TID
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avoralstat
    Investigational medicinal product code
    Other name
    BCX4161
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    5 × 100-mg avoralstat capsules for oral administration 3 times per day (total daily dose of 1500 mg) for 12 weeks

    Arm title
    		 Avoralstat 300mg
    Arm description
    		 3x 100 mg Avoralstat capsules + 2 matched placebo capsules TID
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avoralstat
    Investigational medicinal product code
    Other name
    BCX4161
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    3 × 100-mg avoralstat capsules for oral administration 3 times per day (total daily dose of 900 mg) for 12 weeks. At each dose, subjects received 2 placebo capsules together with avoralstat capsules to maintain dose blind.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    The matching placebo contained the excipients polyethylene glycol 600, polyethylene glycol 400, alpha tocopherol and Vitamin E-TPGS. Subjects received 2 placebo capsules QID for 12 weeks together with avoralstat capsules to maintain dose blind.

    Arm title
    		 Placebo
    Arm description
    		 5x Placebo capsules TID
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    The matching placebo contained the excipients polyethylene glycol 600, polyethylene glycol 400, alpha tocopherol and Vitamin E-TPGS. Subjects received 5 capsules, 3 times a day for 12 weeks.

    Number of subjects in period 1
    		Avoralstat 500mg Avoralstat 300mg Placebo
    Started
    38
    36
    36
    Completed
    35
    35
    33
    Not completed
    3
    1
    3
         Consent withdrawn by subject
    -
    -
    1
         Adverse event, non-fatal
    2
    -
    -
         Pregnancy
    -
    -
    1
         Protocol deviation
    1
    -
    -
         Lack of efficacy
    -
    1
    1

    Baseline characteristics

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

    Reporting group values
    		 Treatment period Total
    Number of subjects
    		 110 110
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 103 103
        From 65-84 years
    		 7 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.2 ( 13.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 85 85
        Male
    		 25 25
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 1
        Asian
    		 2 2
        Black or African American
    		 0 0
        White
    		 102 102
        Other
    		 3 3
        Native Hawaiian or Other Pacific Islander
    		 2 2
    HAE attack rate
    Units: Subjects
        ≥ 1 attack/week
    		 65 65
        < 1 attack/week
    		 45 45

    End points

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    End points reporting groups
    Reporting group title
    Avoralstat 500mg
    Reporting group description
    		 5x 100 mg Avoralstat capsules TID

    Reporting group title
    Avoralstat 300mg
    Reporting group description
    		 3x 100 mg Avoralstat capsules + 2 matched placebo capsules TID

    Reporting group title
    Placebo
    Reporting group description
    		 5x Placebo capsules TID

    Primary: Weekly Rate of Confirmed HAE Attacks

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    End point title
    		 Weekly Rate of Confirmed HAE Attacks
    End point description
    Subjects completed an electronic study diary (e-diary) to record details of all HAE attacks that occurred. Each e-diary recorded HAE attack was reviewed in real-time by the investigator and subjects contacted as needed to discuss any queries or for additional attack details. This information, in conjunction with the e-Diary record, was used by the Investigator to verify or reject the record as an HAE attack. Subject-reported attacks were further adjudicated by the independent Clinical Endpoint Adjudication Panel (CEAP); the CEAP members individually rated each attack as confirmed (C), confirmed with modification (CM) or rejected (R). Attacks confirmed by the adjudication committee were then included in efficacy analyses.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Avoralstat 500mg Avoralstat 300mg Placebo
    Number of subjects analysed
    38
    36
    36
    Units: HAE attacks/week
        least squares mean (standard error)
    0.589 ( 0.086 )
    0.675 ( 0.089 )
    0.593 ( 0.088 )
    Statistical analysis title
    		 HAE attack rate - 500 mg Avoralstat
    Comparison groups
    Avoralstat 500mg v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.975 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Difference Least Mean Square
    Point estimate
    -0.004
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.248
         upper limit
    		 0.24
    Notes
    [1] - ANCOVA Model includes terms of treatment and the randomization strata
    Statistical analysis title
    		 HAE attack rate - 300 mg Avoralstat
    Comparison groups
    Placebo v Avoralstat 300mg
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.512 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Difference Least Mean Square
    Point estimate
    0.082
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.165
         upper limit
    		 0.329
    Notes
    [2] - ANCOVA Model includes terms of treatment and the randomization strata

    Secondary: Number of Attack-Free Days

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    End point title
    		 Number of Attack-Free Days
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Avoralstat 500mg Avoralstat 300mg Placebo
    Number of subjects analysed
    38
    36
    36
    Units: Attack-Free Days
        least squares mean (standard error)
    67.174 ( 2.646 )
    64.100 ( 2.720 )
    64.217 ( 2.703 )
    Statistical analysis title
    		 Attack-Free Days - 500 mg Avoralstat
    Comparison groups
    Avoralstat 500mg v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.434 [3]
    Method
    		 ANCOVA
    Parameter type
    		 Difference Least Mean Square
    Point estimate
    2.957
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.153
         upper limit
    		 10.427
    Notes
    [3] - ANCOVA Model includes terms of treatment and the randomization strata
    Statistical analysis title
    		 Attack-Free Days - 300 mg Avoralstat
    Comparison groups
    Avoralstat 300mg v Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.976 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Difference Least Mean Square
    Point estimate
    -0.117
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.688
         upper limit
    		 7.455
    Notes
    [4] - ANCOVA Model includes terms of treatment and the randomization strata

    Secondary: HAE Disease Activity

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    End point title
    		 HAE Disease Activity
    End point description
    Disease activity was assessed using an Angioedema Activity Score (AAS) calculated from data entered in the eDiaries by the subject over 84 days. The AAS score was defined as the sum of the individual scores for 4 AAS domains (daily activities, appearance, physical discomfort, and overall severity) for all subject-reported attacks reported during the treatment period. Individual domain scores were based on answers to questions each of which had 4 possible responses scored 0-3 (0 - no impact; 1-3 - increasing levels of impact). The total AAS score per attack could range from 0 to 12; lower scores & higher scores represent lower & higher disease activities, respectively. However, the overall total AAS score reported for this study included the total scores for all subject-reported attacks, therefore the upper limit of the range was subject-specific. The statistical analysis of the total modified AAS scores for the treatment period is presented below.
    End point type
    Secondary
    End point timeframe
    84 days
    End point values
    		 Avoralstat 500mg Avoralstat 300mg Placebo
    Number of subjects analysed
    38
    36
    36
    Units: AAS Score
        least squares mean (standard error)
    83.938 ( 14.131 )
    109.081 ( 14.524 )
    94.841 ( 14.434 )
    Statistical analysis title
    		 Disease Activity - 500 mg Avoralstat
    Comparison groups
    Avoralstat 500mg v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.589 [5]
    Method
    		 ANCOVA
    Parameter type
    		 Difference Least Mean Square
    Point estimate
    -10.903
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -50.789
         upper limit
    		 28.983
    Notes
    [5] - ANCOVA Model includes terms of treatment and the randomization strata
    Statistical analysis title
    		 Disease Activity - 300 mg Avoralstat
    Comparison groups
    Avoralstat 300mg v Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.487 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Difference Least Mean Square
    Point estimate
    14.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.189
         upper limit
    		 54.669
    Notes
    [6] - ANCOVA Model includes terms of treatment and the randomization strata

    Secondary: Angioedema Quality of Life (AE-QoL)

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    End point title
    		 Angioedema Quality of Life (AE-QoL)
    End point description
    Quality of Life (QoL) specific to hereditary angioedema (HAE) was assessed via AE-QoL, which consists of 17 questions that spanned 4 domains (functioning, fatigue/mood, fear/shame, and nutrition). Each AE-QoL question had 5 answer options (scored 1-5), with lower and higher scores indicting less and more adverse impact, respectively. Per-subject scores for each domain were computed using the appropriate scoring algorithm applied to the question response scores for each domain. Per-subject total scores (including all 4 domains) were similarly computed using the question response scores for all 17 questions. The outputs from the scoring algorithm were normalized on a scale ranging from 0 (less adverse impact) to 100 (most adverse impact). The statistical analysis of the AE-QoL total score change from baseline to Week 12 is presented below.
    End point type
    Secondary
    End point timeframe
    Angioedema Quality of Life questionnaire (AE QoL) was completed during clinic visits, prior to dosing on Day 1, and on Days 29, 57 & 85 (Weeks 4, 8 & 12) during the treatment period.
    End point values
    		 Avoralstat 500mg Avoralstat 300mg Placebo
    Number of subjects analysed
    38
    36
    36
    Units: AE-QoL Score
        least squares mean (standard error)
    -17.45 ( 2.66 )
    -9.89 ( 3.11 )
    -12.14 ( 2.64 )
    Statistical analysis title
    		 AE-QoL - 500 mg Avoralstat
    Comparison groups
    Avoralstat 500mg v Placebo
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.162 [7]
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Difference Least Mean Square
    Point estimate
    -5.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.8
         upper limit
    		 2.2
    Notes
    [7] - Mixed model for repeated measures includes terms for baseline value, visit, treatment and visit by treatment interaction.
    Statistical analysis title
    		 AE-QoL - 300 mg Avoralstat
    Comparison groups
    Avoralstat 300mg v Placebo
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.585 [8]
    Method
    		 Mixed Model for Repeated Measures
    Parameter type
    		 Difference Least Mean Square
    Point estimate
    2.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 10.4
    Notes
    [8] - Mixed model for repeated measures includes terms for baseline value, visit, treatment and visit by treatment interaction.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) reported from informed consent signature until the follow-up visit (week 14) or until the AE is resolved or the subject is in a clinically stable condition with regards to the AE.
    Adverse event reporting additional description
    Symptoms of HAE were not considered an AE unless they qualify as an SAE.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Avoralstat 500mg
    Reporting group description
    		 5x 100 mg Avoralstat capsules TID

    Reporting group title
    Avoralstat 300mg
    Reporting group description
    		 3x 100 mg Avoralstat capsules + 2 matched placebo capsules TID

    Reporting group title
    Placebo
    Reporting group description
    		 5x Placebo capsules TID

    Serious adverse events
    		 Avoralstat 500mg Avoralstat 300mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 38 (7.89%)
    2 / 36 (5.56%)
    3 / 36 (8.33%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Congenital, familial and genetic disorders
    HAE
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    abortion, induced
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    chest discomfort
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 38 (0.00%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Avoralstat 500mg Avoralstat 300mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 38 (92.11%)
    31 / 36 (86.11%)
    32 / 36 (88.89%)
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 36 (8.33%)
    0 / 36 (0.00%)
         occurrences all number
    0
    3
    0
    Blood urine present
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 36 (8.33%)
    0 / 36 (0.00%)
         occurrences all number
    0
    3
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 36 (8.33%)
    0 / 36 (0.00%)
         occurrences all number
    0
    3
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    Headache
         subjects affected / exposed
    7 / 38 (18.42%)
    4 / 36 (11.11%)
    6 / 36 (16.67%)
         occurrences all number
    7
    4
    6
    Somnolence
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    2
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 36 (8.33%)
    2 / 36 (5.56%)
         occurrences all number
    2
    3
    2
    Abdominal pain
         subjects affected / exposed
    4 / 38 (10.53%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    4
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 38 (0.00%)
    3 / 36 (8.33%)
    0 / 36 (0.00%)
         occurrences all number
    0
    3
    0
    Dyspepsia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    2
    0
    1
    Faeces soft
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 36 (2.78%)
    3 / 36 (8.33%)
         occurrences all number
    1
    1
    3
    Flatulence
         subjects affected / exposed
    10 / 38 (26.32%)
    5 / 36 (13.89%)
    9 / 36 (25.00%)
         occurrences all number
    10
    5
    9
    Nausea
         subjects affected / exposed
    3 / 38 (7.89%)
    4 / 36 (11.11%)
    3 / 36 (8.33%)
         occurrences all number
    3
    4
    3
    Diarrhoea
         subjects affected / exposed
    16 / 38 (42.11%)
    8 / 36 (22.22%)
    12 / 36 (33.33%)
         occurrences all number
    16
    8
    12
    Frequent bowel movements
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    Constipation
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    1
    0
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    2
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    2
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    0
    2
    1
    Back pain
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    1
    1
    2
    Myalgia
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    1
    2
    0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    2
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    1
    1
    2
    Influenza
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    8 / 38 (21.05%)
    5 / 36 (13.89%)
    7 / 36 (19.44%)
         occurrences all number
    8
    5
    7
    Oral herpes
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    2
    Sinusitis
         subjects affected / exposed
    1 / 38 (2.63%)
    1 / 36 (2.78%)
    3 / 36 (8.33%)
         occurrences all number
    1
    1
    3
    Tonsillitis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    1
    Viral infection
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    2
    1
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 38 (5.26%)
    2 / 36 (5.56%)
    1 / 36 (2.78%)
         occurrences all number
    2
    2
    1
    Tooth infection
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    0
    1
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Dec 2014
    UK-Specific Amendment: - Inclusion criterion 4a was modified to indicate that 2 highly effective contraceptive methods must be used by females of childbearing potential. Two or more of the following methods were identified as acceptable and had to include at least one barrier method: surgical sterilization (i.e. bilateral tubal ligation); placement of an intrauterine device or intrauterine system; hormonal contraception (implantable, patch, oral, vaginal ring); or barrier methods (either their partner’s use of a condom or the subject’s use of an occlusive cap [diaphragm, or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository). Estrogen- and progestin-containing hormonal contraception was only permitted if it had been initiated within 60 days prior to screening or expected to be initiated at any time through the end of the study (follow-up); IUDs with progestin were permitted to be placed at any time prior to or during screening. - Inclusion criteria 4c (females) and 5a (males) was modified to include a clear definition of abstinence as true abstinence when in line with the preferred and usual lifestyle of the subject. - Inclusion criterion 5a was modified to indicate that male participants were required to utilize a highly effective contraceptive method with female partners of childbearing potential (defined as postmenopausal ≤ 2 years or a non-menopausal female who had not had a hysterectomy, bilateral oophorectomy, or documented ovarian failure). The term “highly effective contraceptive method” was defined as having had a vasectomy, or utilizing 2 forms of contraception, 1 of which must have been a condom, during intercourse, for the study duration and for 90 days after the last dose of the study drug.
    15 Apr 2015
    Canada-specific Amendment: Canada was added to the list of countries in which study centers were located.

    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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    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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